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Orthopoxvirus

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List of laboratory biosecurity incidents

This list of laboratory biosecurity incidents includes accidental laboratory-acquired infections and laboratory releases of lethal pathogens, containment failures in or during transport of lethal pathogens, and incidents of exposure of lethal pathogens to laboratory personnel, improper disposal of contaminated waste, and/or the escape of laboratory animals. The list is grouped by the year in which the accident or incident occurred and does not include every reported laboratory-acquired infection. virus

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History of smallpox

The history of smallpox extends into pre-history. Genetic evidence suggests that the smallpox virus emerged 3,000 to 4,000 years ago. Prior to that, similar ancestral viruses circulated, but possibly only in other mammals, and possibly with different symptoms. Only a few written reports dating from about 500 AD to 1000 AD are considered reliable historical descriptions of smallpox, so understanding of the disease prior to that has relied on genetics and archaeology. However, during the 2nd millennium AD, especially starting in the 16th century, reliable written reports become more common. The earliest physical evidence of smallpox is found in the Egyptian mummies of people who died some 3,000 years ago. Smallpox has had a major impact on world history, not least because indigenous populations of regions where smallpox was non-native, such as the Americas and Australia, were rapidly and greatly reduced by smallpox (along with other introduced diseases) during periods of initial foreign contact, which helped pave the way for conquest and colonization. During the 18th century the disease killed an estimated 400,000 Europeans each year, including five reigning monarchs , and was responsible for a third of all blindness. Between 20 and 60% of all those infected—and over 80% of infected children—died from the disease. During the 20th century, it is estimated that smallpox was responsible for 300–500 million deaths. In the early 1950s an estimated 50 million cases of smallpox occurred in the world each year. As recently as 1967, the World Health Organization estimated that 15 million people contracted the disease and that two million died in that year. After successful vaccination campaigns throughout the 19th and 20th centuries, the WHO certified the global eradication of smallpox in May 1980. Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest , which was declared eradicated in 2011. It has been suggested that smallpox was a major component of the Plague of Athens that occurred in 430 BCE, during the Peloponnesian Wars , and was described by Thucydides . Galen 's description of the Antonine Plague , which swept through the Roman Empire in 165–180 CE, indicates that it was probably caused by smallpox. Returning soldiers picked up the disease in Seleucia (in modern Iraq), and brought it home with them to Syria and Italy. It raged for fifteen years and greatly weakened the Roman empire, killing up to one-third of the population in some areas. Total deaths have been estimated at 5 million. A second major outbreak of disease in the Roman Empire, known as the Plague of Cyprian (251–266 CE), was also either smallpox or measles . The Roman empire stopped growing as a consequence on these two plagues, according to historians like Theodore Mommsen . Although some historians believe that many historical epidemics and pandemics were early outbreaks of smallpox, contemporary records are not detailed enough to make a definite diagnosis. Around 400 CE, an Indian medical book [ which? ] recorded a disease marked by pustules and boils, saying "the pustules are red, yellow, and white and they are accompanied by burning pain … the skin seems studded with grains of rice." The Indian epidemic was thought to be punishment from a god, and the survivors created a goddess, Sitala , as the anthropomorphic personification of the disease. Smallpox was thus regarded as possession by Sitala. In Hinduism the goddess Sitala both causes and cures high fever, rashes, hot flashes and pustules. All of these are symptoms of smallpox. [ citation needed ] Most of the details about the epidemics are lost, probably due to the scarcity of surviving written records from the Early Middle Ages . The first incontrovertible description of smallpox in Western Europe occurred in 581 CE, when Bishop Gregory of Tours provided an eyewitness account describing the characteristic symptoms of smallpox. Waves of epidemics wiped out large rural populations. In 710 CE, smallpox was re-introduced into Europe via Iberia by the Umayyad conquest of Hispania . The Japanese smallpox epidemic of 735–737 is believed to have killed as much as one-third of Japan's population. The clearest description of smallpox from pre-modern times was given in the 9th century by the Persian physician , Muhammad ibn Zakariya ar-Razi, known in the West as "Rhazes" , who was the first to differentiate smallpox from measles and chickenpox in his Kitab fi al-jadari wa-al-hasbah ( The Book of Smallpox and Measles ). Smallpox was a leading cause of death in the 18th century. Every seventh child born in Russia died from smallpox. It killed an estimated 400,000 Europeans each year in the 18th century, including five reigning European monarchs. Most people became infected during their lifetimes, and about 30% of people infected with smallpox died from the disease, presenting a severe selection pressure on the resistant survivors. In northern Japan, Ainu population decreased drastically in the 19th century, due in large part to infectious diseases like smallpox brought by Japanese settlers pouring into Hokkaido . The Franco-Prussian War triggered a smallpox pandemic of 1870–1875 that claimed 500,000 lives; while vaccination was mandatory in the Prussian army, many French soldiers were not vaccinated. Smallpox outbreaks among French prisoners of war spread to the German civilian population and other parts of Europe. Ultimately, this public health disaster inspired stricter legislation in Germany and England, though not in France. In 1849 nearly 13% of all Calcutta deaths were due to smallpox. Between 1868 and 1907, there were approximately 4.7 million deaths from smallpox in India . Between 1926 and 1930, there were 979,738 cases of smallpox with a mortality of 42.3%. One of the oldest records of what may have been an encounter with smallpox in Africa is associated with the elephant war circa AD 568 CE, when after fighting a siege in Mecca, Ethiopian troops contracted the disease which they carried with them back to Africa. [ citation needed ] Arab ports in Coastal towns in Africa likely contributed to the importation of smallpox into Africa, as early as the 13th century, though no records exist until the 16th century. Upon invasion of these towns by tribes in the interior of Africa, a severe epidemic affected all African inhabitants while sparing the Portuguese. Densely populated areas of Africa connected to the Mediterranean, Nubia and Ethiopia by caravan route likely were affected by smallpox since the 11th century, though written records do not appear until the introduction of the slave trade in the 16th century. The enslavement of Africans continued to spread smallpox to the entire continent, with raiders pushing farther inland along caravan routes in search of people to enslave. The effects of smallpox could be seen along caravan routes, and those who were not affected along the routes were still likely to become infected either waiting to be put onboard or on board ships. Smallpox in Angola was likely introduced shortly after Portuguese settlement of the area in 1484. The 1864 epidemic killed 25,000 inhabitants, one third of the total population in that same area. In 1713, an outbreak occurred in South Africa after a ship from India docked at Cape Town, bringing infected laundry ashore. Many of the settler European population suffered, and whole clans of the Khoisan people were wiped out. A second outbreak occurred in 1755, again affecting both the white population and the Khoisan. The disease spread further, completely eradicating several Khosian clans, all the way to the Kalahari desert. A third outbreak in 1767 similarly affected the Khoisan and Bantu peoples. But the European colonial settlers were not affected nearly to the extent that they were in the first two outbreaks, it has been speculated this is because of variolation . Continued enslavement operations brought smallpox to Cape Town again in 1840, taking the lives of 2500 people, and then to Uganda in the 1840s. It is estimated that up to eighty percent of the Griqua tribe was exterminated by smallpox in 1831, and whole tribes were being wiped out in Kenya up until 1899. Along the Zaire river basin were areas where no one survived the epidemics, leaving the land devoid of human life. In Ethiopia and the Sudan, six epidemics are recorded for the 19th century: 1811–1813, 1838–1839, 1865–1866, 1878–1879, 1885–1887, and 1889–1890. 3164 dead in Montréal (municipality), 5864 for the whole province of Québec. (fr) Smallpox in Montréal in 1885 After first contacts with Europeans and Africans , some believe that the death of 90–95% of the native population of the New World was caused by Old World diseases. It is suspected that smallpox was the chief culprit and responsible for killing nearly all of the native inhabitants of the Americas. For more than 200 years, this disease affected all new world populations, mostly without intentional European transmission, from contact in the early 16th century until possibly as late as the French and Indian Wars (1754–1767). In 1519 Hernán Cortés landed on the shores of what is now Mexico and what was then the Aztec Empire . In 1520 another group of Spanish arrived in Mexico from Hispaniola , bringing with them the smallpox which had already been ravaging that island for two years. When Cortés heard about the other group, he went and defeated them. In this contact, one of Cortés's men contracted the disease. When Cortés returned to Tenochtitlan , he brought the disease with him. [ citation needed ] Soon, the Aztecs rose up in rebellion against Cortés and his men. Outnumbered, the Spanish were forced to flee. In the fighting, the Spanish soldier carrying smallpox died. Cortés would not return to the capital until August 1521. In the meantime smallpox devastated the Aztec population. It killed most of the Aztec army and 25% of the overall population. The Spanish Franciscan Motolinia left this description: "As the Indians did not know the remedy of the disease…they died in heaps, like bedbugs. In many places it happened that everyone in a house died and, as it was impossible to bury the great number of dead, they pulled down the houses over them so that their homes become their tombs." On Cortés's return, he found the Aztec army's chain of command in ruins. The soldiers who still lived were weak from the disease. Cortés then easily defeated the Aztecs and entered Tenochtitlán. The Spaniards said that they could not walk through the streets without stepping on the bodies of smallpox victims. The effects of smallpox on Tahuantinsuyu (or the Inca empire) were even more devastating. Beginning in Colombia , smallpox spread rapidly before the Spanish invaders first arrived in the empire. The spread was probably aided by the efficient Inca road system . Within months, the disease had killed the Incan Emperor Huayna Capac , his successor, and most of the other leaders. Two of his surviving sons warred for power and, after a bloody and costly war, Atahualpa become the new emperor. As Atahualpa was returning to the capital Cuzco , Francisco Pizarro arrived and through a series of deceits captured the young leader and his best general. Within a few years smallpox claimed between 60% and 90% of the Inca population, with other waves of European disease weakening them further. A handful of historians argue that a disease called Bartonellosis might have been responsible for some outbreaks of illness, but this opinion is in the scholarly minority. The effects of Bartonellosis were depicted in the ceramics of the Moche people of ancient Peru . Even after the two largest empires of the Americas were defeated by the virus and disease, smallpox continued its march of death. In 1561, smallpox reached Chile by sea, when a ship carrying the new governor Francisco de Villagra landed at La Serena . Chile had previously been isolated by the Atacama Desert and Andes Mountains from Peru, but at the end of 1561 and in early 1562, it ravaged the Chilean native population. Chronicles and records of the time left no accurate data on mortality but more recent estimates are that the natives lost 20 to 25 percent of their population. The Spanish historian Marmolejo said that gold mines had to shut down when all their Indian labor died. Mapuche fighting Spain in Araucanía regarded the epidemic as a magical attempt by Francisco de Villagra to exterminate them because he could not defeat them in the Arauco War . In 1633 in Plymouth, Massachusetts , the Native Americans were struck by the virus. As it had done elsewhere, the virus wiped out entire population groups of Native Americans. It reached Mohawks in 1634, the Lake Ontario area in 1636, and the lands of the Iroquois by 1679. A particularly virulent sequence of smallpox outbreaks took place in Boston, Massachusetts . From 1636 to 1698, Boston endured six epidemics. In 1721, the most severe epidemic occurred. The entire population fled the city, bringing the virus to the rest of the Thirteen Colonies . During the siege of Fort Pitt , as recorded in his journal by sundries trader and militia Captain, William Trent , on June 24, 1763, dignitaries from the Delaware tribe met with Fort Pitt officials, warned them of "great numbers of Indians" coming to attack the fort, and pleaded with them to leave the fort while there was still time. The commander of the fort refused to abandon the fort. Instead, the British gave as gifts two blankets, one silk handkerchief and one linen from the smallpox hospital, to two Delaware Indian delegates. The dignitaries were met again later and they seemingly hadn't contracted smallpox. A relatively small outbreak of smallpox had begun spreading earlier that spring, with a hundred dying from it among Native American tribes in the Ohio Valley and Great Lakes area through 1763 and 1764. The effectiveness of the biological warfare itself remains unknown, and the method used is inefficient compared to respiratory transmission and these attempts to spread the disease are difficult to differentiate from epidemics occurring from previous contacts with colonists, as smallpox outbreaks happened every dozen or so years. In the late 1770s , during the American Revolutionary War , smallpox returned once more and killed thousands. Peter Kalm in his Travels in North America , described how in that period, the dying Indian villages became overrun with wolves feasting on the corpses and weakened survivors. During the 1770s, smallpox killed at least 30% of the Northwestern Native Americans, killing tens of thousands. The smallpox epidemic of 1780–1782 brought devastation and drastic depopulation among the Plains Indians . This epidemic is a classic instance of European immunity and non-European vulnerability. It is probable that the Indians contracted the disease from the 'Snake Indians' on the Mississippi . From there it spread eastward and northward to the Saskatchewan River . According to David Thompson's account, the first to hear of the disease were fur traders from the Hudson's House on October 15, 1781. A week later, reports were made to William Walker and William Tomison , who were in charge of the Hudson and Cumberland Hudson's Bay Company posts. By February, the disease spread as far as the Basquia Tribe. Smallpox attacked whole tribes and left few survivors. E. E. Rich described the epidemic by saying that "Families lay unburied in their tents while the few survivors fled, to spread the disease." After reading Tomison's journals, Houston and Houston calculated that, of the Indians who traded at the Hudson and Cumberland houses, 95% died of smallpox. Paul Hackett adds to the mortality numbers suggesting that perhaps up to one half to three quarters of the Ojibway situated west of the Grand Portage died from the disease. The Cree also suffered a casualty rate of approximately 75% with similar effects found in the Lowland Cree. By 1785 the Sioux Indians of the great plains had also been affected. Not only did smallpox devastate the Indian population, it did so in an unforgiving way. William Walker described the epidemic stating that "the Indians [are] all Dying by this Distemper … lying Dead about the Barren Ground like a rotten sheep, their Tents left standing & the Wild beast Devouring them." In 1799, the physician Valentine Seaman administered the first smallpox vaccine in the United States. He gave his children a smallpox vaccination using a serum acquired from Edward Jenner , the British physician who invented the vaccine from fluid taken from cowpox lesions. Though vaccines were misunderstood and mistrusted at the time, Seaman advocated their use and, in 1802, coordinated a free vaccination program for the poor in New York City. By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans. In 1900 starting in New York City, smallpox reared its head once again and started a sociopolitical battle with lines drawn between the rich and poor, white and black. In populations of railroad and migrant workers who traveled from city to city the disease had reached an endemic low boil. This fact did not bother the government at the time, nor did it spur them to action. Despite the general acceptance of the germ theory of disease , pioneered by John Snow in 1849, smallpox was still thought to be mostly a malady that followed the less-distinct guidelines of a "filth" disease, and therefore would only affect the "lower classes". The last major smallpox epidemic in the United States occurred in Boston , Massachusetts throughout a three-year period, between 1901 and 1903. During this three-year period, 1596 cases of the disease occurred throughout the city. Of those cases, nearly 300 people died. As a whole, the epidemic had a 17% fatality rate. Those who were infected with the disease were detained in quarantine facilities in the hopes of protecting others from getting sick. These quarantine facilities, or pesthouses, were mostly located on Southampton Street. As the outbreak worsened, men were also moved to hospitals on Gallop's Island . Women and children were primarily sent to Southampton Street. Smallpox patients were not allowed in regular hospital facilities throughout the city, for fear the sickness would spread among the already sick. A reflection of the previous outbreak that occurred in New York, the poor and homeless were blamed for the sickness's spread. In response to this belief, the city instructed teams of physicians to vaccinate anyone living in inexpensive housing. [ citation needed ] In an effort to control the outbreak, the Boston Board of Health began voluntary vaccination programs. Individuals could receive free vaccines at their workplaces or at different stations set up throughout the city. By the end of 1901, some 40,000 of the city's residents had received a smallpox vaccine. However, despite the city's efforts, the epidemic continued to grow. In January 1902, a door-to-door vaccination program was initiated. Health officials were instructed to compel individuals to receive vaccination, pay a $5 fine, or face 15 days in prison. This door-to-door program was met by some resistance as some individuals feared the vaccines to be unsafe and ineffective. Others felt compulsory vaccination in itself was a problem that violated an individual's civil liberties. [ citation needed ] This program of compulsory vaccination eventually led to the famous Jacobson v. Massachusetts case. The case was the result of a Cambridge resident's refusal to be vaccinated. Henning Jacobson, a Swedish immigrant, refused vaccination out of fear it would cause him illness. He claimed a previous smallpox vaccine had made him sick as a child. Rather than pay the five dollar fine, he challenged the state's authority on forcing people to receive vaccination. His case was lost at the state level, but Jacobson appealed the ruling, and so, the case was taken up by the Supreme Court. In 1905 the Supreme Court upheld the Massachusetts law: it was ruled Jacobson could not refuse the mandatory vaccination. In Canada, between 1702 and 1703, nearly a quarter of the population of Quebec city died due to a smallpox epidemic. There is evidence that smallpox reached the Philippine islands from the 4th century onwards – linked possibly to contact between South East Asians and Indian traders . During the 18th century, there were many major outbreaks of smallpox, driven possibly by increasing contact with European colonists and traders. There were epidemics, for instance, in the Sultanate of Banjar (South Kalimantan), in 1734, 1750–51, 1764–65 and 1778–79; in the Sultanate of Tidore (Moluccas ) during the 1720s, and in southern Sumatra during the 1750s, the 1770s and in 1786. Smallpox was externally brought to Australia. The first recorded outbreak, in April 1789, about 16 months after the arrival of the First Fleet , devastated the Aboriginal population. Governor Arthur Phillip said that about half of the Aboriginal people living around Sydney Cove died during the outbreak. Some later estimates have been higher, though precise figures are hard to determine, and Professors Carmody and Hunter argued in 2014 that the figure was more like 30%. There is an ongoing debate, with links to the "History wars" , concerning two main rival theories about how smallpox first entered the continent. (Another hypothesis suggested that the French brought it in 1788, but the timeline does not fit.) The central hypotheses of these theories suggest that smallpox was transmitted to Indigenous Australians by either: In 1914, Dr J. H. L. Cumpston , director of the Australian Quarantine Service tentatively put forward the hypothesis that smallpox arrived with British settlers. Cumpston's theory was most forcefully reiterated by the economic historian Noel Butlin , in his book Our Original Aggression (1983). Likewise David Day, in Claiming a Continent: A New History of Australia (2001), suggested that members of Sydney's garrison of Royal Marines may have attempted to use smallpox as a biological weapon in 1789. However, in 2002, historian John Connor stated that Day's theory was "unsustainable". That same year, theories that smallpox was introduced with settlers, deliberately or otherwise, were contested in a full-length book by historian Judy Campbell : Invisible Invaders: Smallpox and Other Diseases in Aboriginal Australia 1780-1880 (2002). Campbell consulted, during the writing of her book, Frank Fenner , who had overseen the final stages of a successful campaign by the World Health Organization (WHO) to eradicate smallpox. Campbell argued that scientific evidence concerning the viability of variolous matter (used for inoculation) did not support the possibility of the disease being brought to Australia on the long voyage from Europe. Campbell also noted that there was no evidence of Aboriginal people ever having been exposed to the variolous matter, merely speculation that they may have been. Later authors, such as Christopher Warren, and Craig Mear continued to argue that smallpox emanated from the importation of variolous matter on the First Fleet. Warren (2007) suggested that Campbell had erred in assuming that high temperatures would have sterilised the British supply of smallpox. H. A. Willis (2010), in a survey of the literature discussed above, endorsed Campbell's argument. In response, Warren (2011) suggested that Willis had not taken into account research on how heat affects the smallpox virus, cited by the WHO . Willis (2011) replied that his position was supported by a closer reading of Frank Fenner's report to the WHO (1988) and invited readers to consult that report online. The rival hypothesis, that the 1789 outbreak was introduced to Australia by visitors from Makassar , came to prominence in 2002, with Judy Campbell's book Invisible Invaders . Campbell expanded upon the opinion of C. C. Macknight (1986), an authority on the interaction between indigenous Australians and Makassans. Citing the scientific opinion of Fenner (who wrote the foreword to her book) and historical documents, Campbell argued that the 1789 outbreak was introduced to Australia by Makassans, from where it spread overland. Nevertheless, Michael Bennett in a 2009 article in Bulletin of the History of Medicine , argued that imported "variolous matter" may have been the source of the 1789 epidemic in Australia. In 2011, Macknight re-entered the debate, declaring: "The overwhelming probability must be that it [smallpox] was introduced, like the later epidemics, by [Makassan] trepangers on the north coast and spread across the continent to arrive in Sydney quite independently of the new settlement there". Warren (2013) disputed this, on the grounds that: there was no suitable smallpox in Makassar before 1789; there were no trade routes suitable for transmission to Port Jackson ; the theory of a Makassan source for smallpox in 1789 was contradicted by Aboriginal oral tradition ; and, the earliest point at which there was evidence of smallpox entering Australia with Makassan visitors was around 1824. Public health expert Mark Wenitong, a Kabi Kabi man, and John Maynard, Emeritus professor of Aboriginal History at the University of Newcastle agree that this is highly unlikely, with the added obstacle of very low population density between the north coast and Sydney Cove. A quite separate third theory, endorsed by the pathologist Dr G.E. Ford, with support from the academics Curson, Wright and Hunter, holds that the deadly disease was not smallpox but the far more infectious chickenpox, to which the Eora Aboriginal peoples had no resistance. John Carmody, then at the University of Sydney School of Medical Sciences, suggested in 2010 that the epidemic was far more likely to have been chickenpox , as none of the European colonists were threatened by it, as he would have expected to happen. However Wenitong and Maynard continue to believe that there is strong evidence that it was smallpox. Another major outbreak was observed in 1828–30, near Bathurst, New South Wales . A third epidemic occurred in the Northern Territory and northern Western Australia from the mid-1860s, until at least 1870. Elsewhere in the Pacific, smallpox killed many indigenous Polynesians. Nevertheless, Alfred Crosby , in his major work, Ecological Imperialism: The Biological Expansion of Europe, 900-1900 (1986) showed that in 1840 a ship with smallpox on it was successfully quarantined, preventing an epidemic amongst Māori of New Zealand . The only major outbreak in New Zealand was a 1913 epidemic, which affected Māori in northern New Zealand and nearly wiped out the Rapa Nui of Easter Island ( Rapa Nui ), was reported by Te Rangi Hiroa (Dr Peter Buck) to a medical congress in Melbourne in 1914. The whaler ship Delta brought smallpox to the Micronesian island of Pohnpei on 28 February 1854. The Pohnpeians reacted by first feasting their offended spirits and then resorted hiding. The disease eventually wiped out more than half the island's population. The deaths of chiefs threw Pohnpeian society into disarray, and the people started blaming the God of the Christian missionaries. The Christian missionaries themselves saw the epidemic as God's punishment for the people and offered the natives inoculations, though often withheld such treatment from the priests. The epidemic abated in October 1854. There is evidence that smallpox reached the Philippine islands from the 4th century onwards – linked possibly to contact between South East Asians and Indian traders . During the 18th century, there were many major outbreaks of smallpox, driven possibly by increasing contact with European colonists and traders. There were epidemics, for instance, in the Sultanate of Banjar (South Kalimantan), in 1734, 1750–51, 1764–65 and 1778–79; in the Sultanate of Tidore (Moluccas ) during the 1720s, and in southern Sumatra during the 1750s, the 1770s and in 1786. Smallpox was externally brought to Australia. The first recorded outbreak, in April 1789, about 16 months after the arrival of the First Fleet , devastated the Aboriginal population. Governor Arthur Phillip said that about half of the Aboriginal people living around Sydney Cove died during the outbreak. Some later estimates have been higher, though precise figures are hard to determine, and Professors Carmody and Hunter argued in 2014 that the figure was more like 30%. There is an ongoing debate, with links to the "History wars" , concerning two main rival theories about how smallpox first entered the continent. (Another hypothesis suggested that the French brought it in 1788, but the timeline does not fit.) The central hypotheses of these theories suggest that smallpox was transmitted to Indigenous Australians by either: In 1914, Dr J. H. L. Cumpston , director of the Australian Quarantine Service tentatively put forward the hypothesis that smallpox arrived with British settlers. Cumpston's theory was most forcefully reiterated by the economic historian Noel Butlin , in his book Our Original Aggression (1983). Likewise David Day, in Claiming a Continent: A New History of Australia (2001), suggested that members of Sydney's garrison of Royal Marines may have attempted to use smallpox as a biological weapon in 1789. However, in 2002, historian John Connor stated that Day's theory was "unsustainable". That same year, theories that smallpox was introduced with settlers, deliberately or otherwise, were contested in a full-length book by historian Judy Campbell : Invisible Invaders: Smallpox and Other Diseases in Aboriginal Australia 1780-1880 (2002). Campbell consulted, during the writing of her book, Frank Fenner , who had overseen the final stages of a successful campaign by the World Health Organization (WHO) to eradicate smallpox. Campbell argued that scientific evidence concerning the viability of variolous matter (used for inoculation) did not support the possibility of the disease being brought to Australia on the long voyage from Europe. Campbell also noted that there was no evidence of Aboriginal people ever having been exposed to the variolous matter, merely speculation that they may have been. Later authors, such as Christopher Warren, and Craig Mear continued to argue that smallpox emanated from the importation of variolous matter on the First Fleet. Warren (2007) suggested that Campbell had erred in assuming that high temperatures would have sterilised the British supply of smallpox. H. A. Willis (2010), in a survey of the literature discussed above, endorsed Campbell's argument. In response, Warren (2011) suggested that Willis had not taken into account research on how heat affects the smallpox virus, cited by the WHO . Willis (2011) replied that his position was supported by a closer reading of Frank Fenner's report to the WHO (1988) and invited readers to consult that report online. The rival hypothesis, that the 1789 outbreak was introduced to Australia by visitors from Makassar , came to prominence in 2002, with Judy Campbell's book Invisible Invaders . Campbell expanded upon the opinion of C. C. Macknight (1986), an authority on the interaction between indigenous Australians and Makassans. Citing the scientific opinion of Fenner (who wrote the foreword to her book) and historical documents, Campbell argued that the 1789 outbreak was introduced to Australia by Makassans, from where it spread overland. Nevertheless, Michael Bennett in a 2009 article in Bulletin of the History of Medicine , argued that imported "variolous matter" may have been the source of the 1789 epidemic in Australia. In 2011, Macknight re-entered the debate, declaring: "The overwhelming probability must be that it [smallpox] was introduced, like the later epidemics, by [Makassan] trepangers on the north coast and spread across the continent to arrive in Sydney quite independently of the new settlement there". Warren (2013) disputed this, on the grounds that: there was no suitable smallpox in Makassar before 1789; there were no trade routes suitable for transmission to Port Jackson ; the theory of a Makassan source for smallpox in 1789 was contradicted by Aboriginal oral tradition ; and, the earliest point at which there was evidence of smallpox entering Australia with Makassan visitors was around 1824. Public health expert Mark Wenitong, a Kabi Kabi man, and John Maynard, Emeritus professor of Aboriginal History at the University of Newcastle agree that this is highly unlikely, with the added obstacle of very low population density between the north coast and Sydney Cove. A quite separate third theory, endorsed by the pathologist Dr G.E. Ford, with support from the academics Curson, Wright and Hunter, holds that the deadly disease was not smallpox but the far more infectious chickenpox, to which the Eora Aboriginal peoples had no resistance. John Carmody, then at the University of Sydney School of Medical Sciences, suggested in 2010 that the epidemic was far more likely to have been chickenpox , as none of the European colonists were threatened by it, as he would have expected to happen. However Wenitong and Maynard continue to believe that there is strong evidence that it was smallpox. Another major outbreak was observed in 1828–30, near Bathurst, New South Wales . A third epidemic occurred in the Northern Territory and northern Western Australia from the mid-1860s, until at least 1870.Elsewhere in the Pacific, smallpox killed many indigenous Polynesians. Nevertheless, Alfred Crosby , in his major work, Ecological Imperialism: The Biological Expansion of Europe, 900-1900 (1986) showed that in 1840 a ship with smallpox on it was successfully quarantined, preventing an epidemic amongst Māori of New Zealand . The only major outbreak in New Zealand was a 1913 epidemic, which affected Māori in northern New Zealand and nearly wiped out the Rapa Nui of Easter Island ( Rapa Nui ), was reported by Te Rangi Hiroa (Dr Peter Buck) to a medical congress in Melbourne in 1914. The whaler ship Delta brought smallpox to the Micronesian island of Pohnpei on 28 February 1854. The Pohnpeians reacted by first feasting their offended spirits and then resorted hiding. The disease eventually wiped out more than half the island's population. The deaths of chiefs threw Pohnpeian society into disarray, and the people started blaming the God of the Christian missionaries. The Christian missionaries themselves saw the epidemic as God's punishment for the people and offered the natives inoculations, though often withheld such treatment from the priests. The epidemic abated in October 1854. Early in history, it was observed that those who had contracted smallpox once were never struck by the disease again. Thought to have been discovered by accident, it became known that those who contracted smallpox through a break in the skin in which smallpox matter was inserted received a less severe reaction than those who contracted it naturally. This realization led to the practice of purposely infecting people with matter from smallpox scabs in order to protect them later from a more severe reaction. This practice, known today as variolation , was first practiced in China in the 10th century. Methods of carrying out the procedure varied depending upon location. Variolation was the sole method of protection against smallpox other than quarantine until Edward Jenner's discovery of the inoculating abilities of cowpox against the smallpox virus in 1796. Efforts to protect populations against smallpox by way of vaccination followed for centuries after Jenner's discovery. Smallpox has since been completely eradicated since 1979, because of the mass vaccination efforts of the World Health Organization. [ citation needed ] The word variolation is synonymous with inoculation, insertion, en-grafting, or transplantation. The term is used to define insertion of smallpox matter, and distinguishes this procedure from vaccination, where cowpox matter was used to obtain a much milder reaction among patients. The practice of variolation (also known as inoculation ) first came out of East Asia. First writings documenting variolation in China appear around 1500. Scabs from smallpox victims who had the disease in its mild form would be selected, and the powder was kept close to body temperature by means of keeping it close to the chest, killing the majority of the virus and resulting in a more mild case of smallpox. Scabs were generally used when a month old, but could be used more quickly in hot weather (15–20 days), and slower in winter (50 days). The process was carried out by taking eight smallpox scabs and crushing them in a mortar with two grains of Uvularia grandiflora in a mortar. The powder was administered nasally through a silver tube that was curved at its point, through the right nostril for boys and the left nostril for girls. A week after the procedure, those variolated would start to produce symptoms of smallpox, and recovery was guaranteed. In India, where the European colonizers came across variolation in the 17th century, a large, sharp needle was dipped into the pus collected from mature smallpox sores. Several punctures with this needle were made either below the deltoid muscle or in the forehead, and then were covered with a paste made from boiled rice. Variolation spread farther from India to other countries in south west Asia, and then to the Balkans. In 1792 a slave-ship arrived on the French Indian Ocean island of Île de France (Mauritius) from South India, bringing with it smallpox. As the epidemic spread, a heated debate ensued over the practice of inoculation. The island was in the throes of revolutionary politics and the community of French colonists were acutely aware of their new rights as 'citizens'. In the course of the smallpox epidemic, many of the political tensions the period came to focus on the question of inoculation, and were played out on the bodies of slaves. Whilst some citizens asserted their right, as property owners, to inoculate the slaves, others, equally vehemently, objected to the practice and asserted their right to protect their slaves from infection. Eighteenth-century colonial medicine was largely geared to keeping the bodies of slaves and workers productive and useful, but formal medicine never had a monopoly. Slaves on Île de France brought with them a rich array of medical beliefs and practices from Africa, India, and Madagascar. We have little direct historical evidence for these, but we do know that many slaves came from areas in which forms of smallpox inoculation were known and practiced. In 1713, Lady Mary Wortley Montagu 's brother died of smallpox; she too contracted the virus two years later at the age of twenty-six, leaving her badly scarred. When her husband was made ambassador to Ottoman Empire , she accompanied him to Constantinople. It was here that Lady Mary first came upon variolation. Two Greek women made it their business to engraft people with pox that left them un-scarred and unable to catch the pox again. In a letter, she wrote that she intended to have her own son undergo the process and would try to bring variolation into fashion in England. Her son underwent the procedure, which was performed by Charles Maitland , and survived with no ill effects. When an epidemic broke out in London following her return, Lady Mary wanted to protect her daughter from the virus by having her variolated as well. Maitland performed the procedure, which was a success. The story made it to the newspapers and was a topic for discussion in London salons. Princess Caroline of Wales wanted her children variolated as well but first wanted more validation of the operation. She had both an orphanage and several convicts variolated before she was convinced. When the operation, performed by the King's surgeon, Claudius Amyand , and overseen by Maitland, was a success, variolation got the royal seal of approval and the practice became widespread. When the practice of variolation set off local epidemics and caused death in two cases, public reaction was severe. Minister Edmund Massey, in 1772, called variolation dangerous and sinful, saying that people should handle the disease as the biblical figure Job did with his own tribulations, without interfering with God's test for mankind. Lady Mary still worked at promoting variolation but its practice waned until 1743. Robert and Daniel Sutton further revived the practice of variolation in England by advertising their perfect variolation record, maintained by selecting patients who were healthy when variolated and were cared for during the procedure in the Sutton's own hygienic hospital. Other changes that the Suttons made to carrying out the variolation process include reducing and later abolishing the preparatory period before variolation was carried out, making more shallow incisions to distribute the smallpox matter, using smallpox matter collected on the fourth day of the disease, where the pus taken was still clear, and recommending that those inoculated get fresh air during recovery. The introduction of the shallower incision reduced both complications associated with the procedure and the severity of the reaction. The prescription of fresh air caused controversy about Sutton's method and how effective it was in reality when those inoculated could walk about and spread the disease to those that had never before experienced smallpox. It was the Suttons who introduced the idea of mass variolation of an area when an epidemic broke out as means of protection to the inhabitants in that location. News of variolation spread to the royal families of Europe. Several royal families had themselves variolated by English physicians claiming to be specialists. Recipients include the family of Louis XV following his own death of smallpox, and Catherine the Great , whose husband had been horribly disfigured by the disease. Catherine the Great was variolated by Thomas Dimsdale, who followed Sutton's method of inoculation. In France, the practice was sanctioned until an epidemic was traced back to an inoculation . After this instance, variolation was banned within city limits. These conditions caused physicians to move just outside the cities and continue to practice variolation in the suburbs. Edward Jenner was variolated in 1756 at age eight in an inoculation barn in Wotton-under-Edge , England. At this time, in preparation for variolation children were bled repeatedly and were given very little to eat and only given a diet drink made to sweeten their blood. This greatly weakened the children before the actual procedure was given. Jenner's own inoculation was administered by a Mr. Holbrow, an apothecary. The procedure involved scratching the arm with the tip of a knife, placing several smallpox scabs in the cuts and then bandaging the arm. After receiving the procedure, the children stayed in the barn for several weeks to recover. First symptoms occurred after one week and usually cleared up three days later. On average, it took a month to fully recover from the encounter with smallpox combined with weakness from the preceding starvation. At the age of thirteen, Jenner was sent to study medicine in Chipping Sodbury with Daniel Ludlow, a surgeon and apothecary, from 1762 to 1770 who had a strong sense of cleanliness which Jenner learned from him. During his apprenticeship, Jenner heard that upon contracting cowpox , the recipient became immune to smallpox for the remainder of their life. However, this theory was dismissed because of several cases proving that the opposite was true. [ citation needed ] After learning all he could from Ludlow, Jenner apprenticed with John Hunter in London from 1770 to 1773. Hunter was a correspondent of Ludlow's, and it is likely that Ludlow recommended Jenner to apprentice with Hunter. Hunter believed in deviating from the accepted treatment and trying new methods if the traditional methods failed. This was considered unconventional medicine at the time and had a pivotal role in Jenner's development as a scientist. After two years of apprenticeship, Jenner moved back to his hometown of Berkeley in Gloucestershire, where he quickly gained the respect of both his patients and other medical professionals for his work as a physician. It was during this time that Jenner revisited the connection between cowpox and smallpox. He began investigating dairy farms in the Gloucestershire area looking for cowpox. This research was slow going as Jenner often had to wait months or even years before cases of cowpox would again return to the Gloucestershire area. During his study, he found that cowpox was actually several diseases that were similar in nature but were distinguishable through slight differences, and that not all versions had the capacity to make one immune from smallpox upon contraction. Through his study, he incorrectly deduced that smallpox and cowpox were all the same disease, simply manifesting themselves differently in different animals, eventually setting back his research and making it difficult to publish his findings. Though Jenner had seen cases of people becoming immune to smallpox after having cowpox, too many exceptions of people still contracting smallpox after having had cowpox were arising. Jenner was missing crucial information which he later discovered in 1796. Jenner hypothesized that in order to become immune to smallpox using cowpox, the matter from the cowpox pustules must be administered at maximum potency; else it was too weak to be effective in creating immunity to smallpox. He deduced that cowpox was most likely to transfer immunity from smallpox if administered at the eighth day of the disease. On May 14, 1796, he performed an experiment in which he took pus from a sore of a cowpox-infected milkmaid named Sarah Nelmes, and applied it to a few small scratches on the arm of an eight-year-old boy who had never before contracted either smallpox or cowpox, named James Phipps . Phipps recovered as expected. Two months later, Jenner repeated the procedure using matter from smallpox, observing no effect. Phipps became the first person to become immune to smallpox without ever actually having the disease. He was variolated many more times over the course of his life to prove his immunity. When the next cowpox epidemic broke out in 1798, Jenner conducted a series of inoculations using cowpox, all of them successful including on his own son Robert. Because his findings were revolutionary and lacked in evidence, the Royal Society (of which Jenner was a member) refused to publish his findings. Jenner then rode to London and had his book An Inquiry into the Causes and Effects of the Variolæ Vaccinæ published by Sampson Low's firm in June 1798. The book was an instant bestseller among the elite in London salons, in the medical establishment and among the ladies and gentlemen of the enlightenment. Knowledge of the ability of cowpox to provide immunity from smallpox was present in England before Jenner's discovery. In 1774, a cattle dealer named Benjamin Jesty had successfully inoculated his wife and three sons using cowpox. This was before Jenner discovered the immunization capabilities of cowpox. However, Jesty simply performed the procedure; he did not take the discovery any further by inoculating his family with smallpox matter to see if there would be a reaction or perform any other trials. Jenner was the first to prove the effectiveness of vaccination with cowpox using scientific experimentation. Benjamin Franklin , who had lost his own son to smallpox in 1736, made the suggestion to create a pamphlet to distribute to families explaining how to inoculate their children themselves, so as to eliminate cost as the factor in the decision to choose to inoculate children. William Heberden , a friend of Franklin's and an English physician, followed through with Franklin's idea, printing 2000 pamphlets in 1759 which were distributed by Franklin in America. An American physician, John Kirkpatrick , upon his visit to London in 1743, told of an instance where variolation stopped an epidemic in Charleston, South Carolina , in 1738, where 800 people were inoculated and only eight deaths occurred. His account of the success of variolation in Charleston helped to play a role in the revival of its practice in London. Kirkpatrick also advocated inoculating patients with matter from the sores of another inoculated person, instead of using matter from the sore of a smallpox victim, a procedure that Maitland had been using since 1722. In 1832 President Andrew Jackson signed Congressional authorization and funding to set up a smallpox vaccination program for Indian tribes. The goal was to eliminate the deadly threat of smallpox to a population with little or no immunity, and at the same time exhibit the benefits of cooperation with the government. In practice there were severe obstacles. The tribal medicine men launched a strong opposition, warning of white trickery and offering an alternative explanation and system of cure. They taught that the affliction could best be cured by a sweat bath followed by a rapid plunge into cold water. Furthermore the vaccines often lost their potency when transported and stored over long distances with primitive storage facilities. It was too little and too late to avoid the great smallpox epidemic of 1837 to 1840 that swept across North America west of the Mississippi, all the way to Canada and Alaska. Deaths have been estimated in the range of 100,000 to 300,000, with entire tribes such as the Mandans wiped out. The word variolation is synonymous with inoculation, insertion, en-grafting, or transplantation. The term is used to define insertion of smallpox matter, and distinguishes this procedure from vaccination, where cowpox matter was used to obtain a much milder reaction among patients. The practice of variolation (also known as inoculation ) first came out of East Asia. First writings documenting variolation in China appear around 1500. Scabs from smallpox victims who had the disease in its mild form would be selected, and the powder was kept close to body temperature by means of keeping it close to the chest, killing the majority of the virus and resulting in a more mild case of smallpox. Scabs were generally used when a month old, but could be used more quickly in hot weather (15–20 days), and slower in winter (50 days). The process was carried out by taking eight smallpox scabs and crushing them in a mortar with two grains of Uvularia grandiflora in a mortar. The powder was administered nasally through a silver tube that was curved at its point, through the right nostril for boys and the left nostril for girls. A week after the procedure, those variolated would start to produce symptoms of smallpox, and recovery was guaranteed. In India, where the European colonizers came across variolation in the 17th century, a large, sharp needle was dipped into the pus collected from mature smallpox sores. Several punctures with this needle were made either below the deltoid muscle or in the forehead, and then were covered with a paste made from boiled rice. Variolation spread farther from India to other countries in south west Asia, and then to the Balkans. In 1792 a slave-ship arrived on the French Indian Ocean island of Île de France (Mauritius) from South India, bringing with it smallpox. As the epidemic spread, a heated debate ensued over the practice of inoculation. The island was in the throes of revolutionary politics and the community of French colonists were acutely aware of their new rights as 'citizens'. In the course of the smallpox epidemic, many of the political tensions the period came to focus on the question of inoculation, and were played out on the bodies of slaves. Whilst some citizens asserted their right, as property owners, to inoculate the slaves, others, equally vehemently, objected to the practice and asserted their right to protect their slaves from infection. Eighteenth-century colonial medicine was largely geared to keeping the bodies of slaves and workers productive and useful, but formal medicine never had a monopoly. Slaves on Île de France brought with them a rich array of medical beliefs and practices from Africa, India, and Madagascar. We have little direct historical evidence for these, but we do know that many slaves came from areas in which forms of smallpox inoculation were known and practiced. In 1713, Lady Mary Wortley Montagu 's brother died of smallpox; she too contracted the virus two years later at the age of twenty-six, leaving her badly scarred. When her husband was made ambassador to Ottoman Empire , she accompanied him to Constantinople. It was here that Lady Mary first came upon variolation. Two Greek women made it their business to engraft people with pox that left them un-scarred and unable to catch the pox again. In a letter, she wrote that she intended to have her own son undergo the process and would try to bring variolation into fashion in England. Her son underwent the procedure, which was performed by Charles Maitland , and survived with no ill effects. When an epidemic broke out in London following her return, Lady Mary wanted to protect her daughter from the virus by having her variolated as well. Maitland performed the procedure, which was a success. The story made it to the newspapers and was a topic for discussion in London salons. Princess Caroline of Wales wanted her children variolated as well but first wanted more validation of the operation. She had both an orphanage and several convicts variolated before she was convinced. When the operation, performed by the King's surgeon, Claudius Amyand , and overseen by Maitland, was a success, variolation got the royal seal of approval and the practice became widespread. When the practice of variolation set off local epidemics and caused death in two cases, public reaction was severe. Minister Edmund Massey, in 1772, called variolation dangerous and sinful, saying that people should handle the disease as the biblical figure Job did with his own tribulations, without interfering with God's test for mankind. Lady Mary still worked at promoting variolation but its practice waned until 1743. Robert and Daniel Sutton further revived the practice of variolation in England by advertising their perfect variolation record, maintained by selecting patients who were healthy when variolated and were cared for during the procedure in the Sutton's own hygienic hospital. Other changes that the Suttons made to carrying out the variolation process include reducing and later abolishing the preparatory period before variolation was carried out, making more shallow incisions to distribute the smallpox matter, using smallpox matter collected on the fourth day of the disease, where the pus taken was still clear, and recommending that those inoculated get fresh air during recovery. The introduction of the shallower incision reduced both complications associated with the procedure and the severity of the reaction. The prescription of fresh air caused controversy about Sutton's method and how effective it was in reality when those inoculated could walk about and spread the disease to those that had never before experienced smallpox. It was the Suttons who introduced the idea of mass variolation of an area when an epidemic broke out as means of protection to the inhabitants in that location. News of variolation spread to the royal families of Europe. Several royal families had themselves variolated by English physicians claiming to be specialists. Recipients include the family of Louis XV following his own death of smallpox, and Catherine the Great , whose husband had been horribly disfigured by the disease. Catherine the Great was variolated by Thomas Dimsdale, who followed Sutton's method of inoculation. In France, the practice was sanctioned until an epidemic was traced back to an inoculation . After this instance, variolation was banned within city limits. These conditions caused physicians to move just outside the cities and continue to practice variolation in the suburbs. Edward Jenner was variolated in 1756 at age eight in an inoculation barn in Wotton-under-Edge , England. At this time, in preparation for variolation children were bled repeatedly and were given very little to eat and only given a diet drink made to sweeten their blood. This greatly weakened the children before the actual procedure was given. Jenner's own inoculation was administered by a Mr. Holbrow, an apothecary. The procedure involved scratching the arm with the tip of a knife, placing several smallpox scabs in the cuts and then bandaging the arm. After receiving the procedure, the children stayed in the barn for several weeks to recover. First symptoms occurred after one week and usually cleared up three days later. On average, it took a month to fully recover from the encounter with smallpox combined with weakness from the preceding starvation. At the age of thirteen, Jenner was sent to study medicine in Chipping Sodbury with Daniel Ludlow, a surgeon and apothecary, from 1762 to 1770 who had a strong sense of cleanliness which Jenner learned from him. During his apprenticeship, Jenner heard that upon contracting cowpox , the recipient became immune to smallpox for the remainder of their life. However, this theory was dismissed because of several cases proving that the opposite was true. [ citation needed ] After learning all he could from Ludlow, Jenner apprenticed with John Hunter in London from 1770 to 1773. Hunter was a correspondent of Ludlow's, and it is likely that Ludlow recommended Jenner to apprentice with Hunter. Hunter believed in deviating from the accepted treatment and trying new methods if the traditional methods failed. This was considered unconventional medicine at the time and had a pivotal role in Jenner's development as a scientist. After two years of apprenticeship, Jenner moved back to his hometown of Berkeley in Gloucestershire, where he quickly gained the respect of both his patients and other medical professionals for his work as a physician. It was during this time that Jenner revisited the connection between cowpox and smallpox. He began investigating dairy farms in the Gloucestershire area looking for cowpox. This research was slow going as Jenner often had to wait months or even years before cases of cowpox would again return to the Gloucestershire area. During his study, he found that cowpox was actually several diseases that were similar in nature but were distinguishable through slight differences, and that not all versions had the capacity to make one immune from smallpox upon contraction. Through his study, he incorrectly deduced that smallpox and cowpox were all the same disease, simply manifesting themselves differently in different animals, eventually setting back his research and making it difficult to publish his findings. Though Jenner had seen cases of people becoming immune to smallpox after having cowpox, too many exceptions of people still contracting smallpox after having had cowpox were arising. Jenner was missing crucial information which he later discovered in 1796. Jenner hypothesized that in order to become immune to smallpox using cowpox, the matter from the cowpox pustules must be administered at maximum potency; else it was too weak to be effective in creating immunity to smallpox. He deduced that cowpox was most likely to transfer immunity from smallpox if administered at the eighth day of the disease. On May 14, 1796, he performed an experiment in which he took pus from a sore of a cowpox-infected milkmaid named Sarah Nelmes, and applied it to a few small scratches on the arm of an eight-year-old boy who had never before contracted either smallpox or cowpox, named James Phipps . Phipps recovered as expected. Two months later, Jenner repeated the procedure using matter from smallpox, observing no effect. Phipps became the first person to become immune to smallpox without ever actually having the disease. He was variolated many more times over the course of his life to prove his immunity. When the next cowpox epidemic broke out in 1798, Jenner conducted a series of inoculations using cowpox, all of them successful including on his own son Robert. Because his findings were revolutionary and lacked in evidence, the Royal Society (of which Jenner was a member) refused to publish his findings. Jenner then rode to London and had his book An Inquiry into the Causes and Effects of the Variolæ Vaccinæ published by Sampson Low's firm in June 1798. The book was an instant bestseller among the elite in London salons, in the medical establishment and among the ladies and gentlemen of the enlightenment. Knowledge of the ability of cowpox to provide immunity from smallpox was present in England before Jenner's discovery. In 1774, a cattle dealer named Benjamin Jesty had successfully inoculated his wife and three sons using cowpox. This was before Jenner discovered the immunization capabilities of cowpox. However, Jesty simply performed the procedure; he did not take the discovery any further by inoculating his family with smallpox matter to see if there would be a reaction or perform any other trials. Jenner was the first to prove the effectiveness of vaccination with cowpox using scientific experimentation. Benjamin Franklin , who had lost his own son to smallpox in 1736, made the suggestion to create a pamphlet to distribute to families explaining how to inoculate their children themselves, so as to eliminate cost as the factor in the decision to choose to inoculate children. William Heberden , a friend of Franklin's and an English physician, followed through with Franklin's idea, printing 2000 pamphlets in 1759 which were distributed by Franklin in America. An American physician, John Kirkpatrick , upon his visit to London in 1743, told of an instance where variolation stopped an epidemic in Charleston, South Carolina , in 1738, where 800 people were inoculated and only eight deaths occurred. His account of the success of variolation in Charleston helped to play a role in the revival of its practice in London. Kirkpatrick also advocated inoculating patients with matter from the sores of another inoculated person, instead of using matter from the sore of a smallpox victim, a procedure that Maitland had been using since 1722. In 1832 President Andrew Jackson signed Congressional authorization and funding to set up a smallpox vaccination program for Indian tribes. The goal was to eliminate the deadly threat of smallpox to a population with little or no immunity, and at the same time exhibit the benefits of cooperation with the government. In practice there were severe obstacles. The tribal medicine men launched a strong opposition, warning of white trickery and offering an alternative explanation and system of cure. They taught that the affliction could best be cured by a sweat bath followed by a rapid plunge into cold water. Furthermore the vaccines often lost their potency when transported and stored over long distances with primitive storage facilities. It was too little and too late to avoid the great smallpox epidemic of 1837 to 1840 that swept across North America west of the Mississippi, all the way to Canada and Alaska. Deaths have been estimated in the range of 100,000 to 300,000, with entire tribes such as the Mandans wiped out. The practice of variolation (also known as inoculation ) first came out of East Asia. First writings documenting variolation in China appear around 1500. Scabs from smallpox victims who had the disease in its mild form would be selected, and the powder was kept close to body temperature by means of keeping it close to the chest, killing the majority of the virus and resulting in a more mild case of smallpox. Scabs were generally used when a month old, but could be used more quickly in hot weather (15–20 days), and slower in winter (50 days). The process was carried out by taking eight smallpox scabs and crushing them in a mortar with two grains of Uvularia grandiflora in a mortar. The powder was administered nasally through a silver tube that was curved at its point, through the right nostril for boys and the left nostril for girls. A week after the procedure, those variolated would start to produce symptoms of smallpox, and recovery was guaranteed. In India, where the European colonizers came across variolation in the 17th century, a large, sharp needle was dipped into the pus collected from mature smallpox sores. Several punctures with this needle were made either below the deltoid muscle or in the forehead, and then were covered with a paste made from boiled rice. Variolation spread farther from India to other countries in south west Asia, and then to the Balkans. In 1792 a slave-ship arrived on the French Indian Ocean island of Île de France (Mauritius) from South India, bringing with it smallpox. As the epidemic spread, a heated debate ensued over the practice of inoculation. The island was in the throes of revolutionary politics and the community of French colonists were acutely aware of their new rights as 'citizens'. In the course of the smallpox epidemic, many of the political tensions the period came to focus on the question of inoculation, and were played out on the bodies of slaves. Whilst some citizens asserted their right, as property owners, to inoculate the slaves, others, equally vehemently, objected to the practice and asserted their right to protect their slaves from infection. Eighteenth-century colonial medicine was largely geared to keeping the bodies of slaves and workers productive and useful, but formal medicine never had a monopoly. Slaves on Île de France brought with them a rich array of medical beliefs and practices from Africa, India, and Madagascar. We have little direct historical evidence for these, but we do know that many slaves came from areas in which forms of smallpox inoculation were known and practiced. In 1713, Lady Mary Wortley Montagu 's brother died of smallpox; she too contracted the virus two years later at the age of twenty-six, leaving her badly scarred. When her husband was made ambassador to Ottoman Empire , she accompanied him to Constantinople. It was here that Lady Mary first came upon variolation. Two Greek women made it their business to engraft people with pox that left them un-scarred and unable to catch the pox again. In a letter, she wrote that she intended to have her own son undergo the process and would try to bring variolation into fashion in England. Her son underwent the procedure, which was performed by Charles Maitland , and survived with no ill effects. When an epidemic broke out in London following her return, Lady Mary wanted to protect her daughter from the virus by having her variolated as well. Maitland performed the procedure, which was a success. The story made it to the newspapers and was a topic for discussion in London salons. Princess Caroline of Wales wanted her children variolated as well but first wanted more validation of the operation. She had both an orphanage and several convicts variolated before she was convinced. When the operation, performed by the King's surgeon, Claudius Amyand , and overseen by Maitland, was a success, variolation got the royal seal of approval and the practice became widespread. When the practice of variolation set off local epidemics and caused death in two cases, public reaction was severe. Minister Edmund Massey, in 1772, called variolation dangerous and sinful, saying that people should handle the disease as the biblical figure Job did with his own tribulations, without interfering with God's test for mankind. Lady Mary still worked at promoting variolation but its practice waned until 1743. Robert and Daniel Sutton further revived the practice of variolation in England by advertising their perfect variolation record, maintained by selecting patients who were healthy when variolated and were cared for during the procedure in the Sutton's own hygienic hospital. Other changes that the Suttons made to carrying out the variolation process include reducing and later abolishing the preparatory period before variolation was carried out, making more shallow incisions to distribute the smallpox matter, using smallpox matter collected on the fourth day of the disease, where the pus taken was still clear, and recommending that those inoculated get fresh air during recovery. The introduction of the shallower incision reduced both complications associated with the procedure and the severity of the reaction. The prescription of fresh air caused controversy about Sutton's method and how effective it was in reality when those inoculated could walk about and spread the disease to those that had never before experienced smallpox. It was the Suttons who introduced the idea of mass variolation of an area when an epidemic broke out as means of protection to the inhabitants in that location. News of variolation spread to the royal families of Europe. Several royal families had themselves variolated by English physicians claiming to be specialists. Recipients include the family of Louis XV following his own death of smallpox, and Catherine the Great , whose husband had been horribly disfigured by the disease. Catherine the Great was variolated by Thomas Dimsdale, who followed Sutton's method of inoculation. In France, the practice was sanctioned until an epidemic was traced back to an inoculation . After this instance, variolation was banned within city limits. These conditions caused physicians to move just outside the cities and continue to practice variolation in the suburbs. Edward Jenner was variolated in 1756 at age eight in an inoculation barn in Wotton-under-Edge , England. At this time, in preparation for variolation children were bled repeatedly and were given very little to eat and only given a diet drink made to sweeten their blood. This greatly weakened the children before the actual procedure was given. Jenner's own inoculation was administered by a Mr. Holbrow, an apothecary. The procedure involved scratching the arm with the tip of a knife, placing several smallpox scabs in the cuts and then bandaging the arm. After receiving the procedure, the children stayed in the barn for several weeks to recover. First symptoms occurred after one week and usually cleared up three days later. On average, it took a month to fully recover from the encounter with smallpox combined with weakness from the preceding starvation. At the age of thirteen, Jenner was sent to study medicine in Chipping Sodbury with Daniel Ludlow, a surgeon and apothecary, from 1762 to 1770 who had a strong sense of cleanliness which Jenner learned from him. During his apprenticeship, Jenner heard that upon contracting cowpox , the recipient became immune to smallpox for the remainder of their life. However, this theory was dismissed because of several cases proving that the opposite was true. [ citation needed ] After learning all he could from Ludlow, Jenner apprenticed with John Hunter in London from 1770 to 1773. Hunter was a correspondent of Ludlow's, and it is likely that Ludlow recommended Jenner to apprentice with Hunter. Hunter believed in deviating from the accepted treatment and trying new methods if the traditional methods failed. This was considered unconventional medicine at the time and had a pivotal role in Jenner's development as a scientist. After two years of apprenticeship, Jenner moved back to his hometown of Berkeley in Gloucestershire, where he quickly gained the respect of both his patients and other medical professionals for his work as a physician. It was during this time that Jenner revisited the connection between cowpox and smallpox. He began investigating dairy farms in the Gloucestershire area looking for cowpox. This research was slow going as Jenner often had to wait months or even years before cases of cowpox would again return to the Gloucestershire area. During his study, he found that cowpox was actually several diseases that were similar in nature but were distinguishable through slight differences, and that not all versions had the capacity to make one immune from smallpox upon contraction. Through his study, he incorrectly deduced that smallpox and cowpox were all the same disease, simply manifesting themselves differently in different animals, eventually setting back his research and making it difficult to publish his findings. Though Jenner had seen cases of people becoming immune to smallpox after having cowpox, too many exceptions of people still contracting smallpox after having had cowpox were arising. Jenner was missing crucial information which he later discovered in 1796. Jenner hypothesized that in order to become immune to smallpox using cowpox, the matter from the cowpox pustules must be administered at maximum potency; else it was too weak to be effective in creating immunity to smallpox. He deduced that cowpox was most likely to transfer immunity from smallpox if administered at the eighth day of the disease. On May 14, 1796, he performed an experiment in which he took pus from a sore of a cowpox-infected milkmaid named Sarah Nelmes, and applied it to a few small scratches on the arm of an eight-year-old boy who had never before contracted either smallpox or cowpox, named James Phipps . Phipps recovered as expected. Two months later, Jenner repeated the procedure using matter from smallpox, observing no effect. Phipps became the first person to become immune to smallpox without ever actually having the disease. He was variolated many more times over the course of his life to prove his immunity. When the next cowpox epidemic broke out in 1798, Jenner conducted a series of inoculations using cowpox, all of them successful including on his own son Robert. Because his findings were revolutionary and lacked in evidence, the Royal Society (of which Jenner was a member) refused to publish his findings. Jenner then rode to London and had his book An Inquiry into the Causes and Effects of the Variolæ Vaccinæ published by Sampson Low's firm in June 1798. The book was an instant bestseller among the elite in London salons, in the medical establishment and among the ladies and gentlemen of the enlightenment. Knowledge of the ability of cowpox to provide immunity from smallpox was present in England before Jenner's discovery. In 1774, a cattle dealer named Benjamin Jesty had successfully inoculated his wife and three sons using cowpox. This was before Jenner discovered the immunization capabilities of cowpox. However, Jesty simply performed the procedure; he did not take the discovery any further by inoculating his family with smallpox matter to see if there would be a reaction or perform any other trials. Jenner was the first to prove the effectiveness of vaccination with cowpox using scientific experimentation. Edward Jenner was variolated in 1756 at age eight in an inoculation barn in Wotton-under-Edge , England. At this time, in preparation for variolation children were bled repeatedly and were given very little to eat and only given a diet drink made to sweeten their blood. This greatly weakened the children before the actual procedure was given. Jenner's own inoculation was administered by a Mr. Holbrow, an apothecary. The procedure involved scratching the arm with the tip of a knife, placing several smallpox scabs in the cuts and then bandaging the arm. After receiving the procedure, the children stayed in the barn for several weeks to recover. First symptoms occurred after one week and usually cleared up three days later. On average, it took a month to fully recover from the encounter with smallpox combined with weakness from the preceding starvation. At the age of thirteen, Jenner was sent to study medicine in Chipping Sodbury with Daniel Ludlow, a surgeon and apothecary, from 1762 to 1770 who had a strong sense of cleanliness which Jenner learned from him. During his apprenticeship, Jenner heard that upon contracting cowpox , the recipient became immune to smallpox for the remainder of their life. However, this theory was dismissed because of several cases proving that the opposite was true. [ citation needed ] After learning all he could from Ludlow, Jenner apprenticed with John Hunter in London from 1770 to 1773. Hunter was a correspondent of Ludlow's, and it is likely that Ludlow recommended Jenner to apprentice with Hunter. Hunter believed in deviating from the accepted treatment and trying new methods if the traditional methods failed. This was considered unconventional medicine at the time and had a pivotal role in Jenner's development as a scientist. After two years of apprenticeship, Jenner moved back to his hometown of Berkeley in Gloucestershire, where he quickly gained the respect of both his patients and other medical professionals for his work as a physician. It was during this time that Jenner revisited the connection between cowpox and smallpox. He began investigating dairy farms in the Gloucestershire area looking for cowpox. This research was slow going as Jenner often had to wait months or even years before cases of cowpox would again return to the Gloucestershire area. During his study, he found that cowpox was actually several diseases that were similar in nature but were distinguishable through slight differences, and that not all versions had the capacity to make one immune from smallpox upon contraction. Through his study, he incorrectly deduced that smallpox and cowpox were all the same disease, simply manifesting themselves differently in different animals, eventually setting back his research and making it difficult to publish his findings. Though Jenner had seen cases of people becoming immune to smallpox after having cowpox, too many exceptions of people still contracting smallpox after having had cowpox were arising. Jenner was missing crucial information which he later discovered in 1796. Jenner hypothesized that in order to become immune to smallpox using cowpox, the matter from the cowpox pustules must be administered at maximum potency; else it was too weak to be effective in creating immunity to smallpox. He deduced that cowpox was most likely to transfer immunity from smallpox if administered at the eighth day of the disease. On May 14, 1796, he performed an experiment in which he took pus from a sore of a cowpox-infected milkmaid named Sarah Nelmes, and applied it to a few small scratches on the arm of an eight-year-old boy who had never before contracted either smallpox or cowpox, named James Phipps . Phipps recovered as expected. Two months later, Jenner repeated the procedure using matter from smallpox, observing no effect. Phipps became the first person to become immune to smallpox without ever actually having the disease. He was variolated many more times over the course of his life to prove his immunity. When the next cowpox epidemic broke out in 1798, Jenner conducted a series of inoculations using cowpox, all of them successful including on his own son Robert. Because his findings were revolutionary and lacked in evidence, the Royal Society (of which Jenner was a member) refused to publish his findings. Jenner then rode to London and had his book An Inquiry into the Causes and Effects of the Variolæ Vaccinæ published by Sampson Low's firm in June 1798. The book was an instant bestseller among the elite in London salons, in the medical establishment and among the ladies and gentlemen of the enlightenment. Knowledge of the ability of cowpox to provide immunity from smallpox was present in England before Jenner's discovery. In 1774, a cattle dealer named Benjamin Jesty had successfully inoculated his wife and three sons using cowpox. This was before Jenner discovered the immunization capabilities of cowpox. However, Jesty simply performed the procedure; he did not take the discovery any further by inoculating his family with smallpox matter to see if there would be a reaction or perform any other trials. Jenner was the first to prove the effectiveness of vaccination with cowpox using scientific experimentation. Benjamin Franklin , who had lost his own son to smallpox in 1736, made the suggestion to create a pamphlet to distribute to families explaining how to inoculate their children themselves, so as to eliminate cost as the factor in the decision to choose to inoculate children. William Heberden , a friend of Franklin's and an English physician, followed through with Franklin's idea, printing 2000 pamphlets in 1759 which were distributed by Franklin in America. An American physician, John Kirkpatrick , upon his visit to London in 1743, told of an instance where variolation stopped an epidemic in Charleston, South Carolina , in 1738, where 800 people were inoculated and only eight deaths occurred. His account of the success of variolation in Charleston helped to play a role in the revival of its practice in London. Kirkpatrick also advocated inoculating patients with matter from the sores of another inoculated person, instead of using matter from the sore of a smallpox victim, a procedure that Maitland had been using since 1722. In 1832 President Andrew Jackson signed Congressional authorization and funding to set up a smallpox vaccination program for Indian tribes. The goal was to eliminate the deadly threat of smallpox to a population with little or no immunity, and at the same time exhibit the benefits of cooperation with the government. In practice there were severe obstacles. The tribal medicine men launched a strong opposition, warning of white trickery and offering an alternative explanation and system of cure. They taught that the affliction could best be cured by a sweat bath followed by a rapid plunge into cold water. Furthermore the vaccines often lost their potency when transported and stored over long distances with primitive storage facilities. It was too little and too late to avoid the great smallpox epidemic of 1837 to 1840 that swept across North America west of the Mississippi, all the way to Canada and Alaska. Deaths have been estimated in the range of 100,000 to 300,000, with entire tribes such as the Mandans wiped out. Taterapox (which infects rodents) and camelpox are the closest relatives to smallpox, and share the same common ancestor with smallpox about 4,000 years ago. It is not clear exactly when during this period Variola first infected humans. Cowpox , horsepox, and monkeypox are more distantly related. All of these viruses share a common ancestor about 10,000 years ago. All of these viruses belong to the genus Orthopoxvirus .

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Smallpox vaccine

AU : D The smallpox vaccine is the first vaccine to have been developed against a contagious disease. In 1796, British physician Edward Jenner demonstrated that an infection with the relatively mild cowpox virus conferred immunity against the deadly smallpox virus. Cowpox served as a natural vaccine until the modern smallpox vaccine emerged in the 20th century. From 1958 to 1977, the World Health Organization (WHO) conducted a global vaccination campaign that eradicated smallpox , making it the only human disease to be eradicated. Although routine smallpox vaccination is no longer performed on the general public, the vaccine is still being produced to guard against bioterrorism , biological warfare , and mpox . The term vaccine derives from the Latin word for cow, reflecting the origins of smallpox vaccination. Edward Jenner referred to cowpox as variolae vaccinae (smallpox of the cow). The origins of the smallpox vaccine became murky over time, especially after Louis Pasteur developed laboratory techniques for creating vaccines in the 19th century. Allan Watt Downie demonstrated in 1939 that the modern smallpox vaccine was serologically distinct from cowpox, and vaccinia was subsequently recognized as a separate viral species. Whole-genome sequencing has revealed that vaccinia is most closely related to horsepox , and the cowpox strains found in Great Britain are the least closely related to vaccinia . As the oldest vaccine, the smallpox vaccine has gone through several generations of medical technology. From 1796 to the 1880s, the vaccine was transmitted from one person to another through arm-to-arm vaccination. Smallpox vaccine was successfully maintained in cattle starting in the 1840s, and calf lymph vaccine became the leading smallpox vaccine in the 1880s. First-generation vaccines grown on the skin of live animals were widely distributed in the 1950s–1970s to eradicate smallpox. Second-generation vaccines were grown in chorioallantoic membrane or cell cultures for greater purity, and they were used in some areas during the smallpox eradication campaign. Third-generation vaccines are based on attenuated strains of vaccinia and saw limited use prior to the eradication of smallpox. All three generations of vaccine are available in stockpiles. First and second-generation vaccines contain live unattenuated vaccinia virus and can cause serious side effects in a small percentage of recipients, including death in 1–10 people per million vaccinations. Third-generation vaccines are much safer due to the milder side effects of the attenuated vaccinia strains. Second and third-generation vaccines are still being produced, with manufacturing capacity being built up in the 2000s due to fears of bioterrorism and biological warfare. The first-generation vaccines are manufactured by growing live vaccinia virus in the skin of live animals. Most first-generation vaccines are calf lymph vaccines that were grown on the skin of cows, but other animals were also used, including sheep. The development of freeze-dried vaccine in the 1950s made it possible to preserve vaccinia virus for long periods of time without refrigeration, leading to the availability of freeze-dried vaccines such as Dryvax. : 115 The vaccine is administered by multiple puncture of the skin (scarification) with a bifurcated needle that holds vaccine solution in the fork. The skin should be cleaned with water rather than alcohol, as the alcohol could inactivate the vaccinia virus. : 292 If alcohol is used, it must be allowed to evaporate completely before the vaccine is administered. : 292 Vaccination results in a skin lesion that fills with pus and eventually crusts over. This manifestation of localized vaccinia infection is known as a vaccine "take" and demonstrates immunity to smallpox. After 2–3 weeks, the scab will fall off and leave behind a vaccine scar. First generation vaccines consist of live, unattenuated vaccinia virus. One-third of first-time vaccinees develop side effects significant enough to miss school, work, or other activities, or have difficulty sleeping. 15–20% of children receiving the vaccine for the first time develop fevers of over 102 °F (39 °C) . The vaccinia lesion can transmit the virus to other people. Rare side effects include postvaccinal encephalitis and myopericarditis. Many countries have stockpiled first generation smallpox vaccines. In a 2006 predictive analysis of casualties if there were a mass vaccination of the populations of Germany and the Netherlands, it was estimated that a total of 9.8 people in the Netherlands and 46.2 people in Germany would die from uncontrolled vaccinia infection after being vaccinated with the New York City Board of Health strain. More deaths were predicted for vaccines based other strains: Lister (55.1 Netherlands, 268.5 Germany) and Bern (303.5 Netherlands, 1,381 Germany). The second-generation vaccines consist of live vaccinia virus grown in the chorioallantoic membrane or cell culture . The second-generation vaccines are also administered through scarification with a bifurcated needle, and they carry the same side effects as the first-generation vaccinia strain that was cloned. However, the use of eggs or cell culture allows for vaccine production in a sterile environment, while first-generation vaccine contains skin bacteria from the animal that the vaccine was grown on. Ernest William Goodpasture , Alice Miles Woodruff , and G. John Buddingh grew vaccinia virus on the chorioallantoic membrane of chicken embryos in 1932. The Texas Department of Health began producing egg-based vaccine in 1939 and started using it in vaccination campaigns in 1948. : 588 Lederle Laboratories began selling its Avianized smallpox vaccine in the United States in 1959. Egg-based vaccine was also used widely in Brazil, New Zealand, and Sweden, and on a smaller scale in many other countries. Concerns about temperature stability and avian sarcoma leukosis virus prevented it from being used more widely during the eradication campaign, although no increase in leukemia was seen in Brazil and Sweden despite the presence of ASLV in the chickens. : 588 Vaccinia was first grown in cell culture in 1931 by Thomas Milton Rivers . The WHO funded work in the 1960s at the Dutch National Institute for Public Health and the Environment (RIVM) on growing the Lister/Elstree strain in rabbit kidney cells and tested it in 45,443 Indonesian children in 1973, with comparable results to the same strain of calf lymph vaccine. : 588–589 Two other cell culture vaccines were developed from the Lister strain in the 2000s: Elstree-BN (Bavarian Nordic) and VV Lister CEP (Chicken Embryo Primary, Sanofi Pasteur). Lister/Elstree-RIVM was stockpiled in the Netherlands, and Elstree-BN was sold to some European countries for stockpiles. However, Sanofi dropped its own vaccine after it acquired Acambis in 2008. ACAM2000 is a vaccine developed by Acambis , which was acquired by Sanofi Pasteur in 2008, before selling the smallpox vaccine to Emergent Biosolutions in 2017. Six strains of vaccinia were isolated from 3,000 doses of Dryvax and found to exhibit significant variation in virulence. The strain with the most similar virulence to the overall Dryvax mixture was selected and grown in MRC-5 cells to make the ACAM1000 vaccine. After a successful Phase I trial of ACAM1000, the virus was passaged three times in Vero cells to develop ACAM2000, which entered mass production at Baxter . The United States ordered over 200 million doses of ACAM2000 in 1999–2001 for its stockpile, and production is ongoing to replace expired vaccine. The third-generation vaccines are based on attenuated vaccinia viruses that are much less virulent and carry lesser side effects. The attenuated viruses may be replicating or non-replicating. Modified vaccinia Ankara (MVA, German : Modifiziertes Vakziniavirus Ankara ) is a replication-incompetent variant of vaccinia that was developed in West Germany through serial passage . The original Ankara strain of vaccinia was maintained at the vaccine institute in Ankara, Turkey on donkeys and cows. The Ankara strain was taken to West Germany in 1953, where Herrlich and Mayr grew it on chorioallantoic membrane at the University of Munich . After 572 serial passages, the vaccinia virus had lost over 14% of its genome and could no longer replicate in human cells. MVA was used in West Germany in 1977–1980, but the eradication of smallpox ended the vaccination campaign after only 120,000 doses. MVA stimulates the production of fewer antibodies than replicating vaccines. During the smallpox eradication campaign, MVA was considered to be a pre-vaccine that would be administered before a replicating vaccine to reduce the side effects, or an alternative vaccine that could be safely given to people at high risk from a replicating vaccine. : 585 Japan evaluated MVA and rejected it due to its low immunogenicity, deciding to develop its own attenuated vaccine instead. In the 2000s, MVA was tested in animal models at much higher dosages. When MVA is given to monkeys at 40 times the dosage of Dryvax, it stimulates a more rapid immune response while still causing lesser side effects. MVA-BN (also known as: Imvanex in the European Union; Imvamune in Canada; and Jynneos ) is a vaccine manufactured by Bavarian Nordic by growing MVA in cell culture. Unlike replicating vaccines, MVA-BN is administered by injection via the subcutaneous route and does not result in a vaccine "take." A "take" or "major cutaneous reaction" is a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which can be a scab or an ulcer. MVA-BN can also be administered intradermally to increase the number of available doses. It is safer for immunocompromised patients and those who are at risk from a vaccinia [ definition needed ] infection. [ citation needed ] MVA-BN has been approved in the European Union, Canada, and the United States. Clinical trials have found that MVA-BN is safer and just as immunogenic as ACAM2000. This vaccine has also been approved for use against mpox . LC16m8 is a replicating attenuated strain of vaccinia that is manufactured by Kaketsuken in Japan. Working at the Chiba Serum Institute in Japan, So Hashizume passaged the Lister strain 45 times in primary rabbit kidney cells, interrupting the process after passages 36, 42, and 45 to grow clones on chorioallantoic membrane and select for pock size. The resulting variant was designated LC16m8 (Lister clone 16, medium pocks, clone 8). Unlike the severely-damaged MVA, LC16m8 contains every gene that is present in the ancestral vaccinia . However, a single-nucleotide deletion truncates membrane protein B5R from a residue length of 317 to 92. Although the truncated protein decreases production of extracellular enveloped virus, animal models have shown that antibodies against other membrane proteins are sufficient for immunity. LC16m8 was approved in Japan in 1975 after testing in over 50,000 children. Vaccination with LC16m8 results in a vaccine "take", but safety is similar to MVA. The first-generation vaccines are manufactured by growing live vaccinia virus in the skin of live animals. Most first-generation vaccines are calf lymph vaccines that were grown on the skin of cows, but other animals were also used, including sheep. The development of freeze-dried vaccine in the 1950s made it possible to preserve vaccinia virus for long periods of time without refrigeration, leading to the availability of freeze-dried vaccines such as Dryvax. : 115 The vaccine is administered by multiple puncture of the skin (scarification) with a bifurcated needle that holds vaccine solution in the fork. The skin should be cleaned with water rather than alcohol, as the alcohol could inactivate the vaccinia virus. : 292 If alcohol is used, it must be allowed to evaporate completely before the vaccine is administered. : 292 Vaccination results in a skin lesion that fills with pus and eventually crusts over. This manifestation of localized vaccinia infection is known as a vaccine "take" and demonstrates immunity to smallpox. After 2–3 weeks, the scab will fall off and leave behind a vaccine scar. First generation vaccines consist of live, unattenuated vaccinia virus. One-third of first-time vaccinees develop side effects significant enough to miss school, work, or other activities, or have difficulty sleeping. 15–20% of children receiving the vaccine for the first time develop fevers of over 102 °F (39 °C) . The vaccinia lesion can transmit the virus to other people. Rare side effects include postvaccinal encephalitis and myopericarditis. Many countries have stockpiled first generation smallpox vaccines. In a 2006 predictive analysis of casualties if there were a mass vaccination of the populations of Germany and the Netherlands, it was estimated that a total of 9.8 people in the Netherlands and 46.2 people in Germany would die from uncontrolled vaccinia infection after being vaccinated with the New York City Board of Health strain. More deaths were predicted for vaccines based other strains: Lister (55.1 Netherlands, 268.5 Germany) and Bern (303.5 Netherlands, 1,381 Germany). The second-generation vaccines consist of live vaccinia virus grown in the chorioallantoic membrane or cell culture . The second-generation vaccines are also administered through scarification with a bifurcated needle, and they carry the same side effects as the first-generation vaccinia strain that was cloned. However, the use of eggs or cell culture allows for vaccine production in a sterile environment, while first-generation vaccine contains skin bacteria from the animal that the vaccine was grown on. Ernest William Goodpasture , Alice Miles Woodruff , and G. John Buddingh grew vaccinia virus on the chorioallantoic membrane of chicken embryos in 1932. The Texas Department of Health began producing egg-based vaccine in 1939 and started using it in vaccination campaigns in 1948. : 588 Lederle Laboratories began selling its Avianized smallpox vaccine in the United States in 1959. Egg-based vaccine was also used widely in Brazil, New Zealand, and Sweden, and on a smaller scale in many other countries. Concerns about temperature stability and avian sarcoma leukosis virus prevented it from being used more widely during the eradication campaign, although no increase in leukemia was seen in Brazil and Sweden despite the presence of ASLV in the chickens. : 588 Vaccinia was first grown in cell culture in 1931 by Thomas Milton Rivers . The WHO funded work in the 1960s at the Dutch National Institute for Public Health and the Environment (RIVM) on growing the Lister/Elstree strain in rabbit kidney cells and tested it in 45,443 Indonesian children in 1973, with comparable results to the same strain of calf lymph vaccine. : 588–589 Two other cell culture vaccines were developed from the Lister strain in the 2000s: Elstree-BN (Bavarian Nordic) and VV Lister CEP (Chicken Embryo Primary, Sanofi Pasteur). Lister/Elstree-RIVM was stockpiled in the Netherlands, and Elstree-BN was sold to some European countries for stockpiles. However, Sanofi dropped its own vaccine after it acquired Acambis in 2008. ACAM2000 is a vaccine developed by Acambis , which was acquired by Sanofi Pasteur in 2008, before selling the smallpox vaccine to Emergent Biosolutions in 2017. Six strains of vaccinia were isolated from 3,000 doses of Dryvax and found to exhibit significant variation in virulence. The strain with the most similar virulence to the overall Dryvax mixture was selected and grown in MRC-5 cells to make the ACAM1000 vaccine. After a successful Phase I trial of ACAM1000, the virus was passaged three times in Vero cells to develop ACAM2000, which entered mass production at Baxter . The United States ordered over 200 million doses of ACAM2000 in 1999–2001 for its stockpile, and production is ongoing to replace expired vaccine. The third-generation vaccines are based on attenuated vaccinia viruses that are much less virulent and carry lesser side effects. The attenuated viruses may be replicating or non-replicating. Modified vaccinia Ankara (MVA, German : Modifiziertes Vakziniavirus Ankara ) is a replication-incompetent variant of vaccinia that was developed in West Germany through serial passage . The original Ankara strain of vaccinia was maintained at the vaccine institute in Ankara, Turkey on donkeys and cows. The Ankara strain was taken to West Germany in 1953, where Herrlich and Mayr grew it on chorioallantoic membrane at the University of Munich . After 572 serial passages, the vaccinia virus had lost over 14% of its genome and could no longer replicate in human cells. MVA was used in West Germany in 1977–1980, but the eradication of smallpox ended the vaccination campaign after only 120,000 doses. MVA stimulates the production of fewer antibodies than replicating vaccines. During the smallpox eradication campaign, MVA was considered to be a pre-vaccine that would be administered before a replicating vaccine to reduce the side effects, or an alternative vaccine that could be safely given to people at high risk from a replicating vaccine. : 585 Japan evaluated MVA and rejected it due to its low immunogenicity, deciding to develop its own attenuated vaccine instead. In the 2000s, MVA was tested in animal models at much higher dosages. When MVA is given to monkeys at 40 times the dosage of Dryvax, it stimulates a more rapid immune response while still causing lesser side effects. MVA-BN (also known as: Imvanex in the European Union; Imvamune in Canada; and Jynneos ) is a vaccine manufactured by Bavarian Nordic by growing MVA in cell culture. Unlike replicating vaccines, MVA-BN is administered by injection via the subcutaneous route and does not result in a vaccine "take." A "take" or "major cutaneous reaction" is a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which can be a scab or an ulcer. MVA-BN can also be administered intradermally to increase the number of available doses. It is safer for immunocompromised patients and those who are at risk from a vaccinia [ definition needed ] infection. [ citation needed ] MVA-BN has been approved in the European Union, Canada, and the United States. Clinical trials have found that MVA-BN is safer and just as immunogenic as ACAM2000. This vaccine has also been approved for use against mpox . LC16m8 is a replicating attenuated strain of vaccinia that is manufactured by Kaketsuken in Japan. Working at the Chiba Serum Institute in Japan, So Hashizume passaged the Lister strain 45 times in primary rabbit kidney cells, interrupting the process after passages 36, 42, and 45 to grow clones on chorioallantoic membrane and select for pock size. The resulting variant was designated LC16m8 (Lister clone 16, medium pocks, clone 8). Unlike the severely-damaged MVA, LC16m8 contains every gene that is present in the ancestral vaccinia . However, a single-nucleotide deletion truncates membrane protein B5R from a residue length of 317 to 92. Although the truncated protein decreases production of extracellular enveloped virus, animal models have shown that antibodies against other membrane proteins are sufficient for immunity. LC16m8 was approved in Japan in 1975 after testing in over 50,000 children. Vaccination with LC16m8 results in a vaccine "take", but safety is similar to MVA. Modified vaccinia Ankara (MVA, German : Modifiziertes Vakziniavirus Ankara ) is a replication-incompetent variant of vaccinia that was developed in West Germany through serial passage . The original Ankara strain of vaccinia was maintained at the vaccine institute in Ankara, Turkey on donkeys and cows. The Ankara strain was taken to West Germany in 1953, where Herrlich and Mayr grew it on chorioallantoic membrane at the University of Munich . After 572 serial passages, the vaccinia virus had lost over 14% of its genome and could no longer replicate in human cells. MVA was used in West Germany in 1977–1980, but the eradication of smallpox ended the vaccination campaign after only 120,000 doses. MVA stimulates the production of fewer antibodies than replicating vaccines. During the smallpox eradication campaign, MVA was considered to be a pre-vaccine that would be administered before a replicating vaccine to reduce the side effects, or an alternative vaccine that could be safely given to people at high risk from a replicating vaccine. : 585 Japan evaluated MVA and rejected it due to its low immunogenicity, deciding to develop its own attenuated vaccine instead. In the 2000s, MVA was tested in animal models at much higher dosages. When MVA is given to monkeys at 40 times the dosage of Dryvax, it stimulates a more rapid immune response while still causing lesser side effects. MVA-BN (also known as: Imvanex in the European Union; Imvamune in Canada; and Jynneos ) is a vaccine manufactured by Bavarian Nordic by growing MVA in cell culture. Unlike replicating vaccines, MVA-BN is administered by injection via the subcutaneous route and does not result in a vaccine "take." A "take" or "major cutaneous reaction" is a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which can be a scab or an ulcer. MVA-BN can also be administered intradermally to increase the number of available doses. It is safer for immunocompromised patients and those who are at risk from a vaccinia [ definition needed ] infection. [ citation needed ] MVA-BN has been approved in the European Union, Canada, and the United States. Clinical trials have found that MVA-BN is safer and just as immunogenic as ACAM2000. This vaccine has also been approved for use against mpox . LC16m8 is a replicating attenuated strain of vaccinia that is manufactured by Kaketsuken in Japan. Working at the Chiba Serum Institute in Japan, So Hashizume passaged the Lister strain 45 times in primary rabbit kidney cells, interrupting the process after passages 36, 42, and 45 to grow clones on chorioallantoic membrane and select for pock size. The resulting variant was designated LC16m8 (Lister clone 16, medium pocks, clone 8). Unlike the severely-damaged MVA, LC16m8 contains every gene that is present in the ancestral vaccinia . However, a single-nucleotide deletion truncates membrane protein B5R from a residue length of 317 to 92. Although the truncated protein decreases production of extracellular enveloped virus, animal models have shown that antibodies against other membrane proteins are sufficient for immunity. LC16m8 was approved in Japan in 1975 after testing in over 50,000 children. Vaccination with LC16m8 results in a vaccine "take", but safety is similar to MVA. Vaccinia is infectious, which improves its effectiveness, but causes serious complications for people with impaired immune systems (for example chemotherapy and AIDS patients) or history of eczema, and is not considered safe for pregnant women. A woman planning on conceiving should not receive smallpox immunization. Vaccines that only contain attenuated vaccinia viruses (an attenuated virus is one in which the pathogenicity has been decreased through serial passage ) have been proposed, but some researchers [ who? ] have questioned the possible effectiveness of such a vaccine. According to the US Centers for Disease Control and Prevention (CDC), "within 3 days of being exposed to the virus, the vaccine might protect you from getting the disease. If you still get the disease, you might get much less sick than an unvaccinated person would. Within 4 to 7 days of being exposed to the virus, the vaccine likely gives you some protection from the disease. If you still get the disease, you might not get as sick as an unvaccinated person would." In May 2007, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the U.S. Food and Drug Administration (FDA) voted unanimously that a new live virus vaccine produced by Acambis , ACAM2000 , is both safe and effective for use in persons at high risk of exposure to smallpox virus. However, due to the high rate of serious adverse effects, the vaccine will only be made available to the CDC for the Strategic National Stockpile . Since smallpox has been eradicated, the public is not routinely vaccinated against the disease. The World Health Organization maintained a stockpile of 200 million doses in 1980, to guard against reemergence of the disease, but 99% of the stockpile was destroyed in the late 1980s when smallpox failed to return. After the September 11 attacks in 2001, many governments began building up vaccine stockpiles again for fear of bioterrorism. Several companies sold off their stockpiles of vaccines manufactured in the 1970s, and production of smallpox vaccines resumed. Aventis Pasteur discovered a stockpile from the 1950s and donated it to the U.S. government. Stockpiles of newer vaccines must be repurchased periodically since they carry expiration dates. The United States had received 269 million doses of ACAM2000 and 28 million doses of MVA-BN by 2019, but only 100 million doses of ACAM2000 and 65,000 doses of MVA-BN were still available from the stockpile at the start of the 2022 monkeypox outbreak . First-generation vaccines have no specified expiration date and remain viable indefinitely in deep freeze. The U.S. stockpile of WetVax was manufactured in 1956–1957 and maintained since then at −4 °F (−20 °C) , and it was still effective when tested in 2004. Replicating vaccines also remain effective even at 1:10 dilution, so a limited number of doses can be stretched to cover a much larger population. 300,000 ACAM2000 (2nd) 2.4 million various (1st)The mortality of the severe form of smallpox – variola major – was very high without vaccination, up to 35% in some outbreaks. A method of inducing immunity known as inoculation, insufflation or " variolation " was practiced before the development of a modern vaccine and likely occurred in Africa and China well before the practice arrived in Europe. It may also have occurred in India, but this is disputed; other investigators contend the ancient Sanskrit medical texts of India do not describe these techniques. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Douzhen xinfa (痘疹心法) published in 1549. Inoculation for smallpox does not appear to have been widespread in China until the reign era of the Longqing Emperor (r. 1567–1572) during the Ming Dynasty . In China, powdered smallpox scabs were blown up the noses of the healthy. The patients would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers . According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia . Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". Variolation was also practiced throughout the latter half of the 17th century by physicians in Turkey , Persia , and Africa. In 1714 and 1716, two reports of the Ottoman Empire Turkish method of inoculation were made to the Royal Society in England, by Emmanuel Timoni, a doctor affiliated with the British Embassy in Constantinople , and Giacomo Pylarini . Source material tells us on Lady Mary Wortley Montagu; "When Lady Mary was in the Ottoman Empire, she discovered the local practice of inoculation against smallpox called variolation." In 1718 she had her son, aged five variolated. He recovered quickly. She returned to London and had her daughter variolated in 1721 by Charles Maitland , during an epidemic of smallpox. This encouraged the British Royal Family to take an interest and a trial of variolation was carried out on prisoners in Newgate Prison . This was successful and in 1722 Caroline of Ansbach , the Princess of Wales, allowed Maitland to vaccinate her children. The success of these variolations assured the British people that the procedure was safe. ...scarred the wrists, legs, and forehead of the patient, placed a fresh and kindly pock in each incision and bound it there for eight or ten days, after this time the patient was credibly informed. The patient would then develop a mild case [of smallpox], recover, and thereafter be immune. —Dr. Peter Kennedy Stimulated by a severe epidemic, variolation was first employed in North America in 1721. The procedure had been known in Boston since 1706, when preacher Cotton Mather learned it from Onesimus , a man he held as a slave, who – like many of his peers – had been inoculated in Africa before they were kidnapped. This practice was widely criticized at first. However, a limited trial showed six deaths occurred out of 244 who were variolated (2.5%), while 844 out of 5980 died of natural disease (14%), and the process was widely adopted throughout the colonies. The inoculation technique was documented as having a mortality rate of only one in a thousand. Two years after Kennedy's description appeared, March 1718, Dr. Charles Maitland successfully inoculated the five-year-old son of the British ambassador to the Turkish court under orders from the ambassador's wife Lady Mary Wortley Montagu , who four years later introduced the practice to England. An account from letter by Lady Mary Wortley Montagu to Sarah Chiswell, dated 1 April 1717, from the Turkish Embassy describes this treatment: The small-pox so fatal and so general amongst us is here entirely harmless by the invention of ingrafting (which is the term they give it). There is a set of old women who make it their business to perform the operation. Every autumn in the month of September, when the great heat is abated, people send to one another to know if any of their family has a mind to have the small-pox. They make parties for this purpose, and when they are met (commonly fifteen or sixteen together) the old woman comes with a nutshell full of the matter of the best sort of small-pox and asks what veins you please to have opened. She immediately rips open that you offer to her with a large needle (which gives you no more pain than a common scratch) and puts into the vein as much venom as can lye upon the head of her needle, and after binds up the little wound with a hollow bit of shell, and in this manner opens four or five veins. … The children or young patients play together all the rest of the day and are in perfect health till the eighth. Then the fever begins to seize them and they keep their beds two days, very seldom three. They have very rarely above twenty or thirty in their faces, which never mark, and in eight days time they are as well as before the illness. … There is no example of any one that has died in it, and you may believe I am very well satisfied of the safety of the experiment since I intend to try it on my dear little son. I am patriot enough to take pains to bring this useful invention into fashion in England, and I should not fail to write to some of our doctors very particularly about it if I knew any one of them that I thought had virtue enough to destroy such a considerable branch of their revenue for the good of mankind, but that distemper is too beneficial to them not to expose to all their resentment the hardy wight that should undertake to put an end to it. Perhaps if I live to return I may, however, have courage to war with them. In the early empirical days of vaccination, before Louis Pasteur 's work on establishing the germ theory and Joseph Lister 's on antisepsis and asepsis, there was considerable cross-infection. William Woodville , one of the early vaccinators and director of the London Smallpox Hospital is thought to have contaminated the cowpox matter – the vaccine – with smallpox matter and this essentially produced variolation. Other vaccine material was not reliably derived from cowpox, but from other skin eruptions of cattle. During the earlier days of empirical experimentation in 1758, American Calvinist Jonathan Edwards died from a smallpox inoculation. Some of the earliest statistical and epidemiological studies were performed by James Jurin in 1727 and Daniel Bernoulli in 1766. In 1768, Dr John Fewster reported that variolation induced no reaction in persons who had had cowpox. Edward Jenner was born in Berkeley , England as an orphan. As a young child, Jenner was variolated with the other schoolboys through parish funds, but nearly died due to the seriousness of his infection. Fed purgative medicine and going through the bloodletting process, Jenner was put in one of the variolation stables until he recovered. At the age of 13, he was apprenticed to apothecary Daniel Ludlow and later surgeon George Hardwick in nearby Sodbury . He observed that people who caught cowpox while working with cattle were known not to catch smallpox. Jenner assumed a causal connection but the idea was not taken up at that time. From 1770 to 1772 Jenner received advanced training in London at St Georges Hospital and as the private pupil of John Hunter , then returned to set up practice in Berkeley. Perhaps there was already an informal public understanding of some connection between disease resistance and working with cattle. The "beautiful milkmaid " seems to have been a frequent image in the art and literature of this period. But it is known for certain that in the years following 1770, at least six people in England and Germany (Sevel, Jensen, Jesty 1774, Rendall, Plett 1791) tested successfully the possibility of using the cowpox vaccine as an immunization for smallpox in humans. Jenner sent a paper reporting his observations to the Royal Society in April 1797. It was not submitted formally and there is no mention of it in the Society's records. Jenner had sent the paper informally to Sir Joseph Banks , the Society's president, who asked Everard Home for his views. Reviews of his rejected report, published for the first time in 1999, were skeptical and called for further vaccinations. Additional vaccinations were performed and in 1798 Jenner published his work entitled An Inquiry into the Causes and Effects of the Variolae Vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire and Known by the Name of Cow Pox. It was an analysis of 23 cases including several individuals who had resisted natural exposure after previous cowpox. It is not known how many Jenner vaccinated or challenged by inoculation with smallpox virus; e.g. Case 21 included 'several children and adults'. Crucially all of at least four whom Jenner deliberately inoculated with smallpox virus resisted it. These included the first and last patients in a series of arm-to-arm transfers. He concluded that cowpox inoculation was a safe alternative to smallpox inoculation, but rashly claimed that the protective effect was lifelong. This last proved to be incorrect. Jenner also tried to distinguish between 'True' cowpox which produced the desired result and 'Spurious' cowpox which was ineffective and/or produced severe reaction. Modern research suggests Jenner was trying to distinguish between effects caused by what would now [ when? ] be recognised as non-infectious vaccine, a different virus (e.g. paravaccinia /milker's nodes), or contaminating bacterial pathogens. This caused confusion at the time, but would become important criteria in vaccine development. A further source of confusion was Jenner's belief that fully effective vaccine obtained from cows originated in an equine disease, which he mistakenly referred to as grease . This was criticised at the time but vaccines derived from horsepox were soon introduced and later contributed to the complicated problem of the origin of vaccinia virus , the virus in present-day vaccine. : 165–78 The introduction of the vaccine to the New World took place in Trinity, Newfoundland , in 1798 by Dr. John Clinch , boyhood friend and medical colleague of Jenner. The first smallpox vaccine in the United States was administered in 1799. The physician Valentine Seaman gave his children a smallpox vaccination using a serum acquired from Jenner. By 1800, Jenner's work had been published in all the major European languages and had reached Benjamin Waterhouse in the United States – an indication of rapid spread and deep interest. : 262–67 Despite some concern about the safety of vaccination the mortality using carefully selected vaccine was close to zero, and it was soon in use all over Europe and the United States. In 1804 the Balmis Expedition , an official Spanish mission commanded by Francisco Javier de Balmis , sailed to spread the vaccine throughout the Spanish Empire, first to the Canary Islands and on to Spanish Central America. While his deputy, José Salvany, took vaccine to the west and east coasts of Spanish South America, Balmis sailed to Manila in the Philippines and on to Canton and Macao on the Chinese coast. He returned to Spain in 1806. The vaccine was not carried in the form of flasks, but in the form of 22 orphaned boys, who were 'carriers' of the live cowpox virus. After arrival, "other Spanish governors and doctors used enslaved girls to move the virus between islands, using lymph fluid harvested from them to inoculate their local populations". Napoleon was an early proponent of smallpox vaccination and ordered that army recruits be given the vaccine. Additionally a vaccination program was created for the French Army and his Imperial Guard . In 1811 he had his son, Napoleon II , vaccinated after his birth. By 1815 about half of French children were vaccinated and by the end of the Napoleonic Empire smallpox deaths accounted for 1.8% of deaths, as opposed to the 4.8% of deaths it accounted for at the time of the French Revolution . The first state to introduce compulsory vaccinations was the Principality of Lucca and Piombino on 25 September 1806. On 26 August 1807, Bavaria introduced a similar measure. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816, England in 1867 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate. The question of who first tried cowpox inoculation/vaccination cannot be answered with certainty. Most, but still limited, information is available for Benjamin Jesty , Peter Plett and John Fewster . In 1774 Jesty, a farmer of Yetminster in Dorset , observing that the two milkmaids living with his family were immune to smallpox, inoculated his family with cowpox to protect them from smallpox. He attracted a certain amount of local criticism and ridicule at the time then interest waned. Attention was later drawn to Jesty, and he was brought to London in 1802 by critics jealous of Jenner's prominence at a time when he was applying to Parliament for financial reward. During 1790–92 Peter Plett, a teacher from Holstein , reported limited results of cowpox inoculation to the Medical Faculty of the University of Kiel . However, the Faculty favoured variolation and took no action. John Fewster, a surgeon friend of Jenner's from nearby Thornbury, discussed the possibility of cowpox inoculation at meetings as early as 1765. He may have done some cowpox inoculations in 1796 at about the same time that Jenner vaccinated Phipps. However, Fewster, who had a flourishing variolation practice, may have considered this option but used smallpox instead. He thought vaccination offered no advantage over variolation, but maintained friendly contact with Jenner and certainly made no claim of priority for vaccination when critics attacked Jenner's reputation. It seems clear that the idea of using cowpox instead of smallpox for inoculation was considered, and actually tried in the late 18th century, and not just by the medical profession. Therefore, Jenner was not the first to try cowpox inoculation. However, he was the first to publish his evidence and distribute vaccine freely, provide information on selection of suitable material, and maintain it by arm-to-arm transfer. The authors of the official World Health Organization (WHO) account Smallpox and its Eradication assessing Jenner's role wrote: : 264 Publication of the Inquiry and the subsequent energetic promulgation by Jenner of the idea of vaccination with a virus other than variola virus constituted a watershed in the control of smallpox for which he, more than anyone else deserves the credit. As vaccination spread, some European countries made it compulsory. Concern about its safety led to opposition and then repeal of legislation in some instances. : 236–40 Compulsory infant vaccination was introduced in England by the 1853 Vaccination Act . By 1871, parents could be fined for non-compliance, and then imprisoned for non-payment. : 202–13 This intensified opposition, and the 1898 Vaccination Act introduced a conscience clause. This allowed exemption on production of a certificate of conscientious objection signed by two magistrates. Such certificates were not always easily obtained and a further Act in 1907 allowed exemption by a statutory declaration which could not be refused. Although theoretically still compulsory, the 1907 Act effectively marked the end of compulsory infant vaccination in England. : 233–38 In the United States vaccination was regulated by individual states, the first to impose compulsory vaccination being Massachusetts in 1809. There then followed sequences of compulsion, opposition and repeal in various states. By 1930 Arizona, Utah, North Dakota and Minnesota prohibited compulsory vaccination, 35 states allowed regulation by local authorities, or had no legislation affecting vaccination, whilst in ten states, including Washington, D.C. and Massachusetts, infant vaccination was compulsory. : 292–93 Compulsory infant vaccination was regulated by only allowing access to school for those who had been vaccinated. Those seeking to enforce compulsory vaccination argued that the public good overrode personal freedom, a view supported by the U.S. Supreme Court in Jacobson v. Massachusetts in 1905, a landmark ruling which set a precedent for cases dealing with personal freedom and the public good. Louis T. Wright, an African-American Harvard Medical School graduate (1915), introduced, while serving in the Army during World War I , intradermal, smallpox vaccination for the soldiers. Until the end of the 19th century, vaccination was performed either directly with vaccine produced on the skin of calves or, particularly in England, with vaccine obtained from the calf but then maintained by arm-to-arm transfer; initially in both cases vaccine could be dried on ivory points for short-term storage or transport but increasing use was made of glass capillary tubes for this purpose towards the end of the century. During this period there were no adequate methods for assessing the safety of the vaccine and there were instances of contaminated vaccine transmitting infections such as erysipelas, tetanus, septicaemia and tuberculosis. In the case of arm-to-arm transfer there was also the risk of transmitting syphilis. Although this did occur occasionally, estimated as 750 cases in 100 million vaccinations, : 122 some critics of vaccination e.g. Charles Creighton believed that uncontaminated vaccine itself was a cause of syphilis. Smallpox vaccine was the only vaccine available during this period, and so the determined opposition to it initiated a number of vaccine controversies that spread to other vaccines and into the 21st century. [ citation needed ] Sydney Arthur Monckton Copeman , an English Government bacteriologist interested in smallpox vaccine investigated the effects on the bacteria in it of various treatments, including glycerine . Glycerine was sometimes used simply as a diluent by some continental vaccine producers. However, Copeman found that vaccine suspended in 50% chemically pure glycerine and stored under controlled conditions contained very few "extraneous" bacteria and produced satisfactory vaccinations. He later reported that glycerine killed the causative organisms of erysipelas and tuberculosis when they were added to the vaccine in "considerable quantity", and that his method was widely used on the continent. In 1896, Copeman was asked to supply "extra good calf vaccine" to vaccinate the future Edward VIII . Vaccine produced by Copeman's method was the only type issued free to public vaccinators by the English Government Vaccine Establishment from 1899. At the same time the 1898 Vaccination Act banned arm-to-arm vaccination, thus preventing transmission of syphilis by this vaccine. However, private practitioners had to purchase vaccine from commercial producers. Although proper use of glycerine reduced bacterial contamination considerably the crude starting material, scraped from the skin of infected calves, was always heavily contaminated and no vaccine was totally free from bacteria. A survey of vaccines in 1900 found wide variations in bacterial contamination. Vaccine issued by the Government Vaccine Establishment contained 5,000 bacteria per gram, while commercial vaccines contained up to 100,000 per gram. The level of bacterial contamination remained unregulated until the Therapeutic Substances Act, 1925 set an upper limit of 5,000 per gram, and rejected any batch of vaccine found to contain the causative organisms of erysipelas or wound infections. Unfortunately glycerolated vaccine soon lost its potency at ambient temperatures which restricted its use in tropical climates. However, it remained in use into the 1970s where a satisfactory cold chain was available. Animals continued to be widely used by vaccine producers during the smallpox eradication campaign. A WHO survey of 59 producers, some of whom used more than one source of vaccine, found that 39 used calves, 12 used sheep and 6 used water buffalo, whilst only 3 made vaccine in cell culture and 3 in embryonated hens' eggs. : 543–45 English vaccine was occasionally made in sheep during World War I but from 1946 only sheep were used. In the late 1940s and early 1950s, Leslie Collier , an English microbiologist working at the Lister Institute of Preventive Medicine , developed a method for producing a heat-stable freeze-dried vaccine in powdered form. Collier added 0.5% phenol to the vaccine to reduce the number of bacterial contaminants but the key stage was to add 5% peptone to the liquid vaccine before it was dispensed into ampoules. This protected the virus during the freeze drying process. After drying the ampoules were sealed under nitrogen. Like other vaccines, once reconstituted it became ineffective after 1–2 days at ambient temperatures. However, the dried vaccine was 100% effective when reconstituted after 6 months storage at 37 °C (99 °F) allowing it to be transported to, and stored in, remote tropical areas. Collier's method was increasingly used and, with minor modifications, became the standard for vaccine production adopted by the WHO Smallpox Eradication Unit when it initiated its global smallpox eradication campaign in 1967, at which time 23 of 59 manufacturers were using the Lister strain. : 545, 550 In a letter about landmarks in the history of smallpox vaccine, written to and quoted from by Derrick Baxby , Donald Henderson , chief of the Smallpox Eradication Unit from 1967 to 1977 wrote; "Copeman and Collier made an enormous contribution for which neither, in my opinion ever received due credit". Smallpox vaccine was inoculated by scratches into the superficial layers of the skin, with a wide variety of instruments used to achieve this. They ranged from simple needles to multi-pointed and multi-bladed spring-operated instruments specifically designed for the purpose. A major contribution to smallpox vaccination was made in the 1960s by Benjamin Rubin , an American microbiologist working for Wyeth Laboratories. Based on initial tests with textile needles with the eyes cut off transversely half-way he developed the bifurcated needle . This was a sharpened two-prong fork designed to hold one dose of reconstituted freeze-dried vaccine by capillarity. Easy to use with minimum training, cheap to produce ($5 per 1000), using one quarter as much vaccine as other methods, and repeatedly re-usable after flame sterilization, it was used globally in the WHO Smallpox Eradication Campaign from 1968. : 472–73, 568–72 Rubin estimated that it was used to do 200 million vaccinations per year during the last years of the campaign. Those closely involved in the campaign were awarded the "Order of the Bifurcated Needle". This, a personal initiative by Donald Henderson, was a lapel badge, designed and made by his daughter, formed from the needle shaped to form an "O". This represented "Target Zero", the objective of the campaign. Smallpox was eradicated by a massive international search for outbreaks, backed up with a vaccination program, starting in 1967. It was organised and co-ordinated by a World Health Organization (WHO) unit, set up and headed by Donald Henderson . The last case in the Americas occurred in 1971 (Brazil), south-east Asia (Indonesia) in 1972, and on the Indian subcontinent in 1975 (Bangladesh). After two years of intensive searches, what proved to be the last endemic case anywhere in the world occurred in Somalia, in October 1977. : 526–37 A Global Commission for the Certification of Smallpox Eradication chaired by Frank Fenner examined the evidence from, and visited where necessary, all countries where smallpox had been endemic. In December 1979 they concluded that smallpox had been eradicated; a conclusion endorsed by the WHO General Assembly in May 1980. : 1261–62 However, even as the disease was being eradicated there still remained stocks of smallpox virus in many laboratories. Accelerated by two cases of smallpox in 1978, one fatal ( Janet Parker ), caused by an accidental and unexplained containment breach at a laboratory at the University of Birmingham Medical School , the WHO ensured that known stocks of smallpox virus were either destroyed or moved to safer laboratories. By 1979, only four laboratories were known to have smallpox virus. All English stocks held at St Mary's Hospital, London were transferred to more secure facilities at Porton Down and then to the U.S. at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia in 1982, and all South African stocks were destroyed in 1983. By 1984, the only known stocks were kept at the CDC in the U.S. and the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia . : 1273–76 These states report that their repositories are for possible anti- bioweaponry research and insurance if some obscure reservoir of natural smallpox is discovered in the future. [ citation needed ] Among more than 270,000 US military service members vaccinated with smallpox vaccine between December 2002, and March 2003, eighteen cases of probable myopericarditis were reported (all in first-time vaccinees who received the NYCBOH strain of vaccinia virus), an incidence of 7.8 per 100,000 during the 30 days they were observed. All cases were in young, otherwise healthy adult white men and all survived. In 2002, the United States government started a program to vaccinate 500,000 volunteer health care professionals throughout the country. Recipients were healthcare workers who would be first-line responders in the event of a bioterrorist attack. Many healthcare workers refused or did not pursue vaccination, worried about vaccine side effects, compensation and liability. Most did not see an immediate need for the vaccine. Some healthcare systems refused to participate, worried about becoming a destination for smallpox patients in the event of an epidemic. Fewer than 40,000 actually received the vaccine. On 21 April 2022, Public Services and Procurement Canada published a notice of tender seeking to stockpile 500,000 doses of smallpox vaccine in order to protect against a potential accidental or intentional release of the eradicated virus. On 6 May, the contract was awarded to Bavarian Nordic for their Imvamune vaccine. These were deployed by the Public Health Agency of Canada for targeted vaccination in response to the 2022 monkeypox outbreak . The mortality of the severe form of smallpox – variola major – was very high without vaccination, up to 35% in some outbreaks. A method of inducing immunity known as inoculation, insufflation or " variolation " was practiced before the development of a modern vaccine and likely occurred in Africa and China well before the practice arrived in Europe. It may also have occurred in India, but this is disputed; other investigators contend the ancient Sanskrit medical texts of India do not describe these techniques. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Douzhen xinfa (痘疹心法) published in 1549. Inoculation for smallpox does not appear to have been widespread in China until the reign era of the Longqing Emperor (r. 1567–1572) during the Ming Dynasty . In China, powdered smallpox scabs were blown up the noses of the healthy. The patients would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers . According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia . Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". Variolation was also practiced throughout the latter half of the 17th century by physicians in Turkey , Persia , and Africa. In 1714 and 1716, two reports of the Ottoman Empire Turkish method of inoculation were made to the Royal Society in England, by Emmanuel Timoni, a doctor affiliated with the British Embassy in Constantinople , and Giacomo Pylarini . Source material tells us on Lady Mary Wortley Montagu; "When Lady Mary was in the Ottoman Empire, she discovered the local practice of inoculation against smallpox called variolation." In 1718 she had her son, aged five variolated. He recovered quickly. She returned to London and had her daughter variolated in 1721 by Charles Maitland , during an epidemic of smallpox. This encouraged the British Royal Family to take an interest and a trial of variolation was carried out on prisoners in Newgate Prison . This was successful and in 1722 Caroline of Ansbach , the Princess of Wales, allowed Maitland to vaccinate her children. The success of these variolations assured the British people that the procedure was safe. ...scarred the wrists, legs, and forehead of the patient, placed a fresh and kindly pock in each incision and bound it there for eight or ten days, after this time the patient was credibly informed. The patient would then develop a mild case [of smallpox], recover, and thereafter be immune. —Dr. Peter Kennedy Stimulated by a severe epidemic, variolation was first employed in North America in 1721. The procedure had been known in Boston since 1706, when preacher Cotton Mather learned it from Onesimus , a man he held as a slave, who – like many of his peers – had been inoculated in Africa before they were kidnapped. This practice was widely criticized at first. However, a limited trial showed six deaths occurred out of 244 who were variolated (2.5%), while 844 out of 5980 died of natural disease (14%), and the process was widely adopted throughout the colonies. The inoculation technique was documented as having a mortality rate of only one in a thousand. Two years after Kennedy's description appeared, March 1718, Dr. Charles Maitland successfully inoculated the five-year-old son of the British ambassador to the Turkish court under orders from the ambassador's wife Lady Mary Wortley Montagu , who four years later introduced the practice to England. An account from letter by Lady Mary Wortley Montagu to Sarah Chiswell, dated 1 April 1717, from the Turkish Embassy describes this treatment: The small-pox so fatal and so general amongst us is here entirely harmless by the invention of ingrafting (which is the term they give it). There is a set of old women who make it their business to perform the operation. Every autumn in the month of September, when the great heat is abated, people send to one another to know if any of their family has a mind to have the small-pox. They make parties for this purpose, and when they are met (commonly fifteen or sixteen together) the old woman comes with a nutshell full of the matter of the best sort of small-pox and asks what veins you please to have opened. She immediately rips open that you offer to her with a large needle (which gives you no more pain than a common scratch) and puts into the vein as much venom as can lye upon the head of her needle, and after binds up the little wound with a hollow bit of shell, and in this manner opens four or five veins. … The children or young patients play together all the rest of the day and are in perfect health till the eighth. Then the fever begins to seize them and they keep their beds two days, very seldom three. They have very rarely above twenty or thirty in their faces, which never mark, and in eight days time they are as well as before the illness. … There is no example of any one that has died in it, and you may believe I am very well satisfied of the safety of the experiment since I intend to try it on my dear little son. I am patriot enough to take pains to bring this useful invention into fashion in England, and I should not fail to write to some of our doctors very particularly about it if I knew any one of them that I thought had virtue enough to destroy such a considerable branch of their revenue for the good of mankind, but that distemper is too beneficial to them not to expose to all their resentment the hardy wight that should undertake to put an end to it. Perhaps if I live to return I may, however, have courage to war with them. In the early empirical days of vaccination, before Louis Pasteur 's work on establishing the germ theory and Joseph Lister 's on antisepsis and asepsis, there was considerable cross-infection. William Woodville , one of the early vaccinators and director of the London Smallpox Hospital is thought to have contaminated the cowpox matter – the vaccine – with smallpox matter and this essentially produced variolation. Other vaccine material was not reliably derived from cowpox, but from other skin eruptions of cattle. During the earlier days of empirical experimentation in 1758, American Calvinist Jonathan Edwards died from a smallpox inoculation. Some of the earliest statistical and epidemiological studies were performed by James Jurin in 1727 and Daniel Bernoulli in 1766. In 1768, Dr John Fewster reported that variolation induced no reaction in persons who had had cowpox. Edward Jenner was born in Berkeley , England as an orphan. As a young child, Jenner was variolated with the other schoolboys through parish funds, but nearly died due to the seriousness of his infection. Fed purgative medicine and going through the bloodletting process, Jenner was put in one of the variolation stables until he recovered. At the age of 13, he was apprenticed to apothecary Daniel Ludlow and later surgeon George Hardwick in nearby Sodbury . He observed that people who caught cowpox while working with cattle were known not to catch smallpox. Jenner assumed a causal connection but the idea was not taken up at that time. From 1770 to 1772 Jenner received advanced training in London at St Georges Hospital and as the private pupil of John Hunter , then returned to set up practice in Berkeley. Perhaps there was already an informal public understanding of some connection between disease resistance and working with cattle. The "beautiful milkmaid " seems to have been a frequent image in the art and literature of this period. But it is known for certain that in the years following 1770, at least six people in England and Germany (Sevel, Jensen, Jesty 1774, Rendall, Plett 1791) tested successfully the possibility of using the cowpox vaccine as an immunization for smallpox in humans. Jenner sent a paper reporting his observations to the Royal Society in April 1797. It was not submitted formally and there is no mention of it in the Society's records. Jenner had sent the paper informally to Sir Joseph Banks , the Society's president, who asked Everard Home for his views. Reviews of his rejected report, published for the first time in 1999, were skeptical and called for further vaccinations. Additional vaccinations were performed and in 1798 Jenner published his work entitled An Inquiry into the Causes and Effects of the Variolae Vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire and Known by the Name of Cow Pox. It was an analysis of 23 cases including several individuals who had resisted natural exposure after previous cowpox. It is not known how many Jenner vaccinated or challenged by inoculation with smallpox virus; e.g. Case 21 included 'several children and adults'. Crucially all of at least four whom Jenner deliberately inoculated with smallpox virus resisted it. These included the first and last patients in a series of arm-to-arm transfers. He concluded that cowpox inoculation was a safe alternative to smallpox inoculation, but rashly claimed that the protective effect was lifelong. This last proved to be incorrect. Jenner also tried to distinguish between 'True' cowpox which produced the desired result and 'Spurious' cowpox which was ineffective and/or produced severe reaction. Modern research suggests Jenner was trying to distinguish between effects caused by what would now [ when? ] be recognised as non-infectious vaccine, a different virus (e.g. paravaccinia /milker's nodes), or contaminating bacterial pathogens. This caused confusion at the time, but would become important criteria in vaccine development. A further source of confusion was Jenner's belief that fully effective vaccine obtained from cows originated in an equine disease, which he mistakenly referred to as grease . This was criticised at the time but vaccines derived from horsepox were soon introduced and later contributed to the complicated problem of the origin of vaccinia virus , the virus in present-day vaccine. : 165–78 The introduction of the vaccine to the New World took place in Trinity, Newfoundland , in 1798 by Dr. John Clinch , boyhood friend and medical colleague of Jenner. The first smallpox vaccine in the United States was administered in 1799. The physician Valentine Seaman gave his children a smallpox vaccination using a serum acquired from Jenner. By 1800, Jenner's work had been published in all the major European languages and had reached Benjamin Waterhouse in the United States – an indication of rapid spread and deep interest. : 262–67 Despite some concern about the safety of vaccination the mortality using carefully selected vaccine was close to zero, and it was soon in use all over Europe and the United States. In 1804 the Balmis Expedition , an official Spanish mission commanded by Francisco Javier de Balmis , sailed to spread the vaccine throughout the Spanish Empire, first to the Canary Islands and on to Spanish Central America. While his deputy, José Salvany, took vaccine to the west and east coasts of Spanish South America, Balmis sailed to Manila in the Philippines and on to Canton and Macao on the Chinese coast. He returned to Spain in 1806. The vaccine was not carried in the form of flasks, but in the form of 22 orphaned boys, who were 'carriers' of the live cowpox virus. After arrival, "other Spanish governors and doctors used enslaved girls to move the virus between islands, using lymph fluid harvested from them to inoculate their local populations". Napoleon was an early proponent of smallpox vaccination and ordered that army recruits be given the vaccine. Additionally a vaccination program was created for the French Army and his Imperial Guard . In 1811 he had his son, Napoleon II , vaccinated after his birth. By 1815 about half of French children were vaccinated and by the end of the Napoleonic Empire smallpox deaths accounted for 1.8% of deaths, as opposed to the 4.8% of deaths it accounted for at the time of the French Revolution . The first state to introduce compulsory vaccinations was the Principality of Lucca and Piombino on 25 September 1806. On 26 August 1807, Bavaria introduced a similar measure. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816, England in 1867 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate. The question of who first tried cowpox inoculation/vaccination cannot be answered with certainty. Most, but still limited, information is available for Benjamin Jesty , Peter Plett and John Fewster . In 1774 Jesty, a farmer of Yetminster in Dorset , observing that the two milkmaids living with his family were immune to smallpox, inoculated his family with cowpox to protect them from smallpox. He attracted a certain amount of local criticism and ridicule at the time then interest waned. Attention was later drawn to Jesty, and he was brought to London in 1802 by critics jealous of Jenner's prominence at a time when he was applying to Parliament for financial reward. During 1790–92 Peter Plett, a teacher from Holstein , reported limited results of cowpox inoculation to the Medical Faculty of the University of Kiel . However, the Faculty favoured variolation and took no action. John Fewster, a surgeon friend of Jenner's from nearby Thornbury, discussed the possibility of cowpox inoculation at meetings as early as 1765. He may have done some cowpox inoculations in 1796 at about the same time that Jenner vaccinated Phipps. However, Fewster, who had a flourishing variolation practice, may have considered this option but used smallpox instead. He thought vaccination offered no advantage over variolation, but maintained friendly contact with Jenner and certainly made no claim of priority for vaccination when critics attacked Jenner's reputation. It seems clear that the idea of using cowpox instead of smallpox for inoculation was considered, and actually tried in the late 18th century, and not just by the medical profession. Therefore, Jenner was not the first to try cowpox inoculation. However, he was the first to publish his evidence and distribute vaccine freely, provide information on selection of suitable material, and maintain it by arm-to-arm transfer. The authors of the official World Health Organization (WHO) account Smallpox and its Eradication assessing Jenner's role wrote: : 264 Publication of the Inquiry and the subsequent energetic promulgation by Jenner of the idea of vaccination with a virus other than variola virus constituted a watershed in the control of smallpox for which he, more than anyone else deserves the credit. As vaccination spread, some European countries made it compulsory. Concern about its safety led to opposition and then repeal of legislation in some instances. : 236–40 Compulsory infant vaccination was introduced in England by the 1853 Vaccination Act . By 1871, parents could be fined for non-compliance, and then imprisoned for non-payment. : 202–13 This intensified opposition, and the 1898 Vaccination Act introduced a conscience clause. This allowed exemption on production of a certificate of conscientious objection signed by two magistrates. Such certificates were not always easily obtained and a further Act in 1907 allowed exemption by a statutory declaration which could not be refused. Although theoretically still compulsory, the 1907 Act effectively marked the end of compulsory infant vaccination in England. : 233–38 In the United States vaccination was regulated by individual states, the first to impose compulsory vaccination being Massachusetts in 1809. There then followed sequences of compulsion, opposition and repeal in various states. By 1930 Arizona, Utah, North Dakota and Minnesota prohibited compulsory vaccination, 35 states allowed regulation by local authorities, or had no legislation affecting vaccination, whilst in ten states, including Washington, D.C. and Massachusetts, infant vaccination was compulsory. : 292–93 Compulsory infant vaccination was regulated by only allowing access to school for those who had been vaccinated. Those seeking to enforce compulsory vaccination argued that the public good overrode personal freedom, a view supported by the U.S. Supreme Court in Jacobson v. Massachusetts in 1905, a landmark ruling which set a precedent for cases dealing with personal freedom and the public good. Louis T. Wright, an African-American Harvard Medical School graduate (1915), introduced, while serving in the Army during World War I , intradermal, smallpox vaccination for the soldiers. Until the end of the 19th century, vaccination was performed either directly with vaccine produced on the skin of calves or, particularly in England, with vaccine obtained from the calf but then maintained by arm-to-arm transfer; initially in both cases vaccine could be dried on ivory points for short-term storage or transport but increasing use was made of glass capillary tubes for this purpose towards the end of the century. During this period there were no adequate methods for assessing the safety of the vaccine and there were instances of contaminated vaccine transmitting infections such as erysipelas, tetanus, septicaemia and tuberculosis. In the case of arm-to-arm transfer there was also the risk of transmitting syphilis. Although this did occur occasionally, estimated as 750 cases in 100 million vaccinations, : 122 some critics of vaccination e.g. Charles Creighton believed that uncontaminated vaccine itself was a cause of syphilis. Smallpox vaccine was the only vaccine available during this period, and so the determined opposition to it initiated a number of vaccine controversies that spread to other vaccines and into the 21st century. [ citation needed ] Sydney Arthur Monckton Copeman , an English Government bacteriologist interested in smallpox vaccine investigated the effects on the bacteria in it of various treatments, including glycerine . Glycerine was sometimes used simply as a diluent by some continental vaccine producers. However, Copeman found that vaccine suspended in 50% chemically pure glycerine and stored under controlled conditions contained very few "extraneous" bacteria and produced satisfactory vaccinations. He later reported that glycerine killed the causative organisms of erysipelas and tuberculosis when they were added to the vaccine in "considerable quantity", and that his method was widely used on the continent. In 1896, Copeman was asked to supply "extra good calf vaccine" to vaccinate the future Edward VIII . Vaccine produced by Copeman's method was the only type issued free to public vaccinators by the English Government Vaccine Establishment from 1899. At the same time the 1898 Vaccination Act banned arm-to-arm vaccination, thus preventing transmission of syphilis by this vaccine. However, private practitioners had to purchase vaccine from commercial producers. Although proper use of glycerine reduced bacterial contamination considerably the crude starting material, scraped from the skin of infected calves, was always heavily contaminated and no vaccine was totally free from bacteria. A survey of vaccines in 1900 found wide variations in bacterial contamination. Vaccine issued by the Government Vaccine Establishment contained 5,000 bacteria per gram, while commercial vaccines contained up to 100,000 per gram. The level of bacterial contamination remained unregulated until the Therapeutic Substances Act, 1925 set an upper limit of 5,000 per gram, and rejected any batch of vaccine found to contain the causative organisms of erysipelas or wound infections. Unfortunately glycerolated vaccine soon lost its potency at ambient temperatures which restricted its use in tropical climates. However, it remained in use into the 1970s where a satisfactory cold chain was available. Animals continued to be widely used by vaccine producers during the smallpox eradication campaign. A WHO survey of 59 producers, some of whom used more than one source of vaccine, found that 39 used calves, 12 used sheep and 6 used water buffalo, whilst only 3 made vaccine in cell culture and 3 in embryonated hens' eggs. : 543–45 English vaccine was occasionally made in sheep during World War I but from 1946 only sheep were used. In the late 1940s and early 1950s, Leslie Collier , an English microbiologist working at the Lister Institute of Preventive Medicine , developed a method for producing a heat-stable freeze-dried vaccine in powdered form. Collier added 0.5% phenol to the vaccine to reduce the number of bacterial contaminants but the key stage was to add 5% peptone to the liquid vaccine before it was dispensed into ampoules. This protected the virus during the freeze drying process. After drying the ampoules were sealed under nitrogen. Like other vaccines, once reconstituted it became ineffective after 1–2 days at ambient temperatures. However, the dried vaccine was 100% effective when reconstituted after 6 months storage at 37 °C (99 °F) allowing it to be transported to, and stored in, remote tropical areas. Collier's method was increasingly used and, with minor modifications, became the standard for vaccine production adopted by the WHO Smallpox Eradication Unit when it initiated its global smallpox eradication campaign in 1967, at which time 23 of 59 manufacturers were using the Lister strain. : 545, 550 In a letter about landmarks in the history of smallpox vaccine, written to and quoted from by Derrick Baxby , Donald Henderson , chief of the Smallpox Eradication Unit from 1967 to 1977 wrote; "Copeman and Collier made an enormous contribution for which neither, in my opinion ever received due credit". Smallpox vaccine was inoculated by scratches into the superficial layers of the skin, with a wide variety of instruments used to achieve this. They ranged from simple needles to multi-pointed and multi-bladed spring-operated instruments specifically designed for the purpose. A major contribution to smallpox vaccination was made in the 1960s by Benjamin Rubin , an American microbiologist working for Wyeth Laboratories. Based on initial tests with textile needles with the eyes cut off transversely half-way he developed the bifurcated needle . This was a sharpened two-prong fork designed to hold one dose of reconstituted freeze-dried vaccine by capillarity. Easy to use with minimum training, cheap to produce ($5 per 1000), using one quarter as much vaccine as other methods, and repeatedly re-usable after flame sterilization, it was used globally in the WHO Smallpox Eradication Campaign from 1968. : 472–73, 568–72 Rubin estimated that it was used to do 200 million vaccinations per year during the last years of the campaign. Those closely involved in the campaign were awarded the "Order of the Bifurcated Needle". This, a personal initiative by Donald Henderson, was a lapel badge, designed and made by his daughter, formed from the needle shaped to form an "O". This represented "Target Zero", the objective of the campaign. Smallpox was eradicated by a massive international search for outbreaks, backed up with a vaccination program, starting in 1967. It was organised and co-ordinated by a World Health Organization (WHO) unit, set up and headed by Donald Henderson . The last case in the Americas occurred in 1971 (Brazil), south-east Asia (Indonesia) in 1972, and on the Indian subcontinent in 1975 (Bangladesh). After two years of intensive searches, what proved to be the last endemic case anywhere in the world occurred in Somalia, in October 1977. : 526–37 A Global Commission for the Certification of Smallpox Eradication chaired by Frank Fenner examined the evidence from, and visited where necessary, all countries where smallpox had been endemic. In December 1979 they concluded that smallpox had been eradicated; a conclusion endorsed by the WHO General Assembly in May 1980. : 1261–62 However, even as the disease was being eradicated there still remained stocks of smallpox virus in many laboratories. Accelerated by two cases of smallpox in 1978, one fatal ( Janet Parker ), caused by an accidental and unexplained containment breach at a laboratory at the University of Birmingham Medical School , the WHO ensured that known stocks of smallpox virus were either destroyed or moved to safer laboratories. By 1979, only four laboratories were known to have smallpox virus. All English stocks held at St Mary's Hospital, London were transferred to more secure facilities at Porton Down and then to the U.S. at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia in 1982, and all South African stocks were destroyed in 1983. By 1984, the only known stocks were kept at the CDC in the U.S. and the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia . : 1273–76 These states report that their repositories are for possible anti- bioweaponry research and insurance if some obscure reservoir of natural smallpox is discovered in the future. [ citation needed ] Among more than 270,000 US military service members vaccinated with smallpox vaccine between December 2002, and March 2003, eighteen cases of probable myopericarditis were reported (all in first-time vaccinees who received the NYCBOH strain of vaccinia virus), an incidence of 7.8 per 100,000 during the 30 days they were observed. All cases were in young, otherwise healthy adult white men and all survived. In 2002, the United States government started a program to vaccinate 500,000 volunteer health care professionals throughout the country. Recipients were healthcare workers who would be first-line responders in the event of a bioterrorist attack. Many healthcare workers refused or did not pursue vaccination, worried about vaccine side effects, compensation and liability. Most did not see an immediate need for the vaccine. Some healthcare systems refused to participate, worried about becoming a destination for smallpox patients in the event of an epidemic. Fewer than 40,000 actually received the vaccine. On 21 April 2022, Public Services and Procurement Canada published a notice of tender seeking to stockpile 500,000 doses of smallpox vaccine in order to protect against a potential accidental or intentional release of the eradicated virus. On 6 May, the contract was awarded to Bavarian Nordic for their Imvamune vaccine. These were deployed by the Public Health Agency of Canada for targeted vaccination in response to the 2022 monkeypox outbreak . The origin of the modern smallpox vaccine has long been unclear, but horsepox was identified in the 2010s as the most likely ancestor. : 9 Edward Jenner had obtained his vaccine from a cow, so he named the virus vaccinia , after the Latin word for cow. Jenner believed that both cowpox and smallpox were viruses that originated in the horse and passed to the cow, : 52–53 and some doctors followed his reasoning by inoculating their patients directly with horsepox . The situation was further muddied when Louis Pasteur developed techniques for creating vaccines in the laboratory in the late 19th century. As medical researchers subjected viruses to serial passage , inadequate recordkeeping resulted in the creation of laboratory strains with unclear origins. : 4 By the late 19th century, it was unknown whether the vaccine originated from cowpox, horsepox, or an attenuated strain of smallpox. In 1939, Allan Watt Downie showed that the vaccinia virus was serologically distinct from the "spontaneous" cowpox virus. This work established vaccinia and cowpox as two separate viral species. The term vaccinia now refers only to the smallpox vaccine, while cowpox no longer has a Latin name. The development of whole genome sequencing in the 1990s made it possible to compare orthopoxvirus genomes and identify their relationships with each other. The horsepox virus was sequenced in 2006 and found to be most closely related to vaccinia . In a phylogenetic tree of the orthopoxviruses , horsepox forms a clade with vaccinia strains, and cowpox strains form a different clade. Horsepox is extinct in the wild, and the only known sample was collected in 1976. Because the sample was collected at the end of the smallpox eradication campaign, scientists considered the possibility that horsepox is a strain of vaccinia that had escaped into the wild. However, as more smallpox vaccines were sequenced, older vaccines were found to be more similar to horsepox than modern vaccinia strains. A smallpox vaccine manufactured by Mulford in 1902 is 99.7% similar to horsepox, closer than any previously known strain of vaccinia . Modern Brazilian vaccines with a documented introduction date of 1887, made from material collected in an 1866 outbreak of "cowpox" in France, are more similar to horsepox than other strains of vaccinia . Five smallpox vaccines manufactured in the United States in 1859–1873 are most similar to each other and horsepox, as well as the 1902 Mulford vaccine. One of the 1859–1873 vaccines was identified as a novel strain of horsepox, containing a complete gene from the 1976 horsepox sample that has deletions in vaccinia . The word "vaccine" is derived from Variolae vaccinae (i.e. smallpox of the cow), the term devised by Jenner to denote cowpox and used in the long title of his An enquiry into the causes and effects of Variolae vaccinae, known by the name of cow pox . Vaccination , the term which soon replaced cowpox inoculation and vaccine inoculation , was first used in print by Jenner's friend, Richard Dunning in 1800. Initially, the terms vaccine / vaccination referred only to smallpox, but in 1881 Louis Pasteur proposed at the 7th International Congress of Medicine that to honour Jenner the terms be widened to cover the new protective inoculations being introduced. According to some sources the term was first introduced by Jenner's friend Richard Dunning in 1800.

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David Kelly (weapons expert)

David Christopher Kelly CMG (14 May 1944 – 17 July 2003) was a Welsh scientist and authority on biological warfare (BW). A former head of the Defence Microbiology Division working at Porton Down , Kelly was part of a joint US-UK team that inspected civilian biotechnology facilities in Russia in the early 1990s and concluded they were running a covert and illegal BW programme. He was appointed to the United Nations Special Commission (UNSCOM) in 1991 as one of its chief weapons inspectors in Iraq and led ten of the organisation's missions between May 1991 and December 1998. He also worked with UNSCOM's successor, the United Nations Monitoring, Verification and Inspection Commission (UNMOVIC) and led several of their missions into Iraq. During his time with UNMOVIC he was key in uncovering the anthrax production programme at the Salman Pak facility , and a BW programme run at Al Hakum . A year after the publication of the 2002 dossier on Iraqi weapons of mass destruction —which stated that some of Iraq's chemical and biological weapons were deployable within 45 minutes—Kelly had an off-the-record conversation with Andrew Gilligan , a BBC journalist, about the claim. When Gilligan reported this on BBC Radio 4 's Today programme, he stated that the "45 minutes" claim was included at the insistence of Alastair Campbell , the Downing Street Director of Communications ; Kelly denied that he said Campbell had forced in the reference. The government complained to the BBC about the claim, but they refused to recant on it; political tumult between Downing Street and the BBC developed. Kelly informed his line managers in the Ministry of Defence that he might have been the source, but did not think he was the only one, as Gilligan had reported points he had not mentioned. Kelly's name became known to the media, and he was called to appear on 15 July before the parliamentary Intelligence and Security and Foreign Affairs select committees . Two days later Kelly was found dead near his home, having killed himself. Following Kelly's suicide Tony Blair , the Prime Minister , set up a government inquiry under Lord Hutton , a former Lord Chief Justice of Northern Ireland . The inquiry concluded that Kelly had killed himself. Hutton also stated that no other parties were involved in Kelly's death. There was continued debate over the manner of Kelly's death, and the case was reviewed between 2010 and 2011 by Dominic Grieve , the Attorney General ; he concluded that there was "overwhelmingly strong" evidence that Kelly had killed himself. The post-mortem and toxicology reports were released in 2010; both documents supported the conclusion of the Hutton Inquiry. The manner of Kelly's death has been the subject of several documentaries and has been fictionalised on television, on stage and in print. He was appointed as Companion of the Order of St Michael and St George (CMG) in 1994 and might well have been under consideration for a knighthood in May 2003, according to Hutton. His work in Iraq earned him a nomination for the Nobel Peace Prize .David Christopher Kelly was born in Llwynypia , Glamorgan , South Wales , on 14 May 1944. His parents were Thomas John Kelly and Margaret, née Williams; Thomas was a schoolteacher who was serving in the Royal Air Force Volunteer Reserve as a signals officer during the Second World War . Thomas and Margaret divorced in 1951; she took their young son and moved in with her parents in Pontypridd . From the age of eleven he attended the local grammar school . He was a keen sportsman and musician at school, and represented Wales in the youth cross-country running team; he played double bass in the National Youth Orchestra of Wales and played the saxophone to a high standard. In 1963 Kelly was admitted to the University of Leeds to study chemistry, botany and biophysics . His mother died two years later from an overdose of prescription barbiturates . Although the coroner's inquest gave an open verdict , Kelly believed she had killed herself. As a result of the death, Kelly suffered from insomnia and was prescribed sleeping pills; he was also given an extra year to complete his degree. [lower-alpha 1] [lower-alpha 2] He graduated in 1967 with a BSc in bacteriology ; he then obtained an MSc in virology from the University of Birmingham . Between his first and second degrees, on 15 July 1967, he married Janice, née Vawdrey, who was studying at Bingley Teacher Training College. [lower-alpha 3] Kelly joined the Insect Pathology Unit at the University of Oxford in 1968, while a student of Linacre College . In 1971 he received his doctorate in microbiology ; his thesis was "The Replication of Some Iridescent Viruses in Cell Cultures". In the early 1970s he undertook postdoctoral research at the University of Warwick , before moving back to Oxford in the mid-1970s to work at the Institute of Virology and Environmental Microbiology . [lower-alpha 4] There he carried out virology research into pests such as Spodoptera and Aedes . He rose to the position of Chief Scientific Officer; much of his work was in the field of insect viruses. In 1984 Kelly joined the Ministry of Defence (MoD) as the head of the Defence Microbiology Division working at Porton Down , Wiltshire . [lower-alpha 5] The department had only a small number of microbiologists when he arrived, and most of their work involved the decontamination of Gruinard Island , which had been used during the Second World War for experiments with weaponised anthrax . He increased the scope of his department, obtaining additional funding to undertake research into biodefence . Because of the work undertaken by Kelly and his team, the UK were able to deploy a biodefence capability during the 1990–1991 Gulf War . In 1989 Vladimir Pasechnik , the senior Soviet biologist and bioweapons developer, defected to the UK and provided intelligence about the clandestine biological warfare (BW) programme, Biopreparat . The programme was in contravention of the 1972 Biological Weapons Convention which banned the production of chemical and biological weapons. [lower-alpha 6] Pasechnik was debriefed by the Defence Intelligence Staff (DIS), who requested technical assistance to process the information on chemical and biological matters; Kelly was seconded to the DIS to assist with his colleagues Brian Jones and Christopher Davis. They debriefed Pasechnik over a period of three years. Kelly undertook several visits to Russia between 1991 and 1994 as the co-lead of a team from the UK and US which inspected civilian biotechnology facilities in Russia. One of the restrictions placed on the inspectors was that visits could only be to non-military installations, so, for the first visit in January 1991, the team visited the Institute of Engineering Immunology, in Lyubuchany; the State Research Centre for Applied Microbiology in Obolensk ; the Vector State Research Center of Virology and Biotechnology in Koltsovo ; and the Institute of Ultrapure Preparations, in Leningrad (now Saint Petersburg). The Russians obstructed the team and tried to stop inspection of key areas of the facilities; they also lied about the use to which parts of the installations were put. On one visit to the Vector facility, Kelly had a conversation with a laboratory assistant—one who was too low grade to have been fully briefed by the KGB . Kelly asked the assistant about the work he was doing, and was surprised when the man said he was involved in testing smallpox . Kelly questioned Lev Sandakchiev , the head of Vector, about the use of smallpox, but received no answers. Kelly described the questioning sessions as "a very tense moment". In a 2002 review of the verification process, Kelly wrote: The visits did not go without incident. At Obolensk, access to parts of the main research facility—notably the dynamic aerosol test chambers and the plague research laboratories—was denied on the spurious grounds of quarantine requirements. Skirmishes occurred over access to an explosive aerosol chamber because the officials knew that closer examination would reveal damning evidence of offensive BW activities. At Koltsova access was again difficult and problematic. The most serious incident was when senior officials contradicted an admission by technical staff that research on smallpox was being conducted there. The officials were unable to properly account for the presence of smallpox and for the research being undertaken in a dynamic aerosol test chamber on orthopoxvirus, which was capable of explosive dispersal. At the Institute of Ultrapure Preparations in Leningrad (Pasechnik's former workplace), dynamic and explosive test chambers were passed off as being for agricultural projects, contained milling machines were described as being for the grinding of salt, and studies on plague, especially production of the agent, were misrepresented. Candid and credible accounts of many of the activities at these facilities were not provided. Two official reports of the visit concluded that Soviets were running a covert and illegal BW programme . Kelly also took part in reciprocal visits to the United States Army Medical Research Institute of Infectious Diseases at Fort Detrick , Maryland , and visits to Porton Down by Russian and American inspectors. Despite their findings, Kelly concluded that the tripartite inspection programme had failed. It was, he said, "too ambitious; its disarmament objective deflected by issues of reciprocity and access to sites outside the territories of the three parties". He went on to add that "Russia's refusal to provide a complete account of its past and current BW activity and the inability of the American–British teams to gain access to Soviet/Russian military industrial facilities were significant contributory factors". Following the end of the Gulf War , United Nations Security Council Resolution 687 imposed the articles of Iraq's surrender. The document stated "that Iraq shall unconditionally accept the destruction, removal, or rendering harmless, under international supervision, of ... All chemical and biological weapons". This was to be made possible by "The forming of a special commission which shall carry out immediate on-site inspection of Iraq's biological, chemical and missile capabilities, based on Iraq's declarations and the designation of any additional locations by the special commission itself". The group set up was the United Nations Special Commission (UNSCOM), and Kelly was appointed to it in 1991 as one of its chief weapons inspectors in Iraq. The Iraqis had provided Rolf Ekéus , the director of UNSCOM, with a list of sites connected with the research and production of weapons of mass destruction (WMD) in the country, about half of which had been bombed during Operation Desert Storm. These sites provided the starting point for the investigations. In August 1991 Kelly led the first group of UN BW investigators into the country. When asked where the inspection teams would visit, he told reporters "We will go to sites which we deem to have characteristics associated with biological activity, but at the moment ... I have an open mind." The first UNSCOM missions finished with no evidence found of an Iraqi biological or chemical programme, although they did establish that some sites suspected by US intelligence services of involvement in biological or chemical warfare research were legitimate. These included a bakery, a pharmaceutical research business in Samarra, a dairy and a slaughterhouse. UNSCOM undertook 261 inspection missions to Iraq between May 1991 and December 1998, 74 of which were for biological weapons. [lower-alpha 7] Kelly led ten of the missions involved in BW inspections. In 1998 and 1999 Iraq refused to deal with UNSCOM or the inspectors; the country's President , Saddam Hussein , singled out Kelly by name for expulsion from the country. During an inspection mission to Iraq in 1998, Kelly worked alongside an American translator and US Air Force officer, Mai Pederson, who introduced him to the Bahá'í Faith . Kelly remained a member of the faith for the rest of his life, attending spiritual meetings near his home of Southmoor , Oxfordshire . He was, for a time, the treasurer of his local branch, based in Abingdon , Oxfordshire. His time in Iraq left him with a deep affection for the country, its people and culture, although he abhorred Saddam's government. In 2000 UNSCOM was replaced by the United Nations Monitoring, Verification and Inspection Commission (UNMOVIC), whose mission and aims were similar to that of UNSCOM: to remove Iraqi WMDs and "to operate a system of ongoing monitoring and verification to check Iraq's compliance with its obligations not to reacquire the same weapons prohibited to it by the Security Council". Kelly returned to work as a government advisor with the MoD on biological warfare, but also worked with UNMOVIC and continued to visit Iraq. He was involved in at least 36 missions to Iraq as part of UNSCOM and UNMOVIC, [lower-alpha 8] and, despite interference and obstruction tactics by the Iraqis, was instrumental in making the breakthrough to discover Iraq's BW facilities: the anthrax production programme at the Salman Pak facility and a BW programme run at Al Hakum . In his 2002 State of the Union address, George W. Bush , the President of the United States , discussed the use of WMD by the Iraqi regime. Later that year he reaffirmed that "the stated policy of the United States is regime change". As part of the British government's arguments for war on Saddam, Tony Blair , the British Prime Minister , instructed the publication of a dossier on Iraqi WMD on 24 September 2002. [lower-alpha 9] The dossier, which was "based, in large part, on the work of the Joint Intelligence Committee (JIC)", included the statement that the Iraqi government had: continued to produce chemical and biological agents; military plans for the use of chemical and biological weapons, including against its own Shia population. Some of these weapons are deployable within 45 minutes of an order to use them; command and control arrangements in place to use chemical and biological weapons. Authority ultimately resides with Saddam Hussein. Before its publication, Kelly had been shown a draft copy of the dossier and took part in a meeting at the DIS to review it. Four pages of comments were made regarding the information in the report, of which Kelly contributed twelve individual statements. The observations from the DIS were passed up to the Joint Intelligence Organisation ; none of the observations referred to the 45-minute claim. On 8 November 2002 the UN Security Council passed Resolution 1441 , "a final opportunity to comply with its disarmament obligations under relevant resolutions of the Council; and accordingly decides to set up an enhanced inspection regime with the aim of bringing to full and verified completion the disarmament process". The resolution stated that the Iraqi government needed to provide full details of its WMD programme within 30 days. [lower-alpha 10] As a result of the increasing pressure on the Iraqi government, UNSCOM inspectors were readmitted to the country and were provided information on the Iraqi WMD programme. According to Kelly, despite the steps taken, Saddam "refuse[d] to acknowledge the extent of his chemical and biological weapons and associated military and industrial support organisations", and there was still a concern about "8,500 litres of anthrax VX, [ sic ] 2,160 kilograms of bacterial growth media, 360 tonnes of bulk chemical warfare agent, 6,500 chemical bombs and 30,000 munitions capable of delivering chemical and biological warfare agents [which] remained unaccounted for from activities up to 1991". In February 2003 Colin Powell , the US Secretary of State , addressed the United Nations Security Council to discuss Iraq's WMD. He included information on mobile weapons laboratories , which he described as "trucks and train cars ... easily moved and ... designed to evade detection by inspectors. In a matter of months, they can produce a quantity of biological poison equal to the entire amount that Iraq claimed to have produced in the years prior to the Gulf War." Following his examination of the vehicles in question, Kelly spoke, off the record , to journalists from The Observer . In their article in the newspaper on 15 June 2003 they described him as "a British scientist and biological weapons expert", and quoted him as saying: They are not mobile germ warfare laboratories. You could not use them for making biological weapons. They do not even look like them. They are exactly what the Iraqis said they were—facilities for the production of hydrogen gas to fill balloons. One of the journalists who wrote the story, Peter Beaumont , confirmed to the Hutton Inquiry that Kelly was the source of this quote. Kelly was often approached by the press and would either clear the discussion with the press office of the FCO, or use his judgement before doing so; it was within his remit to liaise with the media. [lower-alpha 11] Shortly before the 2003 invasion of Iraq (20 March – 1 May 2003) Kelly anonymously wrote an article on the threat from Saddam which was never published. He outlined his thoughts on the build-up to war: Iraq has spent the past 30 years building up an arsenal of weapons of mass destruction (WMD). Although the current threat presented by Iraq militarily is modest, both in terms of conventional and unconventional weapons, it has never given up its intent to develop and stockpile such weapons for both military and terrorist use. He continued that "The long-term threat, however, remains Iraq's development to military maturity of weapons of mass destruction—something that only regime change will avert." On 20 March 2003 British and American troops entered Iraq to bring about the regime change. Most of the country was occupied and Saddam was overthrown within four weeks; Bush stated that war was over on 1 May 2003. On 7 May 2003 Kelly was telephoned by Susan Watts , the science editor of the BBC 's Newsnight programme; the call lasted 15 to 20 minutes. They discussed various matters relating to Iraq including, towards the end of the conversation, the matter of the 45-minute claim. Watts's handwritten shorthand notes showed Kelly stated the claim was "a mistake to put in. Alastair Campbell seeing something in there, single source but not corroborated, sounded good." [lower-alpha 12] The pair also had a subsequent call on 12 May. Kelly flew to Kuwait on 19 May as part of a military team. He hoped to meet members of the Iraq Survey Group to see how the organisation worked. When he arrived in Kuwait he found that no visa had been arranged for him, so he returned home. On 22 May 2003 Kelly met Andrew Gilligan , the Defence and Diplomatic Correspondent for BBC Radio 4 's Today programme, at the Charing Cross Hotel, London. It was the third time the pair had met. The meeting, initiated by Gilligan, was for the journalist to ask why Kelly thought WMDs had not been discovered in Iraq by the British and American troops. According to Gilligan, after 30 minutes the conversation focussed on the September Dossier and how key areas of the document were altered to give greater impact to the public. Gilligan took notes on an electronic organiser; he said these read as Transformed week before publication to make it sexier. The classic was the 45 minutes. Most things in dossier were double source but that was single source. One source said it took 4 [that should be 45] minutes to set up a missile assembly, that was misinterpreted. Most people in intelligence weren't happy with it because it didn't reflect the considered view they were putting forward. Campbell: real information but unreliable, included against our wishes. Not in original draft - dull, he asked if anything else could go in. [lower-alpha 13] Soon after the meeting, Gilligan claimed, he wrote a full script of the interview, based on his memory and notes. Between the completion of the document and the start of the Hutton Inquiry in August, Gilligan says he lost that script. Kelly was in New York on 29 May 2003, attending the final commissioners' meeting of UNMOVIC under the leadership of Hans Blix . At 6.07 that morning, on the Today programme, Gilligan explained to the programme's host, John Humphrys , what he would be discussing later in the programme: what we've been told by one of the senior officials in charge of drawing up that dossier was that, actually the government probably erm, knew that that forty five minute figure was wrong, even before it decided to put it in. What this person says, is that a week before the publication date of the dossier, it was actually rather erm, a bland production. It didn't, the, the draft prepared for Mr Blair by the Intelligence Agencies actually didn't say very much more than was public knowledge already and erm, Downing Street, our source says, ordered a week before publication, ordered it to be sexed up, to be made more exciting and ordered more facts to be er, to be discovered. Gilligan had not been able to get confirmation from any other sources about the veracity of the claim. The producer of Today , Kevin Marsh , writes that Gilligan went off his pre-prepared script. With news based on an anonymous single source, stories "have to be reported word perfectly" to be precise about the meaning; according to Marsh, "Gilligan had lost control of that precision". Downing Street had not been forewarned of the story, or been contacted to ask for a statement. At 7:32 am the government press office issued a statement to refute the story: "Not one word of the dossier was not entirely the work of the intelligence agencies". Gilligan then broadcast a report for the BBC Radio 5 Live Breakfast programme in which he repeated the claim that the government had inserted the 45-minute claim into the dossier. Kelly did not recognise himself from Gilligan's description of a "senior official in charge of drawing up the document"; Kelly had taken no part in drafting the document and had only been asked for comments on the contents. The following day Watts telephoned Kelly at home to discuss the quotes on the Today programme; she recorded the call. When she asked him if he was being questioned about the identity of the source, Kelly replied "I mean they wouldn't think it was me, I don't think. Maybe they would, maybe they wouldn't. I don't know". Their conversation also included the possible involvement of Campbell in the inclusion of the 45-minute claim in the dossier: SW OK just back momentarily on the 45 minute issue I'm feeling like I ought to just explore that a little bit more with you the um err. So would it be accurate then, as you did that earlier conversation, to say that it was Alastair Campbell himself who... DK No I can't. All I can say is the Number Ten press office. I've never met Alastair Campbell so I can't ... But I think Alastair Campbell is synonymous with that press office because he's responsible for it. Despite the denial from the government, on 1 June—the day after Kelly and Watts had spoken on the telephone—Gilligan wrote an article for The Mail on Sunday in which he specifically named Campbell; it was titled: "I asked my intelligence source why Blair misled us all over Saddam's weapons. His reply? One word ... CAMPBELL". According to the journalist Miles Goslett , the report on the Today programme "caused little more than a ripple" of interest; the newspaper article "was of major international significance. It was career-threatening for all concerned if substantiated". As political tumult between Downing Street and the BBC developed, Kelly alerted his line manager at the MoD, Bryan Wells, that he had met Gilligan and discussed, among other points, the 45-minute claim. In a detailed letter of 30 June, Kelly stated that any mention of Campbell had been raised by Gilligan, not himself, and that this was an aside. Kelly stated that "I did not even consider that I was the 'source' of Gilligan's information"; he only became aware of the possibility after Gilligan had appeared at the Foreign Affairs Select Committee on 19 June. Kelly said of Gilligan's evidence that "The description of that meeting in small part matches my interaction with him especially my personal evaluation of Iraq's capability but the overall character is quite different". In closing, he reiterated that "With hindsight I of course deeply regret talking to Andrew Gilligan even though I am convinced that I am not his primary source of information." Kelly was interviewed twice by his employers—on 3 and 7 July; they concluded that he may have been Gilligan's source, but that Gilligan may have exaggerated what Kelly said. A decision was taken that no official action was to be taken against Kelly. He was also advised that, with journalists pressing for further information, it was possible his name would emerge in press reports. Reports in The Times by the journalist Tom Baldwin on 5 and 8 July gave significant hints on the identity of Gilligan's source. At a meeting chaired by Blair on 8 July it was agreed that a statement should be released that stated a member of the MoD had come forward to say that he was the source. It was also agreed that Kelly's name would not be released to journalists, but if someone guessed who it was, they were allowed to confirm it. Kevin Tebbit , the permanent secretary at the MoD—Kelly's ultimate superior at the department—arrived at the end of the meeting and was unable to provide any input. [lower-alpha 14] At 5:54 pm on 8 July the government statement was released. Without naming Kelly, it said a member of the MoD had come forward to admit that he had met Gilligan at an unauthorised meeting a week before Gilligan's broadcast. The statement said that this MoD employee was not in a position to comment on Campbell's role in the 45 minute issue as he had not helped draw up the intelligence report and had not seen it. At 5:50 pm the following day a journalist from The Financial Times guessed Kelly's name correctly; a journalist from The Times did so soon afterwards after nineteen failed guesses. On the evening of 8 July Nick Rufford, a journalist with The Sunday Times who had known Kelly for five years, visited him at home in Southmoor. Rufford told him that his name would be published in the papers the following day. He advised Kelly to leave his home that night to avoid the media, and said the newspaper would put Kelly and his wife up at a hotel. Soon after Rufford left he contacted the MoD and asked if Kelly could write a piece for the paper putting forward his version of events; the MoD press office said this was unlikely. Soon afterwards the MoD phoned Kelly and advised him to find somewhere else to stay the night. According to Mrs Kelly, the couple left the house within 15 minutes and drove to Cornwall , breaking the journey overnight in Weston-super-Mare , Somerset , where they arrived by 9:45 pm. Although the trip to Cornwall was described by Mrs Kelly at the Hutton Inquiry, Baker considers that there are "problems with the version of events we are asked to accept"; Goslett writes that Kelly played cribbage with a pub team in Kingston Bagpuize that night and was there until at least 10:30 pm. None of those on Kelly's cribbage team were asked to give evidence to the Hutton Inquiry. While in Cornwall, on the morning of 11 July, Kelly had a telephone call from Bryan Wells to tell him that he would have to appear in front of the Intelligence and Security and Foreign Affairs select committees. He was told that the latter of these would be televised, something that upset him greatly, according to his wife. That afternoon, still unhappy with the news from the earlier phone call, he spoke to Wells again nine times. They agreed to meet on Monday 14 July to prepare for the interviews. Kelly returned from Cornwall on 13 July and stayed in Oxford at his daughter Rachel's house. Kelly's appearance before the Foreign Affairs Select Committee was against the advice of Tebbit, the most senior civil servant at the MoD. He had been overruled by Geoff Hoon , the Secretary of State for Defence . Kelly appeared in front of the committee on 15 July in a session that lasted over an hour. He spoke so softly the fans in the room were turned off so the committee members could hear him reply; according to Baker, "Every word [from Kelly] was weighed carefully and some painful circumlocutions resulted". Kelly told the committee that he had met Gilligan but, as the journalist Tom Mangold , in Kelly's biography in the Dictionary of National Biography writes, "denied that he had said the things Gilligan reported his source as having said". Kelly was questioned by the Liberal Democrat MP David Chidgey about conversations with Susan Watts. It was the first time her name had been connected with Kelly in public, and it was later established that Gilligan had not only sent Chidgey excerpts from a recorded conversation, but also gave Chidgey questions to ask Kelly. The quote included Kelly's opinion on the 45 minute claim. The quote read out by Chidgey included: "The 45 minutes was a statement that was made and it got out of all proportion. They were desperate for information. They were pushing hard for information that could be released. That was one that popped up and it was seized on and it is unfortunate that it was." Chidgey asked Kelly if the quotes came from the meeting he had with Watts in November 2002—the only time the pair had met face-to-face; Kelly replied that "I cannot believe that on that occasion I made that statement". According to Goslett, this was a truthful statement, as Kelly had not made the statement in November 2002, but on 30 May that year. Mangold notes that Kelly appeared to be under stress during the interview, and that some of the questioning was overtly hostile. One Labour MP, Andrew MacKinlay , questioned Kelly towards the end of the session: Andrew MacKinlay : I reckon you are chaff; you have been thrown up to divert our probing. Have you ever felt like a fall-guy? You have been set up, have you not? Dr Kelly : That is not a question I can answer. Andrew MacKinlay : But you feel that? Dr Kelly : No, not at all. I accept the process that is going on. After the hearing Kelly described MacKinlay to his daughter as an "utter bastard". On the following day, 16 July 2003, Kelly gave evidence to the Intelligence and Security Committee. He appeared more relaxed than he had in front of the Foreign Affairs Committee, according to Baker. When asked, Kelly described the September dossier as "an accurate document, I think it is a fair reflection of the intelligence that was available and it's presented in a very sober and factual way." On the morning of 17 July Kelly worked from his home in Southmoor, answering written parliamentary questions from two MPs—MacKinlay on the identity of the journalists Kelly had spoken to, and the Conservative MP Bernard Jenkin on Kelly's discussions with Gilligan and whether he would be disciplined for it; Kelly had to provide the information to the MoD to forward on. He had a telephone call with Wing Commander John Clark, a friend and colleague, during which they discussed the general situation Kelly was in, as well as a trip to Iraq on which Kelly was due to go in the following week. Clark reported that Kelly seemed to be "very tired, but in good spirits". He had received several emails from well-wishers, including from The New York Times journalist Judith Miller , to which he replied "I will wait until the end of the week before judging—many dark actors playing games. Thanks for your support." During the course of the day Kelly received a phone call that changed his mood. Mangold states that "[the] most likely explanation is that he learned from a well-meaning friend at the Ministry of Defence that the BBC had tape-recorded evidence which, when published, would show that he had indeed said the things to Susan Watts that he had formally denied saying". Mrs Kelly was ill that day and spent some time lying down in the couple's bedroom, but she got up at 3:00 pm to find Kelly speaking on the phone, before she returned to her bedroom to sleep. Goslett thinks this phone call is likely to have been with Clark, in a discussion about one of the answers to the parliamentary questions. Kelly left for a walk between 3:00 and 3:20 pm and was last seen by Ruth Absalom, a neighbour, with whom he stopped to have a chat. She was the last person known to have seen him alive. Clark tried to contact Kelly at home—where Mrs Kelly told him that her husband had gone for a walk—and then on Kelly's mobile, which was switched off; Clark stated he was surprised it was off as Kelly was normally easily contactable. As far as it is known, Kelly walked a mile (1.6 km) from his house to Harrowdown Hill. It appears he ingested up to 29 tablets of co-proxamol , an analgesic drug; he also cut his left wrist with a pruning knife he had owned since his youth, severing his ulnar artery . Forensic analysis established that neither the knife nor the blister packs showed Kelly's fingerprints on their surfaces. Rachel Kelly spoke to her mother in the late afternoon, then drove to her parents' house at around 6:00 pm. As her father had not returned, Rachel walked a route along a footpath her father was known to use regularly to try and find him; she returned to the house at around 6:30 pm, then drove round to see if she could find anything. Sian, the Kellys' eldest daughter, also came to the house that night, and at 11:40 pm they phoned the police. Three officers from the local station in Abingdon arrived within 15 minutes; they searched the house and garden straight away. By 1:00 am a search helicopter from RAF Benson , fitted with thermal imaging equipment, had been requested; teams of search dogs were also provided and a 26-metre (85 ft) communications mast was erected, as the Kellys' home was in a mobile communications black spot. The police used volunteer search teams, and it was one of these that found Kelly's body on Harrowdown Hill at about 9:20 am on 18 July. The two-person team differed in their description of the position of the body: one stated Kelly was "at the base of the tree with almost his head and his shoulders just slumped back against the tree"; the other stated Kelly was "sitting with his back up against a tree". The police and paramedics differed from both the searchers. DC Coe, one of the first policemen at the scene, stated the body "was laying on its back—the body was laying on its back by a large tree, the head towards the trunk of the tree"; the pathologist called to the scene, Nicholas Hunt, recalled that: "his head was quite close to branches and so forth, but not actually over the tree." David Christopher Kelly was born in Llwynypia , Glamorgan , South Wales , on 14 May 1944. His parents were Thomas John Kelly and Margaret, née Williams; Thomas was a schoolteacher who was serving in the Royal Air Force Volunteer Reserve as a signals officer during the Second World War . Thomas and Margaret divorced in 1951; she took their young son and moved in with her parents in Pontypridd . From the age of eleven he attended the local grammar school . He was a keen sportsman and musician at school, and represented Wales in the youth cross-country running team; he played double bass in the National Youth Orchestra of Wales and played the saxophone to a high standard. In 1963 Kelly was admitted to the University of Leeds to study chemistry, botany and biophysics . His mother died two years later from an overdose of prescription barbiturates . Although the coroner's inquest gave an open verdict , Kelly believed she had killed herself. As a result of the death, Kelly suffered from insomnia and was prescribed sleeping pills; he was also given an extra year to complete his degree. [lower-alpha 1] [lower-alpha 2] He graduated in 1967 with a BSc in bacteriology ; he then obtained an MSc in virology from the University of Birmingham . Between his first and second degrees, on 15 July 1967, he married Janice, née Vawdrey, who was studying at Bingley Teacher Training College. [lower-alpha 3] Kelly joined the Insect Pathology Unit at the University of Oxford in 1968, while a student of Linacre College . In 1971 he received his doctorate in microbiology ; his thesis was "The Replication of Some Iridescent Viruses in Cell Cultures". In the early 1970s he undertook postdoctoral research at the University of Warwick , before moving back to Oxford in the mid-1970s to work at the Institute of Virology and Environmental Microbiology . [lower-alpha 4] There he carried out virology research into pests such as Spodoptera and Aedes . He rose to the position of Chief Scientific Officer; much of his work was in the field of insect viruses. In 1984 Kelly joined the Ministry of Defence (MoD) as the head of the Defence Microbiology Division working at Porton Down , Wiltshire . [lower-alpha 5] The department had only a small number of microbiologists when he arrived, and most of their work involved the decontamination of Gruinard Island , which had been used during the Second World War for experiments with weaponised anthrax . He increased the scope of his department, obtaining additional funding to undertake research into biodefence . Because of the work undertaken by Kelly and his team, the UK were able to deploy a biodefence capability during the 1990–1991 Gulf War . In 1989 Vladimir Pasechnik , the senior Soviet biologist and bioweapons developer, defected to the UK and provided intelligence about the clandestine biological warfare (BW) programme, Biopreparat . The programme was in contravention of the 1972 Biological Weapons Convention which banned the production of chemical and biological weapons. [lower-alpha 6] Pasechnik was debriefed by the Defence Intelligence Staff (DIS), who requested technical assistance to process the information on chemical and biological matters; Kelly was seconded to the DIS to assist with his colleagues Brian Jones and Christopher Davis. They debriefed Pasechnik over a period of three years. Kelly undertook several visits to Russia between 1991 and 1994 as the co-lead of a team from the UK and US which inspected civilian biotechnology facilities in Russia. One of the restrictions placed on the inspectors was that visits could only be to non-military installations, so, for the first visit in January 1991, the team visited the Institute of Engineering Immunology, in Lyubuchany; the State Research Centre for Applied Microbiology in Obolensk ; the Vector State Research Center of Virology and Biotechnology in Koltsovo ; and the Institute of Ultrapure Preparations, in Leningrad (now Saint Petersburg). The Russians obstructed the team and tried to stop inspection of key areas of the facilities; they also lied about the use to which parts of the installations were put. On one visit to the Vector facility, Kelly had a conversation with a laboratory assistant—one who was too low grade to have been fully briefed by the KGB . Kelly asked the assistant about the work he was doing, and was surprised when the man said he was involved in testing smallpox . Kelly questioned Lev Sandakchiev , the head of Vector, about the use of smallpox, but received no answers. Kelly described the questioning sessions as "a very tense moment". In a 2002 review of the verification process, Kelly wrote: The visits did not go without incident. At Obolensk, access to parts of the main research facility—notably the dynamic aerosol test chambers and the plague research laboratories—was denied on the spurious grounds of quarantine requirements. Skirmishes occurred over access to an explosive aerosol chamber because the officials knew that closer examination would reveal damning evidence of offensive BW activities. At Koltsova access was again difficult and problematic. The most serious incident was when senior officials contradicted an admission by technical staff that research on smallpox was being conducted there. The officials were unable to properly account for the presence of smallpox and for the research being undertaken in a dynamic aerosol test chamber on orthopoxvirus, which was capable of explosive dispersal. At the Institute of Ultrapure Preparations in Leningrad (Pasechnik's former workplace), dynamic and explosive test chambers were passed off as being for agricultural projects, contained milling machines were described as being for the grinding of salt, and studies on plague, especially production of the agent, were misrepresented. Candid and credible accounts of many of the activities at these facilities were not provided. Two official reports of the visit concluded that Soviets were running a covert and illegal BW programme . Kelly also took part in reciprocal visits to the United States Army Medical Research Institute of Infectious Diseases at Fort Detrick , Maryland , and visits to Porton Down by Russian and American inspectors. Despite their findings, Kelly concluded that the tripartite inspection programme had failed. It was, he said, "too ambitious; its disarmament objective deflected by issues of reciprocity and access to sites outside the territories of the three parties". He went on to add that "Russia's refusal to provide a complete account of its past and current BW activity and the inability of the American–British teams to gain access to Soviet/Russian military industrial facilities were significant contributory factors". Following the end of the Gulf War , United Nations Security Council Resolution 687 imposed the articles of Iraq's surrender. The document stated "that Iraq shall unconditionally accept the destruction, removal, or rendering harmless, under international supervision, of ... All chemical and biological weapons". This was to be made possible by "The forming of a special commission which shall carry out immediate on-site inspection of Iraq's biological, chemical and missile capabilities, based on Iraq's declarations and the designation of any additional locations by the special commission itself". The group set up was the United Nations Special Commission (UNSCOM), and Kelly was appointed to it in 1991 as one of its chief weapons inspectors in Iraq. The Iraqis had provided Rolf Ekéus , the director of UNSCOM, with a list of sites connected with the research and production of weapons of mass destruction (WMD) in the country, about half of which had been bombed during Operation Desert Storm. These sites provided the starting point for the investigations. In August 1991 Kelly led the first group of UN BW investigators into the country. When asked where the inspection teams would visit, he told reporters "We will go to sites which we deem to have characteristics associated with biological activity, but at the moment ... I have an open mind." The first UNSCOM missions finished with no evidence found of an Iraqi biological or chemical programme, although they did establish that some sites suspected by US intelligence services of involvement in biological or chemical warfare research were legitimate. These included a bakery, a pharmaceutical research business in Samarra, a dairy and a slaughterhouse. UNSCOM undertook 261 inspection missions to Iraq between May 1991 and December 1998, 74 of which were for biological weapons. [lower-alpha 7] Kelly led ten of the missions involved in BW inspections. In 1998 and 1999 Iraq refused to deal with UNSCOM or the inspectors; the country's President , Saddam Hussein , singled out Kelly by name for expulsion from the country. During an inspection mission to Iraq in 1998, Kelly worked alongside an American translator and US Air Force officer, Mai Pederson, who introduced him to the Bahá'í Faith . Kelly remained a member of the faith for the rest of his life, attending spiritual meetings near his home of Southmoor , Oxfordshire . He was, for a time, the treasurer of his local branch, based in Abingdon , Oxfordshire. His time in Iraq left him with a deep affection for the country, its people and culture, although he abhorred Saddam's government. In 2000 UNSCOM was replaced by the United Nations Monitoring, Verification and Inspection Commission (UNMOVIC), whose mission and aims were similar to that of UNSCOM: to remove Iraqi WMDs and "to operate a system of ongoing monitoring and verification to check Iraq's compliance with its obligations not to reacquire the same weapons prohibited to it by the Security Council". Kelly returned to work as a government advisor with the MoD on biological warfare, but also worked with UNMOVIC and continued to visit Iraq. He was involved in at least 36 missions to Iraq as part of UNSCOM and UNMOVIC, [lower-alpha 8] and, despite interference and obstruction tactics by the Iraqis, was instrumental in making the breakthrough to discover Iraq's BW facilities: the anthrax production programme at the Salman Pak facility and a BW programme run at Al Hakum . In his 2002 State of the Union address, George W. Bush , the President of the United States , discussed the use of WMD by the Iraqi regime. Later that year he reaffirmed that "the stated policy of the United States is regime change". As part of the British government's arguments for war on Saddam, Tony Blair , the British Prime Minister , instructed the publication of a dossier on Iraqi WMD on 24 September 2002. [lower-alpha 9] The dossier, which was "based, in large part, on the work of the Joint Intelligence Committee (JIC)", included the statement that the Iraqi government had: continued to produce chemical and biological agents; military plans for the use of chemical and biological weapons, including against its own Shia population. Some of these weapons are deployable within 45 minutes of an order to use them; command and control arrangements in place to use chemical and biological weapons. Authority ultimately resides with Saddam Hussein. Before its publication, Kelly had been shown a draft copy of the dossier and took part in a meeting at the DIS to review it. Four pages of comments were made regarding the information in the report, of which Kelly contributed twelve individual statements. The observations from the DIS were passed up to the Joint Intelligence Organisation ; none of the observations referred to the 45-minute claim. On 8 November 2002 the UN Security Council passed Resolution 1441 , "a final opportunity to comply with its disarmament obligations under relevant resolutions of the Council; and accordingly decides to set up an enhanced inspection regime with the aim of bringing to full and verified completion the disarmament process". The resolution stated that the Iraqi government needed to provide full details of its WMD programme within 30 days. [lower-alpha 10] As a result of the increasing pressure on the Iraqi government, UNSCOM inspectors were readmitted to the country and were provided information on the Iraqi WMD programme. According to Kelly, despite the steps taken, Saddam "refuse[d] to acknowledge the extent of his chemical and biological weapons and associated military and industrial support organisations", and there was still a concern about "8,500 litres of anthrax VX, [ sic ] 2,160 kilograms of bacterial growth media, 360 tonnes of bulk chemical warfare agent, 6,500 chemical bombs and 30,000 munitions capable of delivering chemical and biological warfare agents [which] remained unaccounted for from activities up to 1991". In February 2003 Colin Powell , the US Secretary of State , addressed the United Nations Security Council to discuss Iraq's WMD. He included information on mobile weapons laboratories , which he described as "trucks and train cars ... easily moved and ... designed to evade detection by inspectors. In a matter of months, they can produce a quantity of biological poison equal to the entire amount that Iraq claimed to have produced in the years prior to the Gulf War." Following his examination of the vehicles in question, Kelly spoke, off the record , to journalists from The Observer . In their article in the newspaper on 15 June 2003 they described him as "a British scientist and biological weapons expert", and quoted him as saying: They are not mobile germ warfare laboratories. You could not use them for making biological weapons. They do not even look like them. They are exactly what the Iraqis said they were—facilities for the production of hydrogen gas to fill balloons. One of the journalists who wrote the story, Peter Beaumont , confirmed to the Hutton Inquiry that Kelly was the source of this quote. Kelly was often approached by the press and would either clear the discussion with the press office of the FCO, or use his judgement before doing so; it was within his remit to liaise with the media. [lower-alpha 11] Shortly before the 2003 invasion of Iraq (20 March – 1 May 2003) Kelly anonymously wrote an article on the threat from Saddam which was never published. He outlined his thoughts on the build-up to war: Iraq has spent the past 30 years building up an arsenal of weapons of mass destruction (WMD). Although the current threat presented by Iraq militarily is modest, both in terms of conventional and unconventional weapons, it has never given up its intent to develop and stockpile such weapons for both military and terrorist use. He continued that "The long-term threat, however, remains Iraq's development to military maturity of weapons of mass destruction—something that only regime change will avert." On 20 March 2003 British and American troops entered Iraq to bring about the regime change. Most of the country was occupied and Saddam was overthrown within four weeks; Bush stated that war was over on 1 May 2003. On 7 May 2003 Kelly was telephoned by Susan Watts , the science editor of the BBC 's Newsnight programme; the call lasted 15 to 20 minutes. They discussed various matters relating to Iraq including, towards the end of the conversation, the matter of the 45-minute claim. Watts's handwritten shorthand notes showed Kelly stated the claim was "a mistake to put in. Alastair Campbell seeing something in there, single source but not corroborated, sounded good." [lower-alpha 12] The pair also had a subsequent call on 12 May. Kelly flew to Kuwait on 19 May as part of a military team. He hoped to meet members of the Iraq Survey Group to see how the organisation worked. When he arrived in Kuwait he found that no visa had been arranged for him, so he returned home. On 22 May 2003 Kelly met Andrew Gilligan , the Defence and Diplomatic Correspondent for BBC Radio 4 's Today programme, at the Charing Cross Hotel, London. It was the third time the pair had met. The meeting, initiated by Gilligan, was for the journalist to ask why Kelly thought WMDs had not been discovered in Iraq by the British and American troops. According to Gilligan, after 30 minutes the conversation focussed on the September Dossier and how key areas of the document were altered to give greater impact to the public. Gilligan took notes on an electronic organiser; he said these read as Transformed week before publication to make it sexier. The classic was the 45 minutes. Most things in dossier were double source but that was single source. One source said it took 4 [that should be 45] minutes to set up a missile assembly, that was misinterpreted. Most people in intelligence weren't happy with it because it didn't reflect the considered view they were putting forward. Campbell: real information but unreliable, included against our wishes. Not in original draft - dull, he asked if anything else could go in. [lower-alpha 13] Soon after the meeting, Gilligan claimed, he wrote a full script of the interview, based on his memory and notes. Between the completion of the document and the start of the Hutton Inquiry in August, Gilligan says he lost that script. Kelly was in New York on 29 May 2003, attending the final commissioners' meeting of UNMOVIC under the leadership of Hans Blix . At 6.07 that morning, on the Today programme, Gilligan explained to the programme's host, John Humphrys , what he would be discussing later in the programme: what we've been told by one of the senior officials in charge of drawing up that dossier was that, actually the government probably erm, knew that that forty five minute figure was wrong, even before it decided to put it in. What this person says, is that a week before the publication date of the dossier, it was actually rather erm, a bland production. It didn't, the, the draft prepared for Mr Blair by the Intelligence Agencies actually didn't say very much more than was public knowledge already and erm, Downing Street, our source says, ordered a week before publication, ordered it to be sexed up, to be made more exciting and ordered more facts to be er, to be discovered. Gilligan had not been able to get confirmation from any other sources about the veracity of the claim. The producer of Today , Kevin Marsh , writes that Gilligan went off his pre-prepared script. With news based on an anonymous single source, stories "have to be reported word perfectly" to be precise about the meaning; according to Marsh, "Gilligan had lost control of that precision". Downing Street had not been forewarned of the story, or been contacted to ask for a statement. At 7:32 am the government press office issued a statement to refute the story: "Not one word of the dossier was not entirely the work of the intelligence agencies". Gilligan then broadcast a report for the BBC Radio 5 Live Breakfast programme in which he repeated the claim that the government had inserted the 45-minute claim into the dossier. Kelly did not recognise himself from Gilligan's description of a "senior official in charge of drawing up the document"; Kelly had taken no part in drafting the document and had only been asked for comments on the contents. The following day Watts telephoned Kelly at home to discuss the quotes on the Today programme; she recorded the call. When she asked him if he was being questioned about the identity of the source, Kelly replied "I mean they wouldn't think it was me, I don't think. Maybe they would, maybe they wouldn't. I don't know". Their conversation also included the possible involvement of Campbell in the inclusion of the 45-minute claim in the dossier: SW OK just back momentarily on the 45 minute issue I'm feeling like I ought to just explore that a little bit more with you the um err. So would it be accurate then, as you did that earlier conversation, to say that it was Alastair Campbell himself who... DK No I can't. All I can say is the Number Ten press office. I've never met Alastair Campbell so I can't ... But I think Alastair Campbell is synonymous with that press office because he's responsible for it. Despite the denial from the government, on 1 June—the day after Kelly and Watts had spoken on the telephone—Gilligan wrote an article for The Mail on Sunday in which he specifically named Campbell; it was titled: "I asked my intelligence source why Blair misled us all over Saddam's weapons. His reply? One word ... CAMPBELL". According to the journalist Miles Goslett , the report on the Today programme "caused little more than a ripple" of interest; the newspaper article "was of major international significance. It was career-threatening for all concerned if substantiated". As political tumult between Downing Street and the BBC developed, Kelly alerted his line manager at the MoD, Bryan Wells, that he had met Gilligan and discussed, among other points, the 45-minute claim. In a detailed letter of 30 June, Kelly stated that any mention of Campbell had been raised by Gilligan, not himself, and that this was an aside. Kelly stated that "I did not even consider that I was the 'source' of Gilligan's information"; he only became aware of the possibility after Gilligan had appeared at the Foreign Affairs Select Committee on 19 June. Kelly said of Gilligan's evidence that "The description of that meeting in small part matches my interaction with him especially my personal evaluation of Iraq's capability but the overall character is quite different". In closing, he reiterated that "With hindsight I of course deeply regret talking to Andrew Gilligan even though I am convinced that I am not his primary source of information." Kelly was interviewed twice by his employers—on 3 and 7 July; they concluded that he may have been Gilligan's source, but that Gilligan may have exaggerated what Kelly said. A decision was taken that no official action was to be taken against Kelly. He was also advised that, with journalists pressing for further information, it was possible his name would emerge in press reports. Reports in The Times by the journalist Tom Baldwin on 5 and 8 July gave significant hints on the identity of Gilligan's source. At a meeting chaired by Blair on 8 July it was agreed that a statement should be released that stated a member of the MoD had come forward to say that he was the source. It was also agreed that Kelly's name would not be released to journalists, but if someone guessed who it was, they were allowed to confirm it. Kevin Tebbit , the permanent secretary at the MoD—Kelly's ultimate superior at the department—arrived at the end of the meeting and was unable to provide any input. [lower-alpha 14] At 5:54 pm on 8 July the government statement was released. Without naming Kelly, it said a member of the MoD had come forward to admit that he had met Gilligan at an unauthorised meeting a week before Gilligan's broadcast. The statement said that this MoD employee was not in a position to comment on Campbell's role in the 45 minute issue as he had not helped draw up the intelligence report and had not seen it. At 5:50 pm the following day a journalist from The Financial Times guessed Kelly's name correctly; a journalist from The Times did so soon afterwards after nineteen failed guesses. On the evening of 8 July Nick Rufford, a journalist with The Sunday Times who had known Kelly for five years, visited him at home in Southmoor. Rufford told him that his name would be published in the papers the following day. He advised Kelly to leave his home that night to avoid the media, and said the newspaper would put Kelly and his wife up at a hotel. Soon after Rufford left he contacted the MoD and asked if Kelly could write a piece for the paper putting forward his version of events; the MoD press office said this was unlikely. Soon afterwards the MoD phoned Kelly and advised him to find somewhere else to stay the night. According to Mrs Kelly, the couple left the house within 15 minutes and drove to Cornwall , breaking the journey overnight in Weston-super-Mare , Somerset , where they arrived by 9:45 pm. Although the trip to Cornwall was described by Mrs Kelly at the Hutton Inquiry, Baker considers that there are "problems with the version of events we are asked to accept"; Goslett writes that Kelly played cribbage with a pub team in Kingston Bagpuize that night and was there until at least 10:30 pm. None of those on Kelly's cribbage team were asked to give evidence to the Hutton Inquiry. While in Cornwall, on the morning of 11 July, Kelly had a telephone call from Bryan Wells to tell him that he would have to appear in front of the Intelligence and Security and Foreign Affairs select committees. He was told that the latter of these would be televised, something that upset him greatly, according to his wife. That afternoon, still unhappy with the news from the earlier phone call, he spoke to Wells again nine times. They agreed to meet on Monday 14 July to prepare for the interviews. Kelly returned from Cornwall on 13 July and stayed in Oxford at his daughter Rachel's house. Kelly's appearance before the Foreign Affairs Select Committee was against the advice of Tebbit, the most senior civil servant at the MoD. He had been overruled by Geoff Hoon , the Secretary of State for Defence . Kelly appeared in front of the committee on 15 July in a session that lasted over an hour. He spoke so softly the fans in the room were turned off so the committee members could hear him reply; according to Baker, "Every word [from Kelly] was weighed carefully and some painful circumlocutions resulted". Kelly told the committee that he had met Gilligan but, as the journalist Tom Mangold , in Kelly's biography in the Dictionary of National Biography writes, "denied that he had said the things Gilligan reported his source as having said". Kelly was questioned by the Liberal Democrat MP David Chidgey about conversations with Susan Watts. It was the first time her name had been connected with Kelly in public, and it was later established that Gilligan had not only sent Chidgey excerpts from a recorded conversation, but also gave Chidgey questions to ask Kelly. The quote included Kelly's opinion on the 45 minute claim. The quote read out by Chidgey included: "The 45 minutes was a statement that was made and it got out of all proportion. They were desperate for information. They were pushing hard for information that could be released. That was one that popped up and it was seized on and it is unfortunate that it was." Chidgey asked Kelly if the quotes came from the meeting he had with Watts in November 2002—the only time the pair had met face-to-face; Kelly replied that "I cannot believe that on that occasion I made that statement". According to Goslett, this was a truthful statement, as Kelly had not made the statement in November 2002, but on 30 May that year. Mangold notes that Kelly appeared to be under stress during the interview, and that some of the questioning was overtly hostile. One Labour MP, Andrew MacKinlay , questioned Kelly towards the end of the session: Andrew MacKinlay : I reckon you are chaff; you have been thrown up to divert our probing. Have you ever felt like a fall-guy? You have been set up, have you not? Dr Kelly : That is not a question I can answer. Andrew MacKinlay : But you feel that? Dr Kelly : No, not at all. I accept the process that is going on. After the hearing Kelly described MacKinlay to his daughter as an "utter bastard". On the following day, 16 July 2003, Kelly gave evidence to the Intelligence and Security Committee. He appeared more relaxed than he had in front of the Foreign Affairs Committee, according to Baker. When asked, Kelly described the September dossier as "an accurate document, I think it is a fair reflection of the intelligence that was available and it's presented in a very sober and factual way." In 1989 Vladimir Pasechnik , the senior Soviet biologist and bioweapons developer, defected to the UK and provided intelligence about the clandestine biological warfare (BW) programme, Biopreparat . The programme was in contravention of the 1972 Biological Weapons Convention which banned the production of chemical and biological weapons. [lower-alpha 6] Pasechnik was debriefed by the Defence Intelligence Staff (DIS), who requested technical assistance to process the information on chemical and biological matters; Kelly was seconded to the DIS to assist with his colleagues Brian Jones and Christopher Davis. They debriefed Pasechnik over a period of three years. Kelly undertook several visits to Russia between 1991 and 1994 as the co-lead of a team from the UK and US which inspected civilian biotechnology facilities in Russia. One of the restrictions placed on the inspectors was that visits could only be to non-military installations, so, for the first visit in January 1991, the team visited the Institute of Engineering Immunology, in Lyubuchany; the State Research Centre for Applied Microbiology in Obolensk ; the Vector State Research Center of Virology and Biotechnology in Koltsovo ; and the Institute of Ultrapure Preparations, in Leningrad (now Saint Petersburg). The Russians obstructed the team and tried to stop inspection of key areas of the facilities; they also lied about the use to which parts of the installations were put. On one visit to the Vector facility, Kelly had a conversation with a laboratory assistant—one who was too low grade to have been fully briefed by the KGB . Kelly asked the assistant about the work he was doing, and was surprised when the man said he was involved in testing smallpox . Kelly questioned Lev Sandakchiev , the head of Vector, about the use of smallpox, but received no answers. Kelly described the questioning sessions as "a very tense moment". In a 2002 review of the verification process, Kelly wrote: The visits did not go without incident. At Obolensk, access to parts of the main research facility—notably the dynamic aerosol test chambers and the plague research laboratories—was denied on the spurious grounds of quarantine requirements. Skirmishes occurred over access to an explosive aerosol chamber because the officials knew that closer examination would reveal damning evidence of offensive BW activities. At Koltsova access was again difficult and problematic. The most serious incident was when senior officials contradicted an admission by technical staff that research on smallpox was being conducted there. The officials were unable to properly account for the presence of smallpox and for the research being undertaken in a dynamic aerosol test chamber on orthopoxvirus, which was capable of explosive dispersal. At the Institute of Ultrapure Preparations in Leningrad (Pasechnik's former workplace), dynamic and explosive test chambers were passed off as being for agricultural projects, contained milling machines were described as being for the grinding of salt, and studies on plague, especially production of the agent, were misrepresented. Candid and credible accounts of many of the activities at these facilities were not provided. Two official reports of the visit concluded that Soviets were running a covert and illegal BW programme . Kelly also took part in reciprocal visits to the United States Army Medical Research Institute of Infectious Diseases at Fort Detrick , Maryland , and visits to Porton Down by Russian and American inspectors. Despite their findings, Kelly concluded that the tripartite inspection programme had failed. It was, he said, "too ambitious; its disarmament objective deflected by issues of reciprocity and access to sites outside the territories of the three parties". He went on to add that "Russia's refusal to provide a complete account of its past and current BW activity and the inability of the American–British teams to gain access to Soviet/Russian military industrial facilities were significant contributory factors". Following the end of the Gulf War , United Nations Security Council Resolution 687 imposed the articles of Iraq's surrender. The document stated "that Iraq shall unconditionally accept the destruction, removal, or rendering harmless, under international supervision, of ... All chemical and biological weapons". This was to be made possible by "The forming of a special commission which shall carry out immediate on-site inspection of Iraq's biological, chemical and missile capabilities, based on Iraq's declarations and the designation of any additional locations by the special commission itself". The group set up was the United Nations Special Commission (UNSCOM), and Kelly was appointed to it in 1991 as one of its chief weapons inspectors in Iraq. The Iraqis had provided Rolf Ekéus , the director of UNSCOM, with a list of sites connected with the research and production of weapons of mass destruction (WMD) in the country, about half of which had been bombed during Operation Desert Storm. These sites provided the starting point for the investigations. In August 1991 Kelly led the first group of UN BW investigators into the country. When asked where the inspection teams would visit, he told reporters "We will go to sites which we deem to have characteristics associated with biological activity, but at the moment ... I have an open mind." The first UNSCOM missions finished with no evidence found of an Iraqi biological or chemical programme, although they did establish that some sites suspected by US intelligence services of involvement in biological or chemical warfare research were legitimate. These included a bakery, a pharmaceutical research business in Samarra, a dairy and a slaughterhouse. UNSCOM undertook 261 inspection missions to Iraq between May 1991 and December 1998, 74 of which were for biological weapons. [lower-alpha 7] Kelly led ten of the missions involved in BW inspections. In 1998 and 1999 Iraq refused to deal with UNSCOM or the inspectors; the country's President , Saddam Hussein , singled out Kelly by name for expulsion from the country. During an inspection mission to Iraq in 1998, Kelly worked alongside an American translator and US Air Force officer, Mai Pederson, who introduced him to the Bahá'í Faith . Kelly remained a member of the faith for the rest of his life, attending spiritual meetings near his home of Southmoor , Oxfordshire . He was, for a time, the treasurer of his local branch, based in Abingdon , Oxfordshire. His time in Iraq left him with a deep affection for the country, its people and culture, although he abhorred Saddam's government. In 2000 UNSCOM was replaced by the United Nations Monitoring, Verification and Inspection Commission (UNMOVIC), whose mission and aims were similar to that of UNSCOM: to remove Iraqi WMDs and "to operate a system of ongoing monitoring and verification to check Iraq's compliance with its obligations not to reacquire the same weapons prohibited to it by the Security Council". Kelly returned to work as a government advisor with the MoD on biological warfare, but also worked with UNMOVIC and continued to visit Iraq. He was involved in at least 36 missions to Iraq as part of UNSCOM and UNMOVIC, [lower-alpha 8] and, despite interference and obstruction tactics by the Iraqis, was instrumental in making the breakthrough to discover Iraq's BW facilities: the anthrax production programme at the Salman Pak facility and a BW programme run at Al Hakum . In his 2002 State of the Union address, George W. Bush , the President of the United States , discussed the use of WMD by the Iraqi regime. Later that year he reaffirmed that "the stated policy of the United States is regime change". As part of the British government's arguments for war on Saddam, Tony Blair , the British Prime Minister , instructed the publication of a dossier on Iraqi WMD on 24 September 2002. [lower-alpha 9] The dossier, which was "based, in large part, on the work of the Joint Intelligence Committee (JIC)", included the statement that the Iraqi government had: continued to produce chemical and biological agents; military plans for the use of chemical and biological weapons, including against its own Shia population. Some of these weapons are deployable within 45 minutes of an order to use them; command and control arrangements in place to use chemical and biological weapons. Authority ultimately resides with Saddam Hussein. Before its publication, Kelly had been shown a draft copy of the dossier and took part in a meeting at the DIS to review it. Four pages of comments were made regarding the information in the report, of which Kelly contributed twelve individual statements. The observations from the DIS were passed up to the Joint Intelligence Organisation ; none of the observations referred to the 45-minute claim. On 8 November 2002 the UN Security Council passed Resolution 1441 , "a final opportunity to comply with its disarmament obligations under relevant resolutions of the Council; and accordingly decides to set up an enhanced inspection regime with the aim of bringing to full and verified completion the disarmament process". The resolution stated that the Iraqi government needed to provide full details of its WMD programme within 30 days. [lower-alpha 10] As a result of the increasing pressure on the Iraqi government, UNSCOM inspectors were readmitted to the country and were provided information on the Iraqi WMD programme. According to Kelly, despite the steps taken, Saddam "refuse[d] to acknowledge the extent of his chemical and biological weapons and associated military and industrial support organisations", and there was still a concern about "8,500 litres of anthrax VX, [ sic ] 2,160 kilograms of bacterial growth media, 360 tonnes of bulk chemical warfare agent, 6,500 chemical bombs and 30,000 munitions capable of delivering chemical and biological warfare agents [which] remained unaccounted for from activities up to 1991". In February 2003 Colin Powell , the US Secretary of State , addressed the United Nations Security Council to discuss Iraq's WMD. He included information on mobile weapons laboratories , which he described as "trucks and train cars ... easily moved and ... designed to evade detection by inspectors. In a matter of months, they can produce a quantity of biological poison equal to the entire amount that Iraq claimed to have produced in the years prior to the Gulf War." Following his examination of the vehicles in question, Kelly spoke, off the record , to journalists from The Observer . In their article in the newspaper on 15 June 2003 they described him as "a British scientist and biological weapons expert", and quoted him as saying: They are not mobile germ warfare laboratories. You could not use them for making biological weapons. They do not even look like them. They are exactly what the Iraqis said they were—facilities for the production of hydrogen gas to fill balloons. One of the journalists who wrote the story, Peter Beaumont , confirmed to the Hutton Inquiry that Kelly was the source of this quote. Kelly was often approached by the press and would either clear the discussion with the press office of the FCO, or use his judgement before doing so; it was within his remit to liaise with the media. [lower-alpha 11] Shortly before the 2003 invasion of Iraq (20 March – 1 May 2003) Kelly anonymously wrote an article on the threat from Saddam which was never published. He outlined his thoughts on the build-up to war: Iraq has spent the past 30 years building up an arsenal of weapons of mass destruction (WMD). Although the current threat presented by Iraq militarily is modest, both in terms of conventional and unconventional weapons, it has never given up its intent to develop and stockpile such weapons for both military and terrorist use. He continued that "The long-term threat, however, remains Iraq's development to military maturity of weapons of mass destruction—something that only regime change will avert." On 20 March 2003 British and American troops entered Iraq to bring about the regime change. Most of the country was occupied and Saddam was overthrown within four weeks; Bush stated that war was over on 1 May 2003. On 7 May 2003 Kelly was telephoned by Susan Watts , the science editor of the BBC 's Newsnight programme; the call lasted 15 to 20 minutes. They discussed various matters relating to Iraq including, towards the end of the conversation, the matter of the 45-minute claim. Watts's handwritten shorthand notes showed Kelly stated the claim was "a mistake to put in. Alastair Campbell seeing something in there, single source but not corroborated, sounded good." [lower-alpha 12] The pair also had a subsequent call on 12 May. Kelly flew to Kuwait on 19 May as part of a military team. He hoped to meet members of the Iraq Survey Group to see how the organisation worked. When he arrived in Kuwait he found that no visa had been arranged for him, so he returned home. On 22 May 2003 Kelly met Andrew Gilligan , the Defence and Diplomatic Correspondent for BBC Radio 4 's Today programme, at the Charing Cross Hotel, London. It was the third time the pair had met. The meeting, initiated by Gilligan, was for the journalist to ask why Kelly thought WMDs had not been discovered in Iraq by the British and American troops. According to Gilligan, after 30 minutes the conversation focussed on the September Dossier and how key areas of the document were altered to give greater impact to the public. Gilligan took notes on an electronic organiser; he said these read as Transformed week before publication to make it sexier. The classic was the 45 minutes. Most things in dossier were double source but that was single source. One source said it took 4 [that should be 45] minutes to set up a missile assembly, that was misinterpreted. Most people in intelligence weren't happy with it because it didn't reflect the considered view they were putting forward. Campbell: real information but unreliable, included against our wishes. Not in original draft - dull, he asked if anything else could go in. [lower-alpha 13] Soon after the meeting, Gilligan claimed, he wrote a full script of the interview, based on his memory and notes. Between the completion of the document and the start of the Hutton Inquiry in August, Gilligan says he lost that script. Kelly was in New York on 29 May 2003, attending the final commissioners' meeting of UNMOVIC under the leadership of Hans Blix . At 6.07 that morning, on the Today programme, Gilligan explained to the programme's host, John Humphrys , what he would be discussing later in the programme: what we've been told by one of the senior officials in charge of drawing up that dossier was that, actually the government probably erm, knew that that forty five minute figure was wrong, even before it decided to put it in. What this person says, is that a week before the publication date of the dossier, it was actually rather erm, a bland production. It didn't, the, the draft prepared for Mr Blair by the Intelligence Agencies actually didn't say very much more than was public knowledge already and erm, Downing Street, our source says, ordered a week before publication, ordered it to be sexed up, to be made more exciting and ordered more facts to be er, to be discovered. Gilligan had not been able to get confirmation from any other sources about the veracity of the claim. The producer of Today , Kevin Marsh , writes that Gilligan went off his pre-prepared script. With news based on an anonymous single source, stories "have to be reported word perfectly" to be precise about the meaning; according to Marsh, "Gilligan had lost control of that precision". Downing Street had not been forewarned of the story, or been contacted to ask for a statement. At 7:32 am the government press office issued a statement to refute the story: "Not one word of the dossier was not entirely the work of the intelligence agencies". Gilligan then broadcast a report for the BBC Radio 5 Live Breakfast programme in which he repeated the claim that the government had inserted the 45-minute claim into the dossier. Kelly did not recognise himself from Gilligan's description of a "senior official in charge of drawing up the document"; Kelly had taken no part in drafting the document and had only been asked for comments on the contents. The following day Watts telephoned Kelly at home to discuss the quotes on the Today programme; she recorded the call. When she asked him if he was being questioned about the identity of the source, Kelly replied "I mean they wouldn't think it was me, I don't think. Maybe they would, maybe they wouldn't. I don't know". Their conversation also included the possible involvement of Campbell in the inclusion of the 45-minute claim in the dossier: SW OK just back momentarily on the 45 minute issue I'm feeling like I ought to just explore that a little bit more with you the um err. So would it be accurate then, as you did that earlier conversation, to say that it was Alastair Campbell himself who... DK No I can't. All I can say is the Number Ten press office. I've never met Alastair Campbell so I can't ... But I think Alastair Campbell is synonymous with that press office because he's responsible for it. Despite the denial from the government, on 1 June—the day after Kelly and Watts had spoken on the telephone—Gilligan wrote an article for The Mail on Sunday in which he specifically named Campbell; it was titled: "I asked my intelligence source why Blair misled us all over Saddam's weapons. His reply? One word ... CAMPBELL". According to the journalist Miles Goslett , the report on the Today programme "caused little more than a ripple" of interest; the newspaper article "was of major international significance. It was career-threatening for all concerned if substantiated". As political tumult between Downing Street and the BBC developed, Kelly alerted his line manager at the MoD, Bryan Wells, that he had met Gilligan and discussed, among other points, the 45-minute claim. In a detailed letter of 30 June, Kelly stated that any mention of Campbell had been raised by Gilligan, not himself, and that this was an aside. Kelly stated that "I did not even consider that I was the 'source' of Gilligan's information"; he only became aware of the possibility after Gilligan had appeared at the Foreign Affairs Select Committee on 19 June. Kelly said of Gilligan's evidence that "The description of that meeting in small part matches my interaction with him especially my personal evaluation of Iraq's capability but the overall character is quite different". In closing, he reiterated that "With hindsight I of course deeply regret talking to Andrew Gilligan even though I am convinced that I am not his primary source of information." Kelly was interviewed twice by his employers—on 3 and 7 July; they concluded that he may have been Gilligan's source, but that Gilligan may have exaggerated what Kelly said. A decision was taken that no official action was to be taken against Kelly. He was also advised that, with journalists pressing for further information, it was possible his name would emerge in press reports. Reports in The Times by the journalist Tom Baldwin on 5 and 8 July gave significant hints on the identity of Gilligan's source. At a meeting chaired by Blair on 8 July it was agreed that a statement should be released that stated a member of the MoD had come forward to say that he was the source. It was also agreed that Kelly's name would not be released to journalists, but if someone guessed who it was, they were allowed to confirm it. Kevin Tebbit , the permanent secretary at the MoD—Kelly's ultimate superior at the department—arrived at the end of the meeting and was unable to provide any input. [lower-alpha 14] At 5:54 pm on 8 July the government statement was released. Without naming Kelly, it said a member of the MoD had come forward to admit that he had met Gilligan at an unauthorised meeting a week before Gilligan's broadcast. The statement said that this MoD employee was not in a position to comment on Campbell's role in the 45 minute issue as he had not helped draw up the intelligence report and had not seen it. At 5:50 pm the following day a journalist from The Financial Times guessed Kelly's name correctly; a journalist from The Times did so soon afterwards after nineteen failed guesses. On the evening of 8 July Nick Rufford, a journalist with The Sunday Times who had known Kelly for five years, visited him at home in Southmoor. Rufford told him that his name would be published in the papers the following day. He advised Kelly to leave his home that night to avoid the media, and said the newspaper would put Kelly and his wife up at a hotel. Soon after Rufford left he contacted the MoD and asked if Kelly could write a piece for the paper putting forward his version of events; the MoD press office said this was unlikely. Soon afterwards the MoD phoned Kelly and advised him to find somewhere else to stay the night. According to Mrs Kelly, the couple left the house within 15 minutes and drove to Cornwall , breaking the journey overnight in Weston-super-Mare , Somerset , where they arrived by 9:45 pm. Although the trip to Cornwall was described by Mrs Kelly at the Hutton Inquiry, Baker considers that there are "problems with the version of events we are asked to accept"; Goslett writes that Kelly played cribbage with a pub team in Kingston Bagpuize that night and was there until at least 10:30 pm. None of those on Kelly's cribbage team were asked to give evidence to the Hutton Inquiry. While in Cornwall, on the morning of 11 July, Kelly had a telephone call from Bryan Wells to tell him that he would have to appear in front of the Intelligence and Security and Foreign Affairs select committees. He was told that the latter of these would be televised, something that upset him greatly, according to his wife. That afternoon, still unhappy with the news from the earlier phone call, he spoke to Wells again nine times. They agreed to meet on Monday 14 July to prepare for the interviews. Kelly returned from Cornwall on 13 July and stayed in Oxford at his daughter Rachel's house. Kelly's appearance before the Foreign Affairs Select Committee was against the advice of Tebbit, the most senior civil servant at the MoD. He had been overruled by Geoff Hoon , the Secretary of State for Defence . Kelly appeared in front of the committee on 15 July in a session that lasted over an hour. He spoke so softly the fans in the room were turned off so the committee members could hear him reply; according to Baker, "Every word [from Kelly] was weighed carefully and some painful circumlocutions resulted". Kelly told the committee that he had met Gilligan but, as the journalist Tom Mangold , in Kelly's biography in the Dictionary of National Biography writes, "denied that he had said the things Gilligan reported his source as having said". Kelly was questioned by the Liberal Democrat MP David Chidgey about conversations with Susan Watts. It was the first time her name had been connected with Kelly in public, and it was later established that Gilligan had not only sent Chidgey excerpts from a recorded conversation, but also gave Chidgey questions to ask Kelly. The quote included Kelly's opinion on the 45 minute claim. The quote read out by Chidgey included: "The 45 minutes was a statement that was made and it got out of all proportion. They were desperate for information. They were pushing hard for information that could be released. That was one that popped up and it was seized on and it is unfortunate that it was." Chidgey asked Kelly if the quotes came from the meeting he had with Watts in November 2002—the only time the pair had met face-to-face; Kelly replied that "I cannot believe that on that occasion I made that statement". According to Goslett, this was a truthful statement, as Kelly had not made the statement in November 2002, but on 30 May that year. Mangold notes that Kelly appeared to be under stress during the interview, and that some of the questioning was overtly hostile. One Labour MP, Andrew MacKinlay , questioned Kelly towards the end of the session: Andrew MacKinlay : I reckon you are chaff; you have been thrown up to divert our probing. Have you ever felt like a fall-guy? You have been set up, have you not? Dr Kelly : That is not a question I can answer. Andrew MacKinlay : But you feel that? Dr Kelly : No, not at all. I accept the process that is going on. After the hearing Kelly described MacKinlay to his daughter as an "utter bastard". On the following day, 16 July 2003, Kelly gave evidence to the Intelligence and Security Committee. He appeared more relaxed than he had in front of the Foreign Affairs Committee, according to Baker. When asked, Kelly described the September dossier as "an accurate document, I think it is a fair reflection of the intelligence that was available and it's presented in a very sober and factual way." On the morning of 17 July Kelly worked from his home in Southmoor, answering written parliamentary questions from two MPs—MacKinlay on the identity of the journalists Kelly had spoken to, and the Conservative MP Bernard Jenkin on Kelly's discussions with Gilligan and whether he would be disciplined for it; Kelly had to provide the information to the MoD to forward on. He had a telephone call with Wing Commander John Clark, a friend and colleague, during which they discussed the general situation Kelly was in, as well as a trip to Iraq on which Kelly was due to go in the following week. Clark reported that Kelly seemed to be "very tired, but in good spirits". He had received several emails from well-wishers, including from The New York Times journalist Judith Miller , to which he replied "I will wait until the end of the week before judging—many dark actors playing games. Thanks for your support." During the course of the day Kelly received a phone call that changed his mood. Mangold states that "[the] most likely explanation is that he learned from a well-meaning friend at the Ministry of Defence that the BBC had tape-recorded evidence which, when published, would show that he had indeed said the things to Susan Watts that he had formally denied saying". Mrs Kelly was ill that day and spent some time lying down in the couple's bedroom, but she got up at 3:00 pm to find Kelly speaking on the phone, before she returned to her bedroom to sleep. Goslett thinks this phone call is likely to have been with Clark, in a discussion about one of the answers to the parliamentary questions. Kelly left for a walk between 3:00 and 3:20 pm and was last seen by Ruth Absalom, a neighbour, with whom he stopped to have a chat. She was the last person known to have seen him alive. Clark tried to contact Kelly at home—where Mrs Kelly told him that her husband had gone for a walk—and then on Kelly's mobile, which was switched off; Clark stated he was surprised it was off as Kelly was normally easily contactable. As far as it is known, Kelly walked a mile (1.6 km) from his house to Harrowdown Hill. It appears he ingested up to 29 tablets of co-proxamol , an analgesic drug; he also cut his left wrist with a pruning knife he had owned since his youth, severing his ulnar artery . Forensic analysis established that neither the knife nor the blister packs showed Kelly's fingerprints on their surfaces. Rachel Kelly spoke to her mother in the late afternoon, then drove to her parents' house at around 6:00 pm. As her father had not returned, Rachel walked a route along a footpath her father was known to use regularly to try and find him; she returned to the house at around 6:30 pm, then drove round to see if she could find anything. Sian, the Kellys' eldest daughter, also came to the house that night, and at 11:40 pm they phoned the police. Three officers from the local station in Abingdon arrived within 15 minutes; they searched the house and garden straight away. By 1:00 am a search helicopter from RAF Benson , fitted with thermal imaging equipment, had been requested; teams of search dogs were also provided and a 26-metre (85 ft) communications mast was erected, as the Kellys' home was in a mobile communications black spot. The police used volunteer search teams, and it was one of these that found Kelly's body on Harrowdown Hill at about 9:20 am on 18 July. The two-person team differed in their description of the position of the body: one stated Kelly was "at the base of the tree with almost his head and his shoulders just slumped back against the tree"; the other stated Kelly was "sitting with his back up against a tree". The police and paramedics differed from both the searchers. DC Coe, one of the first policemen at the scene, stated the body "was laying on its back—the body was laying on its back by a large tree, the head towards the trunk of the tree"; the pathologist called to the scene, Nicholas Hunt, recalled that: "his head was quite close to branches and so forth, but not actually over the tree." Blair was on an aeroplane from Washington to Tokyo when the body was found. He was contacted while en route and informed of the news, although Kelly had not been formally identified at that stage. He decided to order a judicial inquiry to examine the circumstances, which was to be headed by Lord Hutton , a former Lord Chief Justice of Northern Ireland . His terms of reference were "urgently to conduct an investigation into the circumstances surrounding the death of Dr Kelly". Hunt undertook the post-mortem examination on 19 July in the presence of eight police officers and two members of the coroner 's office. Hunt concluded that the cause of death was a haemorrhage caused by a self-inflicted injury from "incised wounds to the left wrist", with the contributory factors of "co-proxamol ingestion and coronary artery atherosclerosis ". On 20 July 2003, the day after the post-mortem, the BBC confirmed that Kelly was their only source. Nicholas Gardner, the coroner, opened and adjourned his inquest on 21 July, noting that the pathologist was still awaiting the toxicology report. With the establishment of the inquiry under Hutton, the Lord Chancellor's Department contacted Nicholas Gardner, the coroner, to advise him that under section 17A of the Coroners Act 1988 , the coroner's inquest should only be resumed if there were exceptional circumstances to do so. On 6 August 2003, five days after the preliminary session of the Hutton Inquiry, Kelly was buried at St Mary's Church, Longworth . From 11 August to 4 September 2003 witnesses to the inquiry were called in the order of the chronology of events. The second stage of the inquiry took place between 15 and 25 September 2003; Hutton explained that he "would ask persons, who had already given evidence and whose conduct might possibly be the subject of criticism in my report, to come back to be examined further". There was one additional day used, 13 October 2003, to hear from one witness who had been ill on their scheduled day. As well as members of the Kelly family, evidence was taken from BBC employees (including Gilligan, Watts and Richard Sambrook , the BBC's Director of News) members of the government and its advisors (including Blair, Campbell, Hoon and McKinley) and civil servants, including John Scarlett , chairman of the JIC and Richard Dearlove , head of the Secret Intelligence Service (MI6). One of the witnesses who gave evidence to Hutton was David Broucher , the UK's permanent representative to the Conference on Disarmament . In 2002 or 2003 he had asked Kelly what would happen if Iraq were invaded; Kelly had replied "I will probably be found dead in the woods". [lower-alpha 15] Over the 24 days evidence was taken, the inquiry questioned 74 witnesses and received over 10,000 pages of evidence; most of the documents, along with transcripts of the questioning, were published online by the inquiry team. Hutton reported on 28 January 2004 and wrote "I am satisfied that Dr Kelly took his own life by cutting his left wrist and that his death was hastened by his taking Co-proxamol tablets. I am further satisfied that there was no involvement by a third person in Dr Kelly's death". Hutton also concluded that the September dossier had not been "sexed up" by the government, or by Campbell, but was the work of the JIC. He cleared the government and its ministers of any wrongdoing and reserved his criticism for the BBC and Gilligan. According to George Jones , the political correspondent for The Daily Telegraph , Hutton's judgement on the BBC was "damning and shocked its journalists with its ferocity. He said the corporation had a "defective" editorial system that allowed Gilligan to make "unfounded" claims questioning the Government's integrity". Despite the conclusion of the Hutton report that Kelly killed himself, there was continued debate over the manner of his death. Several doctors questioned the conclusion on medical grounds, although their position has been doubted by pathologists. [lower-alpha 16] The former leader of the Conservative Party, Michael Howard , and the former Liberal Democrat MP, Norman Baker , both thought Kelly was murdered. In 2007 Baker published The Strange Death of David Kelly in which he argued that Kelly did not die by suicide. Kelly's family expressed their displeasure at the publication; his sister-in-law said: "It is just raking over old bones. I can't speak for the whole family, but I've read it all [Baker's theories], every word, and I don't believe it." In March 2004 the Oxfordshire coroner, Nicholas Gardiner, convened a hearing to decide whether there were the "exceptional circumstances" needed to resume the inquest; he concluded that such circumstances did not exist and that an inquest was not required. In December 2009 six doctors applied to the Oxford coroner's office to reopen the inquest, claiming that there was insufficient evidence for Hutton's conclusion of suicide. Their request was turned down on legal advice, and they were informed that evidence relating to Kelly's death was to be kept secret for 70 years. Hutton stated that he did so "solely in order to protect Dr Kelly's widow and daughters for the remainder of their lives (the daughters being in their twenties at that time) from the distress which they would suffer from further discussion of the details of Dr Kelly's death in the media". The Attorney General , Dominic Grieve , reviewed the case between 2010 and 2011. He spoke to both Hutton and Gardner before he concluded that there was no benefit in opening a new inquest into the matter; he stated that there was "overwhelmingly strong" evidence that Kelly killed himself. Prior to Grieve's decision, the government released the post-mortem and toxicology reports that Hutton had said should be sealed for 70 years. Both documents supported the conclusion of the Hutton Inquiry. The pathologist wrote in the post-mortem: It is my opinion that the main factor involved in bringing about the death of David Kelly is the bleeding from the incised wounds to his left wrist. Had this not occurred he may well not have died at this time. Furthermore, on the balance of probabilities, it is likely that the ingestion of an excess number of co-proxamol tablets coupled with apparently clinically silent coronary artery disease would both have played a part in bringing about death more certainly and more rapidly than would have otherwise been the case. Therefore I give as the cause of death: Kelly's grave was a focal point for the campaign group "Justice for Kelly", who left placards demanding an inquest and undertook vigils at the graveside. Following complaints by his widow and a request by her to the Diocese of Oxford , Kelly's remains were exhumed in June 2017 and were reportedly cremated. Kelly's death and the preceding events have served as an inspiration for artistic tributes and dramatisations, including the 2006 song " Harrowdown Hill " by Thom Yorke ; a 2008 painting, Death of David Kelly , by Dexter Dalwood ; Jonathan Coe 's 2015 novel Number 11 ; and a poem, "Hand-Washing Technique – Government Guidelines" (subtitled "i.m. Dr David Kelly"), by Simon Armitage . Kelly was the subject of a 2005 television drama, The Government Inspector , starring Mark Rylance , and "Justifying War: Scenes from the Hutton Inquiry" a radio play by the Tricycle Theatre . Kelly's last moments are featured in the centre monologue of the stage play Palace of the End by Judith Thompson . There have also been documentaries on British television and radio about Kelly. [lower-alpha 17] In the 1996 Birthday Honours Kelly was appointed as Companion of the Order of St Michael and St George (CMG); the citation reads: He devised the scientific basis for the enhanced biological warfare defence programme and led strong research groups in many key areas. Following the Gulf War he led the first biological warfare inspection in Iraq and has spent most of his time since either in Iraq or at various sites in the former Soviet Union helping to shed light on past biological warfare related activities and assisting the UK/US RUS trilateral confidence building process. He has pursued this work tirelessly and with good humour despite the significant hardship, hostility and personal risk encountered during extended periods of service in both countries. ... His efforts in his specialist field have had consequences of international significance. Lord Hutton, in the report to his inquiry, suggested that Kelly might well have been under consideration for a knighthood in May 2003. Kelly's work in Iraq earned him a nomination for the Nobel Peace Prize ; his biographer Norman Baker wrote of Kelly: It is no exaggeration to say that between 1990 and his death in 2003, Dr Kelly probably did more to make the world a more secure place than anyone on the planet. Even among the elite group of international weapons inspectors, he was regarded with some awe, as the inspectors' inspector.

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Orthopoxvirus

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Ribavirin

AU : X (High risk) 1-[(2"R",3"R",4"S",5"R")-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1"H"-1,2,4-triazole-3-carboxamide OC[C@@H](O1)[C@@H](O)[C@@H](O)[C@@H]1N2N=C(C(N)=O)N=C2 InChI=1S/C8H12N4O5/c9-6(16)7-10-2-12(11-7)8-5(15)4(14)3(1-13)17-8/h2-5,8,13-15H,1H2,(H2,9,16)/t3-,4-,5-,8-/m1/s1 Y Key:IWUCXVSUMQZMFG-AFCXAGJDSA-N Y Ribavirin , also known as tribavirin , is an antiviral medication used to treat RSV infection , hepatitis C and some viral hemorrhagic fevers . For hepatitis C, it is used in combination with other medications such as simeprevir , sofosbuvir , peginterferon alfa-2b or peginterferon alfa-2a . Among the viral hemorrhagic fevers it is sometimes used for Lassa fever , Crimean–Congo hemorrhagic fever , and Hantavirus infection but should not be used for Ebola or Marburg infections. Ribavirin is taken orally (swallowed by mouth) or inhaled . Despite widespread usage, since the 2010s it has faced scrutiny for a lack of efficacy in treating viral infections it has historically been prescribed for. Common side effects include tiredness, headache, nausea, fever, muscle pains, and an irritable mood. Serious side effects include red blood cell breakdown , liver problems , and allergic reactions . Use during pregnancy results in harm to the baby. Effective birth control is recommended for both males and females for at least seven months during and after use. The mechanism of action of ribavirin is not entirely clear. Ribavirin was patented in 1971 and approved for medical use in 1986. It is on the World Health Organization's List of Essential Medicines . It is available as a generic medication . Ribavirin is used primarily to treat chronic hepatitis C and viral hemorrhagic fevers (which is an orphan indication in most countries). Its efficacy for these purposes has been questioned: it has an FDA boxed warning against its use as a monotherapy (sole drug) for chronic hepatitis C, and thus it may only be prescribed in the United States as an adjunct to one or more other medications. Its efficacy against other viruses, including those that cause viral hemorrhagic fever, has not been conclusively demonstrated, and it is not approved in the United States for treatment of viruses other than HCV. For chronic hepatitis C, the oral (capsule or tablet) form of ribavirin is used only in combination with pegylated interferon alfa . Statins may improve this combination's efficacy in treating hepatitis C. When possible, genotyping of the specific viral strain is done; ribavirin is only used as a dose-escalating [lower-alpha 1] adjuvant to specific combinations of genotypes and other medications. Acute hepatitis C infection (within the first 6 months) often does not require immediate treatment, as many infections eventually resolve without treatment. When the decision is made to treat acute hepatitis C, ribavirin may be used as an adjunct to several drug combinations. However, other medications are preferred. Ribavirin is the only known treatment for a variety of viral hemorrhagic fevers , including Lassa fever , Crimean-Congo hemorrhagic fever , Venezuelan hemorrhagic fever , and Hantavirus infection, although data regarding these infections are scarce and the drug might be effective only in early stages. It is noted by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) that "Ribavirin has poor in vitro and in vivo activity against the filoviruses ( Ebola and Marburg ) and the flaviviruses ( dengue , yellow fever , Omsk hemorrhagic fever , and Kyasanur forest disease )" The aerosol form has been used in the past to treat respiratory syncytial virus -related diseases in children, although the evidence to support this is rather weak. Despite questions surrounding its efficacy, ribavirin remains the only antiviral known to be effective in treating Lassa fever. It has been used (in combination with ketamine , midazolam , and amantadine ) in treatment of rabies . Experimental data indicate that ribavirin may have useful activity against canine distemper and poxviruses . Ribavirin has also been used as a treatment for herpes simplex virus . One small study found that ribavirin treatment reduced the severity of herpes outbreaks and promoted recovery, as compared with placebo treatment. Another study found that ribavirin potentiated the antiviral effect of acyclovir . Some interest has been seen in its possible use as a treatment for cancers with elevated eukaryotic translation initiation factor eIF4E, especially acute myeloid leukemia (AML) as well as in head and neck cancers. Ribavirin targeted eIF4E in AML patients in monotherapy and combination studies and this corresponded to objective clinical responses including complete remissions. Ribavirin resistance in AML patients arose leading to loss of eIF4E targeting and relapse. Resistance was caused by deactivation of ribavirin through its glucuronidation in AML cells or impaired drug entry/retention in the AML cells. There may be additional forms of ribavirin resistance displayed by cancer cells. In HPV related oropharyngeal cancers, ribavirin reduced levels of phosphorylated form of eIF4E in some patients. The best response here was stable disease but another head and neck study had more promising results. For chronic hepatitis C, the oral (capsule or tablet) form of ribavirin is used only in combination with pegylated interferon alfa . Statins may improve this combination's efficacy in treating hepatitis C. When possible, genotyping of the specific viral strain is done; ribavirin is only used as a dose-escalating [lower-alpha 1] adjuvant to specific combinations of genotypes and other medications. Acute hepatitis C infection (within the first 6 months) often does not require immediate treatment, as many infections eventually resolve without treatment. When the decision is made to treat acute hepatitis C, ribavirin may be used as an adjunct to several drug combinations. However, other medications are preferred. Ribavirin is the only known treatment for a variety of viral hemorrhagic fevers , including Lassa fever , Crimean-Congo hemorrhagic fever , Venezuelan hemorrhagic fever , and Hantavirus infection, although data regarding these infections are scarce and the drug might be effective only in early stages. It is noted by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) that "Ribavirin has poor in vitro and in vivo activity against the filoviruses ( Ebola and Marburg ) and the flaviviruses ( dengue , yellow fever , Omsk hemorrhagic fever , and Kyasanur forest disease )" The aerosol form has been used in the past to treat respiratory syncytial virus -related diseases in children, although the evidence to support this is rather weak. Despite questions surrounding its efficacy, ribavirin remains the only antiviral known to be effective in treating Lassa fever. It has been used (in combination with ketamine , midazolam , and amantadine ) in treatment of rabies . Experimental data indicate that ribavirin may have useful activity against canine distemper and poxviruses . Ribavirin has also been used as a treatment for herpes simplex virus . One small study found that ribavirin treatment reduced the severity of herpes outbreaks and promoted recovery, as compared with placebo treatment. Another study found that ribavirin potentiated the antiviral effect of acyclovir . Some interest has been seen in its possible use as a treatment for cancers with elevated eukaryotic translation initiation factor eIF4E, especially acute myeloid leukemia (AML) as well as in head and neck cancers. Ribavirin targeted eIF4E in AML patients in monotherapy and combination studies and this corresponded to objective clinical responses including complete remissions. Ribavirin resistance in AML patients arose leading to loss of eIF4E targeting and relapse. Resistance was caused by deactivation of ribavirin through its glucuronidation in AML cells or impaired drug entry/retention in the AML cells. There may be additional forms of ribavirin resistance displayed by cancer cells. In HPV related oropharyngeal cancers, ribavirin reduced levels of phosphorylated form of eIF4E in some patients. The best response here was stable disease but another head and neck study had more promising results. The medication has two FDA "black box" warnings: One raises concerns that use before or during pregnancy by either sex may result in birth defects in the baby, and the other is regarding the risk of red blood cell breakdown. Ribavirin should not be given with zidovudine because of the increased risk of anemia; concurrent use with didanosine should likewise be avoided because of an increased risk of mitochondrial toxicity . It is a guanosine (ribonucleic) analog used to stop viral RNA synthesis and viral mRNA capping, thus, it is a nucleoside analog. Ribavirin is a prodrug , which when metabolized resembles purine RNA nucleotides . In this form, it interferes with RNA metabolism required for viral replication. Over five direct and indirect mechanisms have been proposed for its mechanism of action. The enzyme inosine triphosphate pyrophosphatase (ITPase) dephosphorylates ribavirin triphosphate in vitro to ribavirin monophosphate, and ITPase reduced enzymatic activity present in 30% of humans potentiates mutagenesis in hepatitis C virus. Ribavirin's amide group can make the native nucleoside drug resemble adenosine or guanosine, depending on its rotation. For this reason, when ribavirin is incorporated into RNA, as a base analog of either adenine or guanine, it pairs equally well with either uracil or cytosine , inducing mutations in RNA-dependent replication in RNA viruses. Such hypermutation can be lethal to RNA viruses. Neither of these mechanisms explains ribavirin's effect on many DNA viruses, which is more of a mystery, especially given the complete inactivity of ribavirin's 2' deoxyribose analogue, which suggests that the drug functions only as an RNA nucleoside mimic, and never a DNA nucleoside mimic. Ribavirin 5'-monophosphate inhibits cellular inosine monophosphate dehydrogenase , thereby depleting intracellular pools of GTP. [ failed verification ]Ribavirin's amide group can make the native nucleoside drug resemble adenosine or guanosine, depending on its rotation. For this reason, when ribavirin is incorporated into RNA, as a base analog of either adenine or guanine, it pairs equally well with either uracil or cytosine , inducing mutations in RNA-dependent replication in RNA viruses. Such hypermutation can be lethal to RNA viruses. Neither of these mechanisms explains ribavirin's effect on many DNA viruses, which is more of a mystery, especially given the complete inactivity of ribavirin's 2' deoxyribose analogue, which suggests that the drug functions only as an RNA nucleoside mimic, and never a DNA nucleoside mimic. Ribavirin 5'-monophosphate inhibits cellular inosine monophosphate dehydrogenase , thereby depleting intracellular pools of GTP. [ failed verification ]The eukaryotic translation initiation factor eIF4E plays multiple roles in RNA metabolism with translation being the best described. Biophysical and NMR studies first revealed that ribavirin directly bound the eIF4E,  providing another mechanism for its action. 3 H Ribavirin also interacts with eIF4E in cells. While inosine monophosphate dehydrogenase (IMPDH) presumably only binds the ribavirin monophosphate metabolite (RMP), eIF4E can bind ribavirin and with higher affinity ribavirin's phosphorylated forms. In many cell lines, studies into steady state levels of metabolites indicate that ribavirin triphosphate (RTP) is more abundant than the RMP metabolite which is the IMPDH ligand. RTP binds to eIF4E in its cap-binding site as observed by NMR. Ribavirin inhibits eIF4E activities in cells including in its RNA export, translation and oncogenic activities lines. In AML patients treated with ribavirin, ribavirin blocked the nuclear import of eIF4E through interfering with its interaction with its nuclear importer, Importin 8, thereby impairing its nuclear activities. Clinical relapse in AML patients corresponded to loss of ribavirin binding leading to nuclear re-entry of eIF4E and re-emergence of its nuclear activities. Ribavirin was first made in 1972 under the national cancer institute's Virus-Cancer program. This was done by researchers from International Chemical and Nuclear Corporation including Roberts A. Smith, Joseph T. Witkovski and Roland K. Robins. It was reported that ribavirin was active against a variety of RNA and DNA viruses in culture and in animals, without undue toxicity in the context of cancer chemotherapies. By the late 1970s, the Virus-Cancer program was widely considered a failure, and the drug development was abandoned. [ citation needed ] After the US Government announced that AIDS was caused by a retrovirus in 1984, drugs examined during the Virus-Cancer program and its focus on retroviruses were re-examined. Although the FDA first approved ribavirin as an antiviral in 1986, it was not indicated to treat HIV or AIDS. As a result, many people with AIDS sought to obtain black market ribavirin via buyer's clubs . The drug was approved for investigational use against hantavirus in the United States in 1993, but the results from a non-randomized uncontrolled trial were not encouraging: 71% of recipients became anemic and 47% died. In 2002 with the SARS outbreak , early speculation focused on Ribavirin as a possible anti-SARS agent. Early protocols adopted in Hong Kong adopted a "Hit Hard Hit Early" approach treating SARS with high doses of off-label steroids and Ribavirin. Unfortunately, it later turned out this haphazard approach was at best ineffective and at worst fatal, with many deaths attributed to SARS caused by ribavirin toxicity. Ribavirin is the INN and USAN , whereas tribavirin is the BAN . Brand names of generic forms include Copegus, Ribasphere, Rebetol. Ribavirin is the INN and USAN , whereas tribavirin is the BAN . Brand names of generic forms include Copegus, Ribasphere, Rebetol. Ribavirin is possibly best viewed as a ribosyl purine analogue with an incomplete purine 6-membered ring. This structural resemblance historically prompted replacement of the 2' nitrogen of the triazole with a carbon (which becomes the 5' carbon in an imidazole ), in an attempt to partly "fill out" the second ring--- but to no great effect. Such 5' imidazole riboside derivatives show antiviral activity with 5' hydrogen or halide, but the larger the substituent, the smaller the activity, and all proved less active than ribavirin. Note that two natural products were already known with this imidazole riboside structure: substitution at the 5' carbon with OH results in pyrazofurin , an antibiotic with antiviral properties but unacceptable toxicity, and replacement with an amino group results in the natural purine synthetic precursor 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside ( AICAR ), which has only modest antiviral properties. [ citation needed ] The most successful ribavirin derivative to date is the 3-carboxamidine derivative of the parent 3-carboxamide, first reported in 1973 by J. T. Witkowski et al., and now called taribavirin (former names "viramidine" and "ribamidine"). This drug shows a similar spectrum of antiviral activity to ribavirin, which is not surprising as it is now known to be a pro-drug for ribavirin. Taribavirin, however, has useful properties of less erythrocyte-trapping and better liver-targeting than ribavirin. The first property is due to taribavirin's basic amidine group which inhibits drug entry into RBCs, and the second property is probably due to increased concentration of the enzymes which convert amidine to amide in liver tissue. Taribavirin completed phase III human trials in 2012. The most successful ribavirin derivative to date is the 3-carboxamidine derivative of the parent 3-carboxamide, first reported in 1973 by J. T. Witkowski et al., and now called taribavirin (former names "viramidine" and "ribamidine"). This drug shows a similar spectrum of antiviral activity to ribavirin, which is not surprising as it is now known to be a pro-drug for ribavirin. Taribavirin, however, has useful properties of less erythrocyte-trapping and better liver-targeting than ribavirin. The first property is due to taribavirin's basic amidine group which inhibits drug entry into RBCs, and the second property is probably due to increased concentration of the enzymes which convert amidine to amide in liver tissue. Taribavirin completed phase III human trials in 2012.

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Orthopoxvirus

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Lumpy skin disease

Lumpy skin disease ( LSD ) is an infectious disease in cattle caused by a virus of the family Poxviridae , also known as Neethling virus . The disease is characterized by fever, enlarged superficial lymph nodes , and multiple nodules (measuring 2–5 centimetres (1–2 in) in diameter) on the skin and mucous membranes , including those of the respiratory and gastrointestinal tracts. Infected cattle may also develop edematous swelling in their limbs and exhibit lameness . The virus has important economic implications since affected animals tend to have permanent damage to their skin, lowering the commercial value of their hide . Additionally, the disease often results in chronic debility , reduced milk production, poor growth, infertility, abortion, and sometimes death. [ citation needed ] Onset of fever occurs almost one week after infection by the virus. This initial fever may exceed 41 °C (106 °F) and persist for one week. At this time, all of the superficial lymph nodes become enlarged. The nodules, which the disease is characterized by, appear seven to nineteen days after virus inoculation. Coinciding with the appearance of the nodules, discharge from the eyes and nose becomes mucopurulent . The nodular lesions involve the dermis and the epidermis , but may extend to the underlying subcutis or even to the muscle. These lesions, occurring all over the body (but particularly on the head, neck, udder , scrotum , vulva , and perineum ), may be either well-circumscribed or they may coalesce. Cutaneous lesions may be resolved rapidly or they may persist as hard lumps. The lesions can also become sequestrated, leaving deep ulcers filled with granulation tissue and often suppurating (forming pus ). At the initial onset of the nodules, they have a creamy grey to white color upon cut section, and may exude serum . After about two weeks, a cone-shaped central core of necrotic material may appear within the nodules. Additionally, the nodules on the mucous membranes of the eyes, nose, mouth, rectum , udder and genitalia quickly ulcerate, aiding in transmission of the virus. In mild cases of LSD, the clinical symptoms and lesions are often confused with Bovine Herpesvirus 2 (BHV-2), which is, in turn, referred to as pseudo-lumpy skin disease. However, the lesions associated with BHV-2 infections are more superficial. BHV-2 also has a shorter course and is more mild than LSD. Electron microscopy can be used to differentiate between the two infections. BHV-2 is characterized by intranuclear inclusion bodies , as opposed to the intracytoplasmic inclusions characteristic of LSD. Isolation of BHV-2, or its detection in negatively-stained biopsy specimens, is only possible approximately one week after the development of skin lesions. Lumpy skin disease virus (LSDV) is double-stranded DNA virus . It is a member of the capripoxvirus genus of Poxviridae . Capripoxviruses (CaPVs) represent one of eight genera within the Chordopoxvirus (ChPV) subfamily. The capripoxvirus genus consists of LSDV, as well as sheeppox virus , and goatpox virus. CaPV infections are usually host-specific within specific geographic distributions even though they are serologically indistinguishable from one another. Like other viruses in the Poxviridae family, capripoxviruses are brick-shaped. Capripoxvirus virions are different than orthopoxvirus virions in that they have a more oval profile, as well as larger lateral bodies. The average size of capripoxvirions is 320 nm by 260 nm. [ citation needed ] The virus has a 151-kbp genome , consisting of a central coding region which is bounded by identical 2.4 kbp-inverted terminal repeats and contains 156 genes. There are 146 conserved genes when comparing LSDV with chordopoxviruses of other genera. These genes encode proteins which are involved in transcription and mRNA biogenesis, nucleotide metabolism, DNA replication , protein processing, virion structure and assembly, and viral virulence and host range. Within the central genomic region, LSDV genes share a high degree of collinearity and amino acid identity with the genes of other mammalian poxviruses. Examples of viruses with similar amino acid identity include suipoxvirus , yatapoxvirus , and leporipoxvirus . In terminal regions, however, collinearity is interrupted. In these regions, poxvirus homologues are either absent or share a lower percentage of amino acid identity. Most of these differences involve genes that are likely associated with viral virulence and host range. Unique to Chordopoxviridae, LSDV contains homologues of interleukin-10 (IL-10), IL-1 binding proteins , G protein-coupled CC chemokine receptor , and epidermal growth factor-like protein, which are found in other poxvirus genera. Lumpy skin disease virus (LSDV) is double-stranded DNA virus . It is a member of the capripoxvirus genus of Poxviridae . Capripoxviruses (CaPVs) represent one of eight genera within the Chordopoxvirus (ChPV) subfamily. The capripoxvirus genus consists of LSDV, as well as sheeppox virus , and goatpox virus. CaPV infections are usually host-specific within specific geographic distributions even though they are serologically indistinguishable from one another. Like other viruses in the Poxviridae family, capripoxviruses are brick-shaped. Capripoxvirus virions are different than orthopoxvirus virions in that they have a more oval profile, as well as larger lateral bodies. The average size of capripoxvirions is 320 nm by 260 nm. [ citation needed ]The virus has a 151-kbp genome , consisting of a central coding region which is bounded by identical 2.4 kbp-inverted terminal repeats and contains 156 genes. There are 146 conserved genes when comparing LSDV with chordopoxviruses of other genera. These genes encode proteins which are involved in transcription and mRNA biogenesis, nucleotide metabolism, DNA replication , protein processing, virion structure and assembly, and viral virulence and host range. Within the central genomic region, LSDV genes share a high degree of collinearity and amino acid identity with the genes of other mammalian poxviruses. Examples of viruses with similar amino acid identity include suipoxvirus , yatapoxvirus , and leporipoxvirus . In terminal regions, however, collinearity is interrupted. In these regions, poxvirus homologues are either absent or share a lower percentage of amino acid identity. Most of these differences involve genes that are likely associated with viral virulence and host range. Unique to Chordopoxviridae, LSDV contains homologues of interleukin-10 (IL-10), IL-1 binding proteins , G protein-coupled CC chemokine receptor , and epidermal growth factor-like protein, which are found in other poxvirus genera. LSDV mainly affects cattle and zebus , but has also been seen in giraffes , water buffalo , and impalas . Fine-skinned Bos taurus cattle breeds such as Holstein-Friesian and Jersey are the most susceptible to the disease. Thick-skinned Bos indicus breeds including the Afrikaner and Afrikaner cross-breeds show less severe signs of the disease. This is probably due to the decreased susceptibility to ectoparasites that Bos indicus breeds exhibit relative to Bos taurus breeds. Young calves and cows at peak lactation show more severe clinical symptoms, but all age-groups are susceptible to the disease. Outbreaks of LSDV are associated with high temperature and high humidity. It is usually more prevalent during wet summer and autumn months, especially in low-lying areas or near bodies of water; however, outbreaks can also occur during the dry season. Blood-feeding insects such as mosquitos and flies act as mechanical vectors to spread the disease. A single species vector has not been identified. Instead, the virus has been isolated from Stomoxys , Biomyia fasciata , Tabanidae , Glossina , and Culicoides species. The particular role of each of these insects in the transmission of LSDV continues to be evaluated. Outbreaks of lumpy skin disease tend to be sporadic since they are dependent upon animal movements, immune status and wind and rainfall patterns, which affect the vector populations. The virus can be transmitted through blood, nasal discharge, lacrimal (tear duct) secretions, semen, and saliva . The disease can also be transmitted through infected milk to suckling calves. In experimentally infected cattle, LSDV was found in saliva 11 days after the development of fever, in semen after 22 days, and in skin nodules after 33 days. The virus is not found in urine or stool . Like other pox viruses, which are known to be highly resistant, LSDV can remain viable in infected tissue for more than 120 days. [ citation needed ]Outbreaks of LSDV are associated with high temperature and high humidity. It is usually more prevalent during wet summer and autumn months, especially in low-lying areas or near bodies of water; however, outbreaks can also occur during the dry season. Blood-feeding insects such as mosquitos and flies act as mechanical vectors to spread the disease. A single species vector has not been identified. Instead, the virus has been isolated from Stomoxys , Biomyia fasciata , Tabanidae , Glossina , and Culicoides species. The particular role of each of these insects in the transmission of LSDV continues to be evaluated. Outbreaks of lumpy skin disease tend to be sporadic since they are dependent upon animal movements, immune status and wind and rainfall patterns, which affect the vector populations. The virus can be transmitted through blood, nasal discharge, lacrimal (tear duct) secretions, semen, and saliva . The disease can also be transmitted through infected milk to suckling calves. In experimentally infected cattle, LSDV was found in saliva 11 days after the development of fever, in semen after 22 days, and in skin nodules after 33 days. The virus is not found in urine or stool . Like other pox viruses, which are known to be highly resistant, LSDV can remain viable in infected tissue for more than 120 days. [ citation needed ]There have been two different approaches to immunization against LSDV. In South Africa , the Neethling strain of the virus was first attenuated by 20 passages on the chorio-allantoic membranes of hens' eggs. Now the vaccine virus is propagated in cell culture . [ citation needed ] In Kenya , the vaccine produced from sheep or goatpox viruses has been shown to provide immunity in cattle. However, the level of attenuation required for safe use in sheep and goats is not sufficient for cattle. For this reason the sheeppox and goatpox vaccines are restricted to countries where sheeppox or goatpox is already endemic since the live vaccines could provide a source of infection for the susceptible sheep and goat populations. [ citation needed ] In order to ensure adequate protection against LSDV, susceptible adult cattle should be vaccinated annually. [ citation needed ] Approximately 50% of cattle develop swelling ( 10–20 millimetres ( 1 ⁄ 2 – 3 ⁄ 4 in) in diameter) at the site of inoculation. This swelling disappears within a few weeks. Upon inoculation, dairy cows may also exhibit a temporary decrease in milk production. Most cattle develop lifelong immunity after recovery from a natural infection. Additionally, calves of immune cows acquire maternal antibodies and are resistant to clinical disease until about 6 months of age. To avoid interference with maternal antibodies, calves under 6 months of age whose dams were either naturally infected or were vaccinated should not be vaccinated. On the other hand, calves born from susceptible cows are also susceptible and should be vaccinated. [ citation needed ]There have been two different approaches to immunization against LSDV. In South Africa , the Neethling strain of the virus was first attenuated by 20 passages on the chorio-allantoic membranes of hens' eggs. Now the vaccine virus is propagated in cell culture . [ citation needed ] In Kenya , the vaccine produced from sheep or goatpox viruses has been shown to provide immunity in cattle. However, the level of attenuation required for safe use in sheep and goats is not sufficient for cattle. For this reason the sheeppox and goatpox vaccines are restricted to countries where sheeppox or goatpox is already endemic since the live vaccines could provide a source of infection for the susceptible sheep and goat populations. [ citation needed ] In order to ensure adequate protection against LSDV, susceptible adult cattle should be vaccinated annually. [ citation needed ] Approximately 50% of cattle develop swelling ( 10–20 millimetres ( 1 ⁄ 2 – 3 ⁄ 4 in) in diameter) at the site of inoculation. This swelling disappears within a few weeks. Upon inoculation, dairy cows may also exhibit a temporary decrease in milk production. Most cattle develop lifelong immunity after recovery from a natural infection. Additionally, calves of immune cows acquire maternal antibodies and are resistant to clinical disease until about 6 months of age. To avoid interference with maternal antibodies, calves under 6 months of age whose dams were either naturally infected or were vaccinated should not be vaccinated. On the other hand, calves born from susceptible cows are also susceptible and should be vaccinated. [ citation needed ]Lumpy skin disease was first seen as an epidemic in Zambia in 1929. Initially, it was thought to be the result of either poisoning or a hypersensitivity to insect bites. Additional cases occurred between 1943 and 1945 in Botswana , Zimbabwe , and South Africa. Approximately, 8 million cattle were affected in a panzootic infection in South Africa in 1949, causing enormous economic losses. LSD spread throughout Africa between the 1950s and 1980s, affecting cattle in Kenya, Sudan , Tanzania , Somalia , and Cameroon . [ citation needed ] In 1989 there was an LSD outbreak in Israel . This outbreak was the first instance of LSD north of the Sahara desert and outside of the African continent. This particular outbreak was thought to be the result of infected Stomoxys calcitrans being carried on wind from Ismailiya in Egypt. During a period of 37 days between August and September 1989, fourteen of the seventeen dairy herds in Peduyim became infected with LSD. All of the cattle as well as small flocks of sheep and goats in the village were slaughtered. Throughout the past decade, LSD occurrences have been reported in Middle Eastern, European, and west Asian regions. LSD was first reported to the Bangladesh livestock department in July 2019. Eventually 500,000 head were estimated to have been infected in this outbreak. The Food and Agriculture Organization (FAO) recommended mass vaccination. As a result of the introduction of fall armyworm and this cattle plague within a few months of each other, the FAO, the World Food Programme , Bangladesh Government officials, and others agreed to begin improving Bangladesh's livestock disease surveillance and emergency response capabilities. Method of entry of the virus into Bangladesh remains unknown. In 2022 a lumpy skin disease outbreak in Pakistan killed over 7000 cattle. In India, between July and September 2022 the lumpy skin disease outbreak in India resulted in the death of over 80,000 cattle. The state of Rajasthan has seen a majority of the deaths. Inter- state and inter- district movement of cattle in a number of states has been restricted. Indian Council of Agricultural Research labs have undertaken creation of an indigenous vaccine. A goat pox vaccine is being used; 15 million doses had been administered by September 2022. There are at least three centres manufacturing the goat pox vaccine in India. Institutions with authority to test have been expanded. As of June 2023 [ update ] , LSD has spread to Koshi Province in Nepal, killing over 10,000 cattle.

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Orthopoxvirus

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Progressive vaccinia

Progressive vaccinia is a rare cutaneous condition caused by the vaccinia virus, characterized by painless but progressive necrosis and ulceration. Opportunistic fungal , protozoal , or bacterial infections and the vaccinia virus itself may lead to septic shock and disseminated intravascular coagulation , in addition to necrosis and ulcerated skin tissue. Some of these tissues may eventually become large, requiring not only a skin graft but surgical removal of the destroyed tissue, in order to avoid graft-versus-host disease in organ transplanted patients, in whom immunosuppressive therapy would otherwise have to be discontinued to allow healing of the wound. [ citation needed ]Opportunistic fungal , protozoal , or bacterial infections and the vaccinia virus itself may lead to septic shock and disseminated intravascular coagulation , in addition to necrosis and ulcerated skin tissue. Some of these tissues may eventually become large, requiring not only a skin graft but surgical removal of the destroyed tissue, in order to avoid graft-versus-host disease in organ transplanted patients, in whom immunosuppressive therapy would otherwise have to be discontinued to allow healing of the wound. [ citation needed ]Vaccinia is introduced into the skin by means of multiple punctures of a bifurcated needle . The virus replicates in the basal layer and disseminates from cell to cell, causing necrosis and the formation of fluid-filled vesicles. Nonetheless, the initial spread of the virus is slowed by innate antiviral mechanisms, and, by the second week, the cell-mediated immune response begins to eliminate infected cells [lower-alpha 1] . Neutrophils, macrophages, and lymphocytes infiltrate the inoculation site, forming a confluent pustule and releasing cytokines and chemokines that cause hyperemia and edema in surrounding tissues. This may initially manifest into complaints of malaise and other mild constitutional symptoms, fever, vomiting, and tender enlarged axillary lymph nodes. Some vaccinees develop additional local "satellite" pustules that resolve along with the primary lesion. [ citation needed ] The virus may gain access to the blood at an early stage, and secondary skin lesions, which follow the same evolution as the inoculation site, may appear across the body. Bacteria, like Staphylococcus aureus , may infect the ulcerated, and necrotic lesions. Coalescent lesions may cover large portions of the body with extensive tissue destruction. Although some vaccinia viruses commonly disseminate through the bloodstream, the NYCBOH strain reportedly causes only limited viremia in a small percentage of recipients during the period of pustule formation. The inflammatory process reaches its peak by days 10–12 after vaccination and begins to resolve by day 14, with the shedding of the scab and other pustules by day 21. This sequence of events, which simulates the development of smallpox "pock", is known as a "take" reaction. A successful "take" is required for the development of antivaccinia antibody and cell-mediated responses. In addition to a skin graft , some medications also work. Among antiviral substances, cidofovir showed some effect in preliminary studies. Apart from treating opportunistic infections with anti-viral , and antibiotic medications, for HIV or immunocompromised (or at the very least iatrogenic immunosuppression like cancer and autoimmune disease) people, immediate highly active antiretroviral therapy (HAART) in HIV patients and withdrawal of immunosuppressive therapy accompanied by aggressive administration of VIG are given to save the patient's life. Intensive care and supportive treatment are required. VIG is given at up to 10 ml / kg body weight. [ citation needed ]

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Orthopoxvirus

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2022–2023 mpox outbreak in the United States

The 2022–2023 mpox outbreak in the United States is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . The United States was the fourth country outside of the African countries with endemic mpox, to experience an outbreak in 2022. The first case was documented in Boston , Massachusetts , on May 17, 2022. As of August 22, mpox has spread to all 50 states in the United States , as well as Washington, D.C. , and Puerto Rico . The United States has the highest number of mpox cases in the world. California has the highest number of mpox cases in the United States. On August 4, 2022, the U.S. Centers for Disease Control and Prevention declared mpox a public health emergency in the United States. Wyoming was the last state in the United States to report at least one mpox case. On August 30, 2022, the first mpox death in the United States was reported. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on May 6, 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on April 29, 2022. The resident returned to the United Kingdom on May 4, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys, and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis, an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . The CDC has stated that, among mpox cases with available data, 99% occurred in men, 94% of whom reported recent male-to-male sexual or close intimate contact. The 2022–2023 mpox outbreak in California . As of July 2022, the virus has infected 4,886 people in the U.S. state of California, with 1 death. The state has the highest number of recorded cases in the country. Florida currently has 2,444 people infected by the virus, with no deaths. It started on May 23, 2022, in Fort Lauderdale and quickly started spreading across the State. The 2022–2023 mpox outbreak in New York currently has no deaths. This state has the second highest number of recorded cases in the country with 3,679 cases. In New York the outbreak began on June 10, 2022, with the first mpox case recorded in Ithaca . On July 29, Governor Kathy Hochul declared a public state disaster emergency in New York State. New York is currently the state with the highest recorded number of cases in the US. The World Health Organization in New York reports its first mpox case outside New York City on June 7. On July 13, New York becomes the epicenter of the outbreak. With 489 cases only behind California with 266 cases. On July 27, New York reaches 1,228 cases, with an increase of 739 cases in only 14 days. On August 1, Mayor Eric Adams declares a state of emergency over the mpox outbreak. Based from the NYSDOH . The 2022–2023 mpox outbreak in California . As of July 2022, the virus has infected 4,886 people in the U.S. state of California, with 1 death. The state has the highest number of recorded cases in the country. Florida currently has 2,444 people infected by the virus, with no deaths. It started on May 23, 2022, in Fort Lauderdale and quickly started spreading across the State. The 2022–2023 mpox outbreak in New York currently has no deaths. This state has the second highest number of recorded cases in the country with 3,679 cases. In New York the outbreak began on June 10, 2022, with the first mpox case recorded in Ithaca . On July 29, Governor Kathy Hochul declared a public state disaster emergency in New York State. New York is currently the state with the highest recorded number of cases in the US. The World Health Organization in New York reports its first mpox case outside New York City on June 7. On July 13, New York becomes the epicenter of the outbreak. With 489 cases only behind California with 266 cases. On July 27, New York reaches 1,228 cases, with an increase of 739 cases in only 14 days. On August 1, Mayor Eric Adams declares a state of emergency over the mpox outbreak. Based from the NYSDOH . Based from the NYSDOH . The first known case was detected on May 18, 2022, in a man from Boston, Massachusetts , who had traveled to Canada, where a case of the virus was reported the following day. The person was hospitalized in Boston. There, he tested positive for mpox, becoming the first case in the United States. Two days after the man tested positive for the virus, other states began reporting cases, with New York reporting its first case on May 21. On May 22, President Biden gave a speech at Osan Air Base in South Korea during which he indicated the disease was "something that everybody should be concerned about". On May 26, Virginia reported its first case in a woman who had traveled to Africa , followed by California and Hawaii on June 4, 2022. As of June 3, the United States had 21 confirmed cases, a number which had risen to 460 as of July 1. On May 23, 2022, Florida reported a case of mpox. On the same day, the Tampa Bay Times reported that the Florida Department of Health had announced the case on a man that had been isolated since the day before. WESH later on also confirmed the case, which was in Broward County . The following day, WESH reported another mpox case as being "investigated". The case was then confirmed to be in the same county as the first case, adding up the total in the county to two. Later, a third case was also investigated, this time being reported by CBS Miami to also be in the same county as the first and second case. This case added up the total in the United States to 18. A fourth case was reported by the Sun-Sentinel , although the state of Florida did not disclose the county where it was detected. In early June 2022, a man in Washington, D.C. , was reported to test positive for orthopox , potentially mpox. On July 26, 2022, the United States had more mpox cases than any other country. At the end of August 2022, there were early signs that the mpox spread in the U.S. may be slowing. Ref:Data sourced from the CDC As of May 8, 2023 there have been 42 mpox-related deaths reported in the US. As of May 8, 2023 there have been 42 mpox-related deaths reported in the US. On 18 May 2022, Bavarian Nordic announced that BARDA , part of the Department of Health and Human Services (HHS), exercised a $119 million option, under a $299 million contract, to supply a freeze-dried version of JYNNEOS vaccine, converting existing bulk vaccine. The United States spent $119 million to purchase doses of the Modified vaccinia Ankara -based two-shot Jynneos vaccine from Bavarian Nordic in May 2022. The contract also allows the United States to purchase an additional $180 million worth of the vaccine at a later date. The vaccine, JYNNEOS (also known by the brand names Imvamune and Imvanex ), was approved by FDA in 2019 to prevent both smallpox and mpox. As of June 14, the United States had around 70,000 doses of JYNNEOS in its stockpile, and the federal government placed an order for 500,000 more on June 10, 2022. Dawn O'Connell, assistant secretary for preparedness and response at Department of Health and Human Services (HHS), said around 300,000 doses would be delivered in June–July 2022, and the remainder would be delivered later in that year. In addition, the Strategic National Stockpile (SNS) holds over 100 million doses of an older smallpox vaccine ( ACAM2000 ). As of June 28, the Biden administration was allocating tens of thousands of vaccine doses from the Strategic National Stockpile to clinics nation-wide. The rollout of vaccines and testing was criticized as too slow, as well as for having similar problems to the rollout of vaccines and tests during the COVID-19 pandemic in the United States . The United States government's response is coordinated by the National Security Council Directorate on Global Health Security and Biodefense – more commonly known as the White House Pandemic Office – in collaboration with the Department of Health and Human Services (HHS). The White House Pandemic Office had previously reinstated Dr. Beth Cameron to the executive position. The HHS is overseen by Secretary of Health and Human Services Xavier Becerra . As of June 29, HHS has received requests from 32 states and jurisdictions, deploying over 9,000 doses of JYNNEOS vaccine and 300 courses of ST-246 ( tecovirimat ) antiviral smallpox treatments. The United States expanded deployment of JYNNEOS vaccines, allocating 296,000 doses over the coming weeks, 56,000 of which will be allocated immediately. Over the coming months a combined 2.5 million additional doses will become available. As of November 2022, New York state ended its state of emergency, mobile mass vaccination sites set up since summer in New York city closed, but vaccinations were moved to outpatient and sexual health clinics. Hospitals have begun making their own preparations to help control the current mpox outbreak, including screening patients, increasing decontamination and cleaning procedures, and wearing appropriate safety gear when interacting with infected patients.On 18 May 2022, Bavarian Nordic announced that BARDA , part of the Department of Health and Human Services (HHS), exercised a $119 million option, under a $299 million contract, to supply a freeze-dried version of JYNNEOS vaccine, converting existing bulk vaccine. The United States spent $119 million to purchase doses of the Modified vaccinia Ankara -based two-shot Jynneos vaccine from Bavarian Nordic in May 2022. The contract also allows the United States to purchase an additional $180 million worth of the vaccine at a later date. The vaccine, JYNNEOS (also known by the brand names Imvamune and Imvanex ), was approved by FDA in 2019 to prevent both smallpox and mpox. As of June 14, the United States had around 70,000 doses of JYNNEOS in its stockpile, and the federal government placed an order for 500,000 more on June 10, 2022. Dawn O'Connell, assistant secretary for preparedness and response at Department of Health and Human Services (HHS), said around 300,000 doses would be delivered in June–July 2022, and the remainder would be delivered later in that year. In addition, the Strategic National Stockpile (SNS) holds over 100 million doses of an older smallpox vaccine ( ACAM2000 ). As of June 28, the Biden administration was allocating tens of thousands of vaccine doses from the Strategic National Stockpile to clinics nation-wide. The rollout of vaccines and testing was criticized as too slow, as well as for having similar problems to the rollout of vaccines and tests during the COVID-19 pandemic in the United States . The United States government's response is coordinated by the National Security Council Directorate on Global Health Security and Biodefense – more commonly known as the White House Pandemic Office – in collaboration with the Department of Health and Human Services (HHS). The White House Pandemic Office had previously reinstated Dr. Beth Cameron to the executive position. The HHS is overseen by Secretary of Health and Human Services Xavier Becerra . As of June 29, HHS has received requests from 32 states and jurisdictions, deploying over 9,000 doses of JYNNEOS vaccine and 300 courses of ST-246 ( tecovirimat ) antiviral smallpox treatments. The United States expanded deployment of JYNNEOS vaccines, allocating 296,000 doses over the coming weeks, 56,000 of which will be allocated immediately. Over the coming months a combined 2.5 million additional doses will become available. As of November 2022, New York state ended its state of emergency, mobile mass vaccination sites set up since summer in New York city closed, but vaccinations were moved to outpatient and sexual health clinics. Hospitals have begun making their own preparations to help control the current mpox outbreak, including screening patients, increasing decontamination and cleaning procedures, and wearing appropriate safety gear when interacting with infected patients.

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Orthopoxvirus

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Raccoonpox virus

Raccoonpox virus (RCN) is a double-stranded DNA virus and a member of the orthopoxviruses in the family Poxviridae and subfamily Chordopoxvirinae which consists of eight genera: Avipoxvirus, Capripoxvirus, Leporipoxvirus, Molluscipoxvirus, Orthopoxvirus, Parapoxvirus, Suipoxvirus and Yatapoxvirus Vertebrates are the natural host of Chordopoxvirinae subfamily viruses. More specifically, raccoons are the natural hosts of RCN. RCN was isolated in 1961 from the upper respiratory tissues of 2 raccoons in a group of 92 observably healthy raccoons ( Procyon lotor ) trapped close to Aberdeen , Maryland . Of the 92 apparently healthy raccoons trapped near Aberdeen, Maryland in 1961, 22 had sera containing RCN HA1 antibodies. The sera partially cross-reacted with a vaccinia virus HA preparation, suggesting a close relation between the viruses. Unlike the HA of other vaccinia-like viruses, the HA of RCN did not cross-react with monkeypox virus HA. Though RPV is a close relative of vaccinia and cowpox viruses, it is distinct enough to be classified as a novel entity in the vaccinia/variola subgroup of poxviruses. RCN is a double-stranded DNA virus. It is an orthopoxvirus in the family Poxviridae and subfamily Chordopoxvirinae.DNA sequences encoding the HA's of RCN and VV ( vaccinia virus ) strain WR (western reserve) as well as HA's of VV, RCN, VPX ( vole poxvirus ), and SKP ( skunk poxvirus ) are rather divergent. Cross-hybridizations suggest that the HA of RCN, VPX, and SKP are separately diverged and that the HA of VV, ECT (ectromelia virus), VAR (variola virus), and most other orthopoxviruses are closely related. Hybridizations also indicate that orthopoxvirus regulatory sequences flanking the HA ORF are rather conserved. RCN vaccine-laden baits increased antibodies against plague in both antigens . In contrast to known members of the poxvirus group, RCN is serologically (diagnostic identification of antibodies in serum ) unique in its ability to cross-react with a monkeypox agent. RCN is an orthopoxvirus . It is an enveloped virus with brick-shaped virion geometries. It has a linear genomic arrangement and monopartite genomic segmentation. It is a large virus particle with a genome of 150 to 300 kbp of dsDNA (Ropp). A hairpin loop exists at either end of the genome. The Guanine/Cytosine (G-C) content of the genome is 35%. There are large regions within the RCN virus genome that cross hybridize between members of the genus. Differences between terminal region patterns of DNA restriction enzyme digests of different RCN isolates suggest that varied passaging has promoted the advancement of polymorphisms since the virus was first isolated in 1961. RCN tandem repeat sequences found on the terminal Sal1 restriction fragment were found to be distinct from varicella and cowpox virus, lending further support to the claim that RCN is a distinct virus within the orthopoxviruses. In order to distinguish between the orthopoxvirus species and strains of RCN, PCR is used. The distinction is drawn based on the sequences encoding the hemagglutinin (HA) protein. Entry into Cell: The virion attaches to the cell surface as the viral proteins come into contact with host cell glycosaminoglycan receptors and is taken into the cell through endocytosis. From here it must enter into the cytoplasm. The replication of RCN occurs in the cytoplasm- never in the nucleus. Replication and Transcription: The replication and transcription of the viral genome occur in the cytoplasm. Genome replication begins with the uncoating of the virus core as it comes into contact with the plasma membrane. Once uncoated, the viral DNA is expressed and replication follows. Replication of the RCN genome occurs through the strand displacement method. Assembly and Release: Viral assembly occurs in the cytoplasm. The release of the mature virus particle always results in lysing of the host cell. RCN has a negative effect on the mRNA synthesis of the host cell. RCN isolated from 2 of 92 raccoons in Maryland, proposed to be an orthopoxvirus when it was noted that a RCN hemagglutinin preparation reacted with VV (vaccinia virus) hyperimmune rabbit serum. However, it was later reported that sera from 22 of the raccoons reacted highly with a RCN hemagglutinin preparation, but hemagglutinin preparations of VV or monkeypox virus (MPV) showed little or no cross-reactivity. Identify via agglutination with cardiolipin sensitive chicken erythrocytes . RCN infected Strain 143 human osteosarcoma cells produce cytoplasmic A-type inclusions (ATIs) where a number of mature virions are lodged to maintain viral infectivity even if the cell lyses. Cell lines infected with RCN, volepox virus (VPX), or skunk poxvirus (SKP), and other orthopoxviruses that are all HAD+ (hemagglutinating viruses based on adherence to erythrocytes to infected cells), form large syncytia (multinucleated cells that can result from the fusion of uninuclear cells), suggest that, conformationally, distinct functional HA's influence polykaryocytosis (process of fusion). RCN has cytopathic effects (CPE) in monkey kidney tissue cultures (MKTC). Seen on 11h day of incubation, characterized by rounding and granular appearance of cells. When inoculated on the chorioallantoic membrane (CAM) of 12-day embryonated hens' eggs, the RCN produced many small discrete embedded poxes. Raccoon poxvirus has been shown to infect Strain 143 human osteosarcoma cells grown in monolayer culture, producing A-type inclusions in the cytoplasm as is typical of poxviruses in later multiplication cycles. To date, most oral vaccines cannot withstand the alimentary tract or do not elicit strong mucosal immune response. Poxviruses are good candidates for the development of wildlife vaccines. They infect mucosal tissue and retain stability when disrupted by the environment. RCN has been developed as a recombinant for the delivery of vaccines against the plague (caused by bacterium Yersinia pestis ), feline panleukopenia virus, rabies virus and other pathogens in wildlife and domestic animals. Controlling diseases such as the plague in wildlife and domestic animals is important to reducing its transmission to humans. RCN is favored as a vector for wildlife and veterinary management over other potential poxvirus vectors because it triggers an immune response when it is taken in through mucosal routes, which is important for the widespread immunization of wildlife. Recombinant RCN (rRCN) vaccines been given to a number of mammalian species such as mice, raccoons, cats and sheep without side effects. The rRCN rabies virus glycoprotein recombinant vaccine was effective when given to sheep both intradermally and intramuscularly. Fortunately, the rRCN vaccine did relatively little harm to sheep when ingested orally, suggesting that rRCN vaccines used for wildlife management delivered as oral baits would be safe if accidentally ingested by sheep. Further studies are needed to determine the effect of ingestion of oral bait rRCN vaccines by non-target farm and domestic animals. Particular rRCN vaccines have been designed to effectively confer protective immunity against multiple pathogens. rRCN vaccines have been successful too in treating rabies virus in mice. These vaccines functioned by either expressing the rabies virus internal structural nucleoprotein (RCN-N) or by expressing the rabies virus glycoprotein (RCN-G). RCN, and all poxviridae viruses, are especially useful in creating vaccines because they create cost-effective, stable, multivalent vaccines that are easy to manufacture, and can be administered through multiple routes. It is believed that RCN vaccination triggers action from both the humoral and cell mediated immune responses and that this immunity is long term after only one vaccination. Poxvirus recombinant vectors have been implemented to successfully vaccinate against heterologous bacterial, viral, and parasitic pathogens upon use in animals (e.g. raccoons) and humans. Uses in veterinary medicine: have potential use for this treatment technique in infectious disease, ex vivo therapies, and cancer immunotherapy. *Under clinical trials as well as some licensed commercialization at time of publication. RCN viral vectors have the potential to replace expensive and labor-intensive pesticide applications in disease prevention. Recombinant RCN vaccine promote effective immunity against plague (Y. pestis) via the oral route, could provide a practical, alternative approach, although more work is needed to determine the timing of vaccine, the duration of immunity provided, and the effects on nontarget animals. RCN recombinants expressing rabies virus glycoprotein or nucleoprotein were created. Promoting rabies virus neutralizing antibodies in raccoons , dogs , cotton rats , rabbits , bobcats , and foxes ; sometimes at lethal doses. RCN is used as an oral delivery system for fraction 1 (F1) capsular antigen of Y.pestis. (replacement of thymidine kinase (TK)). RCN was successful in 50% of voluntary participants allowing them to survive subsequent challenges. RCN-vectored vaccine with the LcrV (V) gene, which can also provide protection against Y. pestis.

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Orthopoxvirus

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Rijk Gispen

Rijk Gispen (1910 – 6 December 2000), was a Dutch virologist and former Director of the National Institute of Public Health in the Netherlands. He is well known for his research in immunology and the study of Orthopoxviruses . In 1949, he reported naturally occurring pox infections in non-human primates . Fifteen years later, he isolated monkeypox virus from healthy monkey kidneys in the Netherlands, "silent monkeypox virus infections". At the time, the virus appeared indistinguishable from smallpox . Despite the finding being of some debate, it gave cause for concern and provided the impetus to continue World Health Organization (WHO) field research into the potential existence of a smallpox reservoir. In the 1970s, he contributed to the immunology of orthopoxvirus infections by being the first to develop means of distinguishing between antibodies due to infections with variola , vaccinia and monkeypox.Rijk Gispen was born in 1910 to Willem Hendrik Gispen, a minister, and Anna Maria Catharina van der Dussen. At the age of 27, he was promoted by J.J. van Loghem and travelled to the Dutch East Indies to take up a post with Professor Johannes Ernst Dinger (1892–1983). Following the second world war, Gispen succeeded Dinger at the Queen Wilhelmina Institute for Hygiene and Bacteriology in Batavia . In 1951 he was appointed director of Fundamental Scientific Research at the National Institute for Public Health (RIV) and in 1958 he became head of the newly established Laboratory of Virology, a centre he helped design. Three years later, he was appointed professor of Virology at the Utrecht University . Between 1963 and 1966, he was one of the editors of the Dutch Journal of Medicine . Throughout the 1970s, he contributed to the immunology of orthopoxvirus infections by being the first to develop means of distinguishing between antibodies due to infections with variola, vaccinia and monkeypox. As a member of the Health Council, he frequently advised government on matters including the use of enhanced inactivated polio vaccine for immunizing infants. Subsequent to experiences with the measures to control yellow fever and malaria , it became apparent that the eradication of smallpox relied upon the knowledge that no animal reservoir existed. Hence, the search for a reservoir continued. Up until 1968, seven suspected smallpox cases in monkeys were reported, but Gispen's case was the only one that confirmed the disease by isolating the virus in 1949. Two orangutans in a Djakarta zoo became unwell during a smallpox epidemic amongst humans. It was concluded that human-to-orangutan transmission had taken place and not animal-to-animal. "Silent monkeypox virus infections" were observed on three separate occasions during the 1964 and 1965 outbreaks in cynomolgus colonies in the Netherlands. In 1964, Gispen isolated two viruses from the kidneys of laboratory monkeys that were not unwell. The monkeys remained without symptoms. These viruses appeared identical to smallpox. A number of further discoveries of the smallpox-like virus were later isolated from chimpanzees in West Africa and in well sun-squirrels . These incidents gave cause for concern and provided the impetus to continue WHO field research into the potential existence of a smallpox reservoir. A personal correspondence from Gispen's colleague, J. G. Kapsenberg in the early 1980s, revealed that the cases of silent monkeypox were probably a result of contamination from monkeypox virus isolated in the same laboratory that tested samples from cases at an outbreak at Rotterdam Zoo . Gispen also demonstrated cross protection from monkeypox in monkeys with smallpox vaccine. Subsequent to experiences with the measures to control yellow fever and malaria , it became apparent that the eradication of smallpox relied upon the knowledge that no animal reservoir existed. Hence, the search for a reservoir continued. Up until 1968, seven suspected smallpox cases in monkeys were reported, but Gispen's case was the only one that confirmed the disease by isolating the virus in 1949. Two orangutans in a Djakarta zoo became unwell during a smallpox epidemic amongst humans. It was concluded that human-to-orangutan transmission had taken place and not animal-to-animal. "Silent monkeypox virus infections" were observed on three separate occasions during the 1964 and 1965 outbreaks in cynomolgus colonies in the Netherlands. In 1964, Gispen isolated two viruses from the kidneys of laboratory monkeys that were not unwell. The monkeys remained without symptoms. These viruses appeared identical to smallpox. A number of further discoveries of the smallpox-like virus were later isolated from chimpanzees in West Africa and in well sun-squirrels . These incidents gave cause for concern and provided the impetus to continue WHO field research into the potential existence of a smallpox reservoir. A personal correspondence from Gispen's colleague, J. G. Kapsenberg in the early 1980s, revealed that the cases of silent monkeypox were probably a result of contamination from monkeypox virus isolated in the same laboratory that tested samples from cases at an outbreak at Rotterdam Zoo . Gispen also demonstrated cross protection from monkeypox in monkeys with smallpox vaccine. He died on 6 December 2000 in Bilthoven , at the age of 90. Gispen published numerous papers and has been cited on many occasions.

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Orthopoxvirus

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Brincidofovir

({[(2S)-1-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-hydroxypropan-2-yl]oxy}methyl)[3-(hexadecyloxy)propoxy]phosphinic acid CCCCCCCCCCCCCCCCOCCCOP(=O)(O)CO[C@H](CO)Cn1ccc(N)nc1=O InChI=1S/C27H52N3O7P/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-19-35-20-16-21-37-38(33,34)24-36-25(23-31)22-30-18-17-26(28)29-27(30)32/h17-18,25,31H,2-16,19-24H2,1H3,(H,33,34)(H2,28,29,32)/t25-/m0/s1 Key:WXJFKKQWPMNTIM-VWLOTQADSA-N Brincidofovir , sold under the brand name Tembexa , is an antiviral drug used to treat smallpox . Brincidofovir is a prodrug of cidofovir . Conjugated to a lipid , the compound is designed to release cidofovir intracellularly , allowing for higher intracellular and lower plasma concentrations of cidofovir, effectively increasing its activity against dsDNA viruses , as well as oral bioavailability . The most common side effects include diarrhea, nausea, vomiting, and abdominal pain. It carries an FDA-mandated black box warning of an increased risk of death with extended use. Brincidofovir was approved for medical use in the United States in June 2021.Brincidofovir is indicated for the treatment of human smallpox disease caused by variola virus. Brincidofovir is a prodrug that is composed of cidofovir conjugated with a lipid molecule. The lipid aspect of the molecule takes on the action of endogenous lysophosphatidyl choline, which then is able to enter cells in the body which are infected with smallpox. Once the infected cell takes in the drug, the drug cleaves to generate cidofovir. Cidofovir is then consequently phosphorylated to yield cidofovir diphosphate, which is the active drug. Cidofovir diphosphate inhibits the variola virus' DNA polymerase -mediated DNA synthesis. The drug acts as an acyclic nucleotide and incorporates itself into the viral DNA chain, which then stops viral DNA synthesis. The oral bioavailability of Brincidofovir is 13.4% as a tablet and 16.8% in a suspension. The metabolism of the drug is as such: once the drug enters the target infected cell, Brincidofovir's phosphodiester bond is then hydrolyzed to generate cidofovir which is then phosphorylated to the active cidofovir diphosphate. The volume of distribution of the drug is 1230 L. Because smallpox is eradicated, the effectiveness of brincidofovir was studied in animals infected with viruses that are closely related to the variola virus. Effectiveness was determined by measuring animals' survival at the end of the studies. Safety information to support approval of brincidofovir was derived from clinical trials of the drug for a non-smallpox indication, primarily from patients who received hematopoietic stem cell transplants. The U.S. Food and Drug Administration (FDA) granted the application for brincidofovir priority review , fast track , and orphan drug designations. The FDA approved brincidofovir under the agency's Animal Rule, which allows findings from adequate and well-controlled animal efficacy studies to serve as the basis of an approval when it is not feasible or ethical to conduct efficacy trials in humans. Brincidofovir (CMX001) was the subject of widespread social media campaigning in 2014, which was then picked up by national news sources about a boy with an adenovirus infection following a bone marrow transplant . The family requested legal access to the still-unapproved drug outside of any clinical trial , and Chimerix initially denied the request. After a short and intense media campaign, Chimerix got permission from the FDA to start a limited open-label trial which allowed the boy to receive the drug. This media event sparked a debate on the ethics of using social media, the allocation of limited resources of a small company, and the emphasis on the individual over the group. The new use of any drug has the potential to interfere with the process to get the drug approved and widely marketed, through means such as consuming limited staff time that may be needed elsewhere – staff time that has the potential to save thousands of lives in the long-term, rather than one life now – overwhelming manufacturing capabilities, or by causing adverse effects or even death. These adverse events are more likely during these programs, because the people seeking access are usually much sicker than most, and problems experienced by these people can result in an unfavorable and inaccurate perception of the drug's safety profile. In this case, the boy recovered from the infection in 2014, and died in 2016 from complications of cancer. Brincidofovir is one of several experimental drugs administered to a small number of patients to treat Ebola virus disease during the 2014 outbreak. The WHO published a report on the ethics of using unregistered interventions to treat Ebola, where they concluded that "In the particular context of the current Ebola outbreak in West Africa, it is ethically acceptable to offer unproven interventions that have shown promising results in the laboratory and in animal models but have not yet been evaluated for safety and efficacy in humans as potential treatment or prevention." Brincidofovir is under investigation for the treatment of cytomegalovirus , adenovirus , poxvirus , and ebolavirus infections. It has been used off-label for the treatment of monkeypox . As of 2014 [ update ] , brincidofovir is in Phase III clinical trials for use in humans against cytomegalovirus and adenovirus. Preliminary safety data from a database of 1000 patients supported progression into later phase trials, Chimerix announced in December 2015 that the Phase III trials for use of the drug in preventing cytomegalovirus infection in stem cell transplant patients had failed, and in February 2016 shut down two other late-stage trials for use of the drug in preventing infection after kidney transplants . Brincidofovir is not yet FDA approved for adenovirus or cytomegalovirus due to lack of efficacy in clinical trials. In a trial of brincidofovir for patients with CMV brincidofovir was associated with a 15.5% week 24 all-cause mortality compared with 10.1% among placebo recipients. Additionally brincidofovir was associated with increased serious adverse events (57.1% versus 37.6%) compared with placebo. Brincidofovir was initially offered via an FDA expanded access trial; however as of 9 May 2019, Chimerix discontinued clinical trials of brincidofovir for the treatment of adenovirus and discontinued the expanded access program in 2019. After initial studies by the Centers for Disease Control and Prevention (CDC, Atlanta, Georgia, US) in cell culture models, on 6 October 2014, Chimerix received an FDA authorization for emergency investigational new drug applications of brincidofovir for the treatment of Ebola virus disease. Brincidofovir was administered to the first patient diagnosed in the Ebola virus disease outbreak in the US in 2014 . The patient was given the drug starting six days after hospital admission when he was already critically ill; he died four days later. Brincidofovir was also given to Ebola patient Ashoka Mukpo at the Nebraska Medical Center, who had developed the disease and then was pronounced Ebola-free and released from the center on 22 October 2014. In October 2014, Chimerix reported it had been given approval by the FDA to start Phase 2 trials in patients infected with ebolaviruses for brincidofovir's safety, tolerability, and efficacy. Organised by a team of scientists at the University of Oxford, including Peter Horby , Jake Dunning, Laura Merson and Trudie Lang , a trial commenced during January 2015 in Liberia, but was subsequently discontinued. Because of a lack of suitable subjects in Liberia, Oxford University and Médecins Sans Frontières planned to extend the trial to Sierra Leone , where there were still Ebola cases; but on 30 January 2015, the manufacturer decided to withdraw support for the trial and end discussion of future trials. In animal trials brincidofovir has shown activity against cytomegalovirus, adenoviruses , BK virus , poxvirus es, and herpes simplex viruses . Brincidofovir appears to have potential for the treatment of Ebola virus disease , which is somewhat paradoxical, as ebolaviruses are RNA viruses and thus do not contain DNA as the above-mentioned viruses. As of 2014 [ update ] , brincidofovir is in Phase III clinical trials for use in humans against cytomegalovirus and adenovirus. Preliminary safety data from a database of 1000 patients supported progression into later phase trials, Chimerix announced in December 2015 that the Phase III trials for use of the drug in preventing cytomegalovirus infection in stem cell transplant patients had failed, and in February 2016 shut down two other late-stage trials for use of the drug in preventing infection after kidney transplants . Brincidofovir is not yet FDA approved for adenovirus or cytomegalovirus due to lack of efficacy in clinical trials. In a trial of brincidofovir for patients with CMV brincidofovir was associated with a 15.5% week 24 all-cause mortality compared with 10.1% among placebo recipients. Additionally brincidofovir was associated with increased serious adverse events (57.1% versus 37.6%) compared with placebo. Brincidofovir was initially offered via an FDA expanded access trial; however as of 9 May 2019, Chimerix discontinued clinical trials of brincidofovir for the treatment of adenovirus and discontinued the expanded access program in 2019. After initial studies by the Centers for Disease Control and Prevention (CDC, Atlanta, Georgia, US) in cell culture models, on 6 October 2014, Chimerix received an FDA authorization for emergency investigational new drug applications of brincidofovir for the treatment of Ebola virus disease. Brincidofovir was administered to the first patient diagnosed in the Ebola virus disease outbreak in the US in 2014 . The patient was given the drug starting six days after hospital admission when he was already critically ill; he died four days later. Brincidofovir was also given to Ebola patient Ashoka Mukpo at the Nebraska Medical Center, who had developed the disease and then was pronounced Ebola-free and released from the center on 22 October 2014. In October 2014, Chimerix reported it had been given approval by the FDA to start Phase 2 trials in patients infected with ebolaviruses for brincidofovir's safety, tolerability, and efficacy. Organised by a team of scientists at the University of Oxford, including Peter Horby , Jake Dunning, Laura Merson and Trudie Lang , a trial commenced during January 2015 in Liberia, but was subsequently discontinued. Because of a lack of suitable subjects in Liberia, Oxford University and Médecins Sans Frontières planned to extend the trial to Sierra Leone , where there were still Ebola cases; but on 30 January 2015, the manufacturer decided to withdraw support for the trial and end discussion of future trials. In animal trials brincidofovir has shown activity against cytomegalovirus, adenoviruses , BK virus , poxvirus es, and herpes simplex viruses . Brincidofovir appears to have potential for the treatment of Ebola virus disease , which is somewhat paradoxical, as ebolaviruses are RNA viruses and thus do not contain DNA as the above-mentioned viruses.

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Orthopoxvirus

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Modified vaccinia Ankara

none Modified vaccinia Ankara ( MVA ) is an attenuated (weakened) strain of the vaccinia virus. It is being used as a vaccine (called MVA-BN , brand names: Imvanex in the EU, Imvamune in Canada, and Jynneos in the US ) against smallpox and mpox , having fewer side effects than smallpox vaccines derived from other poxviruses . This third-generation smallpox vaccine has the advantage that it cannot reproduce complete virions in human cells, "the block of the MVA life cycle occurs at the step of virion assembly resulting in assembly of immature virus particles that are not released from the infected cell." By inserting antigen genes into its genome, modified vaccinia Ankara virus is also used as an experimental viral vector for vaccines against non- poxvirus diseases. The traditional smallpox vaccine, which was used in the smallpox eradication campaign 1958–1977, consists of a live vaccinia virus which can replicate in humans but usually does not cause disease. It can however sometimes lead to serious side effects. Modified vaccinia Ankara virus is a highly attenuated strain of vaccinia virus that was developed in Munich, Germany between 1953 and 1968. It was produced by more than 500 serial passages of vaccinia virus (from a wild strain discovered by the Turkish vaccine institute of Ankara ) in chicken embryo fibroblasts . After testing the safety and effectiveness as a vaccine, it was approved in Germany in 1977, and then given to about 120,000 people until 1980, when smallpox vaccinations ended in Germany. No severe adverse events were seen during this time. It was later found that through the passaging, modified vaccinia virus Ankara had lost about 10% of the ancestral vaccinia genome and with it the ability to replicate efficiently in most mammalian cells. While it can enter host cells, express its genes and replicate its genome, it fails to assemble virus particles that are released from the cell. The vaccine was further developed and manufactured by the Danish company Bavarian Nordic , resulting in the vaccine MVA-BN, which is unable to replicate in human cells. The vaccine is given subcutaneously in two doses, at least 28 days apart. It was approved in Canada in 2013, as a smallpox vaccine and in 2020 also against mpox and related orthopoxvirus infections. It was approved in the European Union in 2013, as a vaccine against smallpox and in the US in September 2019, against smallpox and mpox. In August 2022, the US Food and Drug Administration (FDA) gave emergency use authorization for intradermal (rather than subcutaneous) mpox vaccination using a lower dose of Jynneos, which would increase the number of available doses up to five-fold. The vaccination would still be given in two doses, 28 days apart. A 2015 study had tested a regimen of one-fifth dose given intradermally. Modified vaccinia Ankara strains engineered to express foreign genes are vectors for production of recombinant proteins, the most common being a vaccine delivery system for antigens . A recombinant MVA-based vector for vaccination with different fluorescent reporter genes was developed, which indicate the progress of genetic recombination with the transgene of an antigen (green, colorless, red). In animal models, MVA-based vector vaccines have been found to be immunogenic and protective against various infectious agents including immunodeficiency viruses, influenza , parainfluenza , measles virus, flaviviruses , tuberculosis , Plasmodium parasites as well as certain cancers . MVA-B is an experimental vaccine to protect against HIV infection , produced by inserting HIV genes into the genome of modified vaccinia virus Ankara. In phase I clinical trials in 2013, it was found to be safe but produced only moderate levels of anti-HIV immunity. After removing a certain MVA gene, the vaccine produced an improved immune response in mice. A US Centers for Disease Control and Prevention (CDC) analysis of the vaccination status of 5402 individuals who had mpox infections during the summer of 2022 showed that unvaccinated people appeared to be 14 times more likely to be infected than those with a single (of two recommended) doses; the results were noted to be admittedly preliminary.

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Orthopoxvirus

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Mpox in the Democratic Republic of the Congo

Mpox is endemic in western and central Africa, with the majority of cases occurring in the Democratic Republic of the Congo (DRC), where the disease is reportable. There, the more virulent Congo basin virus type has been affecting some of the world's poorest and socially excluded communities. Many cases occur sporadically or in small clusters, but large outbreaks also occur. The world's first case of human mpox was detected in a nine-month old child in 1970 in the Democratic Republic of the Congo (then Zaire), two years after it reported its last case of smallpox . The onset of their rash was on 24 August. That year, the disease was identified in another four children, including three in Liberia who were playmates. At the time, evidence of the virus was found in non-human primates in Liberia and Sierre Leone. Active surveillance by the World Health Organization (WHO) between 1981 and 1986, identified 338 cases with a human-to-human transmission rate of 28%. Until 1986, 95% of cases worldwide were identified in the DRC. Cases were rare in people over the age of 15-years, and over two-thirds of infections could be traced to animal contact within the rainforests. Initially it was uncommon for a family member to contract the infection unless they did not have a smallpox scar. A reemergence of the disease in the DRC in 1996 also saw a large number of reported but not all laboratory confirmed cases, with a high transmission rate and lower fatality rate; leading experts to believe a significant number may have actually been chicken pox . Some likely had both mpox and chickenpox at the same time. The DRC's Kasaï-Oriental region saw the largest number of cases during 1996–1997. Between 1996 and 2005, mpox cases appeared increasingly in gradually older people, with less than a quarter of cases being traced to rainforest animal contact, and with greater close contact infections. Between January 2001 and December 2004, 2,734 cases of suspected human mpox were reported from the DRC. However, civil war limited surveillance and only 171 clinical specimens were obtained from 136 suspected cases; less than 5% of all reported cases. After 2005, the DRC was reporting more than 1000 suspected cases per year. Between November 2005 and November 2007, 760 laboratory-confirmed human mpox cases were detected; particularly in people living in forested areas, males, age less than 15-years, and no previous smallpox vaccination. Many cases occur sporadically or in small clusters, but large outbreaks also occur. The risk of human-to-human transmission within households in the DRC was noted to range from 50% to 100% during the 2013 outbreak. The DRC's Bokungu Health Zone saw an increase in cases of 600-fold that year. In 2019 the DRC reported 3,794 suspected cases and 73 deaths. In the first nine-months of 2020, it reported over 4,500 suspected cases of mpox, including 171 deaths. Mpox is reportable in the DRC, where the disease is endemic, and disease burden remains high. There, the more virulent Congo basin virus type has been affecting some of the world's poorest and socially excluded communities. A regional surveillance system collects reports of all suspected mpox cases, and where possible, they may be investigated. During 2023, a Clade I outbreak of mpox disease in the DRC resulted in 14,626 suspected cases being reported, with 654 associated deaths, making for a case-fatality rate (CFR) of 4.5%. The outbreak continued into 2024 with an additional 3,576 suspected mpox cases and 265 deaths being reported in the DRC through the first 9 weeks of the year, making for an estimated CFR of 7.4%. The outbreak appears to be of a primarily sexually transmitted nature and cases are occurring in areas without a history of mpox, such as South Kivu and Kinshasa. The outbreak seems to consist of two separate sub-variants of clade I, with one of the sub-variants having a novel mutation making detection with standard assays unreliable. The outbreak spread to the neighbouring country of the Republic of Congo , with 43 mpox cases being reported in March 2024.

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Carbocyclic nucleoside

Carbocyclic nucleosides (also referred to as carbanucleosides) are nucleoside analogues in which a methylene group has replaced the oxygen atom of the furanose ring. These analogues have the nucleobase attached at a simple alkyl carbon rather than being part of a hemiaminal ether linkage. As a result, they have increased chemical stability. They also have increased metabolic stability because they are unaffected by phosphorylases and hydrolases that cleave the glycosidic bond between the nucleobase and furanose ring of nucleosides. They retain many of the biological properties of the original nucleosides with respect to recognition by various enzymes and receptors. Carbocyclic nucleosides were originally limited to a five-membered ring system, matching the ring-size of the nucleosides; however, this term has been broadened to three-, four-, and six-membered rings. The 5-membered ring carbocyclic nucleosides aristeromycin, the analog of adenosine , and neplanocin A, the cyclopentene analog of aristeromycin, have been isolated from natural sources. They both exhibit significant biological activity as antiviral and antitumour agents. A large number of novel carbocyclic nucleosides of pyrimidines and purines have been prepared, and many of these compounds are endowed with interesting biological activities. The cyclopentenylcytosine (CPE-C) was developed as a potent antitumor and antiviral agent (phase 1 trials) and exhibited potent anti-orthopoxvirus as well as anti-West Nile virus activities. Carbocyclic (E)-5-(2-bromovinyl)-2-deoxyuridine( (+) C-BVDU) GR95168 possesses activity against herpes simplex virus type l (HSV-1) and varicella zoster virus (VZV, chicken pox and shingles) in-vitro and in-vivo. The two guanine antiviral carbocyclic nucleosides, the anti- HIV agent abacavir and the anti- hepatitis B agent entecavir , are reverse-transcriptase inhibitors . Abacavir, was developed from racemic (±)-carbovir which was reported in 1988 by Robert Vince as the first carbocyclic nucleoside analogue to show potent activity against HIV with low cytotoxicity. The (-) enantiomer of carbovir was later shown to be the biologically active form for inhibition of HIV. However carbovir's low aqueous solubility and poor oral bioavailability, as well as inefficient central nervous system penetration prevented it from further developing as an anti-HIV agent. These difficulties were overcome by investigating prodrug analogues of (-) carbovir which lead to the 6-cyclopropylamino-2-aminopurine nucleoside abacavir, which was approved in 1998 by the FDA for the treatment of HIV infection. Entecavir, a guanosine analog, was reported in 1997 as a potent and selective inhibitor for the hepatitis B virus , and approved by the FDA in March 2005 for oral treatment of hepatitis B infection. The fluorocarbocyclic nucleoside carbocyclic 2′- ara -fluoro-guanosine was reported in 1988 as the first example of a carbocyclic analogue of an unnatural nucleoside to exhibit greater anti-herpes activity against the herpesviruses HSV-1 and HSV-2 in-vitro than its furanose parent. The cyclopentenylcytosine (CPE-C) was developed as a potent antitumor and antiviral agent (phase 1 trials) and exhibited potent anti-orthopoxvirus as well as anti-West Nile virus activities. Carbocyclic (E)-5-(2-bromovinyl)-2-deoxyuridine( (+) C-BVDU) GR95168 possesses activity against herpes simplex virus type l (HSV-1) and varicella zoster virus (VZV, chicken pox and shingles) in-vitro and in-vivo. The two guanine antiviral carbocyclic nucleosides, the anti- HIV agent abacavir and the anti- hepatitis B agent entecavir , are reverse-transcriptase inhibitors . Abacavir, was developed from racemic (±)-carbovir which was reported in 1988 by Robert Vince as the first carbocyclic nucleoside analogue to show potent activity against HIV with low cytotoxicity. The (-) enantiomer of carbovir was later shown to be the biologically active form for inhibition of HIV. However carbovir's low aqueous solubility and poor oral bioavailability, as well as inefficient central nervous system penetration prevented it from further developing as an anti-HIV agent. These difficulties were overcome by investigating prodrug analogues of (-) carbovir which lead to the 6-cyclopropylamino-2-aminopurine nucleoside abacavir, which was approved in 1998 by the FDA for the treatment of HIV infection. Entecavir, a guanosine analog, was reported in 1997 as a potent and selective inhibitor for the hepatitis B virus , and approved by the FDA in March 2005 for oral treatment of hepatitis B infection. The fluorocarbocyclic nucleoside carbocyclic 2′- ara -fluoro-guanosine was reported in 1988 as the first example of a carbocyclic analogue of an unnatural nucleoside to exhibit greater anti-herpes activity against the herpesviruses HSV-1 and HSV-2 in-vitro than its furanose parent. There are two approaches used in the synthesis of carbocyclic nucleosides. Linear approaches to chiral carbocyclic nucleosides 2 rely on the construction of the heterocyclic base onto a suitable protected chiral cyclopentylamine ( 1 → 2 ). In the convergent approach the intact heterocyclic base is coupled directly to a suitably protected functionalised carbocyclic moiety ( 3 → 2 ).

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Buffalopox

Buffalopox is caused by buffalopox virus (BPXV); it is a Poxviridae for which the natural host is buffalo. It mainly infects buffalo but has been known to infect cows and humans. It is classified in the Orthopoxvirus (OPV) genus and the subfamily Chordopoxvirinae . The appearance of buffalopox follows a pattern and is described as emerging and re-emerging, it commonly occurs in sporadic and epidemic forms in domestic and commercial farm settings. The first recorded incidence of buffalopox occurred in India in 1934. Since then many outbreaks have occurred in many parts of the world including Pakistan, Egypt, Nepal, and Bangladesh. While the disease was characterized in 1934, the agent causing the disease was not identified until 1977 when researchers, Singh and Singh, were able to isolate and characterize the virus. In buffaloes the disease is mainly reported in the young and old. BPXV can be spread by sand flies and midges, and transmission studies showed that in addition to infecting buffaloes and cows the virus can also infect guinea pigs and suckling mice. Between 2006 and 2008, there were four outbreaks in domestic buffaloes in India. The buffaloes presented with lesions on the udder, teats, limbs, around the ear, and hindquarters which was indicative of a generalized infection. In this case, there was a reduction of milk yield of about 30-35% which was followed by mastitis that was a consequence of a secondary bacterial infection. The milk attendants developed lesions on their chest, lower abdomen, fingers, hands, forearms, legs, scapular region, feet, and forehead and also presented with a fever, lymphadenopathy, and general malaise. There is also some evidence of milk attendants spreading the virus between buffalo and from buffalo to cows. In the mild form, lesions occur localized on the udder, teats, and inguinal region, over the parotid, and the base and inner surface of the ear and eyes. In the severe form, the lesions are generalized. The severe form is now rare, and the disease is mainly mild. The result is high morbidity and productivity loss. When the virus infects milk animals it causes mastitis which reduces milk yield and the working capacity of draft animals. The mastitis occurs in approximately fifty percent of the infected animals; in severe cases, the reduction in milk production can be permanent. The incubation time in animals is about 2–4 days and in humans it is 3–19 days. Structurally BPXV looks like other OPVs and especially Vaccinia Virus (VACV). Studies have shown that the virus particle is brick shaped and measures 280-330 nm by 200-250 nm in size. Before maturation the particle appears oval or spherical and may or may not have a central core. Research has shown that, depending on the specific strain of the virus it can yield between 19 and 26 polypeptides, some of which are glycoproteins. Humans in close contact with buffaloes are susceptible to buffalopox; with the cessation of the smallpox vaccine in 1980, humans do not develop an antibody titer against the Poxviridae, and as a result have become even more susceptible to viruses like buffalopox. In humans the virus causes lesions that are mainly confined to the hands, forehead, face, buttocks, and legs, and occasionally lymphadenopathy. Human-to-human transmission has not been reported. Milking of infected animals is one of the major modes of spread, thus the main people in danger of contracting the disease are veterinarians, milk attendants, and other people who are in close proximity of the infected animals. There have also been recent reports of nosocomial infections in burn patients and paramedical staff.

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2022–2023 mpox outbreak in Belgium

The 2022–2023 mpox outbreak in Belgium is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . Belgium was the fifth country, outside of the African countries with endemic mpox, to experience an outbreak in 2022. The first case was documented in Antwerp , Belgium , on 19 May 2022. As of 10 August, Belgium has 546 cases and 1 suspected case. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on 4 May, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis, an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . The first two known cases were detected in on 19 May 2022. The first infected person was diagnosed in Antwerp , and the second from a region called Flemish Brabant . Both had gone to the same party, and thus began the mpox outbreak in Belgium. It is unknown what hospital they went to, although it is very likely that the first infected person went to an Antwerp hospital, and the second infected person went to a Flemish Brabant region hospital. There, they both tested positive for mpox, becoming the first cases in Belgium. A day after both tested positive, there was another case reported in a man of unknown age who was relatively healthy but had bullous lesions on his hands. More and more cases were reported in Belgium days later and more continue to be reported. As of 10 August, there are 546 cases and 1 suspected case. On 5 July the Office of European Commissioner for Health, Stella Kyriakides , told Belga News Agency that 3,040 mpox vaccines were shipped to Belgium on 7 July. According to the Cypriot commissioner, these deliveries will "protect Belgian citizens and respond to this outbreak." She also praised the European Health Emergency Response and Preparedness Authority 's (HERA) quick response. Kyriakides concluded that more doses will be delivered to Belgium in the following weeks. Hospitals have also begun making their own preparations to help control the current mpox outbreak, including screening patients, increasing decontamination and cleaning procedures, and wearing appropriate safety gear ( Personal protective equipment / Medical gown ) when interacting with infected patients. Belgium also introduced a mandatory 21-day quarantine for infected mpox patients in hopes of containing the disease in the country. Close contacts are not required to self-isolate but are encouraged to remain vigilant, especially if in contact with vulnerable people.

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Outbreak of monkeypox at Rotterdam Zoo

In 1964 there was an outbreak of monkeypox at Rotterdam Zoo , where two Central / South American giant anteaters were first identified with the disease. Until then, monkeypox was thought to occur only in primates . Housed in one large enclosure, the monkeypox virus subsequently spread to several orangutans , chimpanzees , gorillas , guenons , squirrel monkeys , macaques , marmosets and gibbons . Unlike previous monkeypox outbreaks in laboratory monkeys, the outbreak in Rotterdam Zoo occurred in animals that were not for laboratory use, showed varying clinical presentations, and was particularly severe for orangutans. There were no reports of cases of transmission to humans . In total, 11 of the 23 affected animals died, including six orangutans, the anteaters, three squirrel monkeys, the only one Asian gibbon and an American common marmoset. Several were complicated by fatal secondary bacterial infections .Between 1958 and 1968, mainly for the purpose of producing and testing the polio vaccine , a small number of non-human primates from Africa and a larger number from Asia were being imported to Europe and the US. During transit, there were often other wild animals with several opportunities to spread infection. On 9 December 1964, without being quarantined , two Central/South American giant anteaters arrived at Rotterdam Zoo , and on 21 December developed a blistering rash. The lesions appeared on the tongue, nose, legs and soles of feet. A diagnosis of monkeypox was confirmed at the National Institute for Public Health and the Environment laboratory in Utrecht . Until 1964, monkeypox was thought to occur only in primates . The anteaters had been bought from dealers, and the virus was suspected to have been contracted from previous contact with infected monkeys elsewhere, possibly from close contact with a shipment of Malaysian cynomolgus monkeys . [lower-alpha 1]Ten days after the onset of sickness in the anteaters, two Asian orangutans that were housed in a glass cage nearby, developed small blisters. Whether transmission was by air or contaminated objects is not clear. The disease spread to several other orangutans , who became unwell with yellow nasal discharge and lesions on their face, body and legs. Also affected, and all housed in one large enclosure, were chimpanzees , gorillas , guenons , squirrel monkeys , macaques , marmosets and gibbons . Affected animals typically had a generalised illness, some with skin lesions, and several died during early symptoms, before the spots appeared. Unlike previous monkeypox outbreaks in laboratory monkeys, the outbreak at Rotterdam Zoo occurred in animals that were not for laboratory use, showed varying clinical presentations, and was particularly severe for orangutans. All 10 orangutans became ill and six died, five of whom died before the onset of the rash. Of those orangutans that survived, recovery was prolonged. They found it difficult to eat, and the ones that died were noted to have suffered problems in breathing. The affected chimpanzees had blisters on their lips and face, but were otherwise well. One of the two infected African gorillas became seriously sick, but both survived. Four of the infected guenons suffered mild illness with skin lesions. Most infected marmosets had mild symptoms. The Vervet monkey had subclinical infection ; the Asian monkeys ( cynomolgus monkey and rhesus macaque ) were noted to have a generalised rash; and the baboons also experienced a generalised rash and severe illness. The only Asian gibbon presented with lesions on its face, limbs and body, and died 18-days after suffering severe illness. Two of the three affected squirrel monkeys had no rash. The owl-faced monkey became ill with sores on their lips but recovered. Some of the marmosets had reddening and swellings around their eyes and nose with blisters on the face and tummy. One American common marmoset had a similar swelling, but with severe illness. In total, 11 of the 23 affected animals died, including in addition to the orangutans and anteaters, all three squirrel monkeys , the Asian gibbon and the severely ill American common marmoset. Several were complicated by fatal bacterial infections. No cases of transmission to humans were reported. Primates that had exposure but did not contract the disease included Ateles paniscus , red-faced spider monkey , black-headed spider monkey , siamang , Colombian white-faced capuchin , mona monkey , and L'Hoest's monkey . According to Isao Arita and Donald Henderson in 1976, how relevant that a strain of whitepox viruses, which resembled variola, were isolated from two cynomolgus monkeys at the National Institute for Public Health and the Environment three-months prior to the arrival of the anteaters was not clear. On 9 December 1964 and 4 May 1965, poxviruses resembling monkeypox were isolated from kidneys of cynomolgus monkeys at the same laboratory. A personal correspondence from Rijk Gispen 's colleague, Jacoba G. Kapsenberg , in the early 1980s, revealed that the so-called cases of "silent monkeypox" were probably a result of contamination from monkeypox virus isolated from the Zoo cases. Six years after the outbreak, Gispen detected high levels of monkeypox neutralizing antibody in two of the surviving orangutans, and concluded that it lasts long after infection. The antiviral methisazone was used unsuccessfully. Of more importance was the use of antibiotics to treat secondary bacterial infections. The outbreak was reported by J.C. Peters. The incident is an example of how an outbreak may occur in animals following an accidental infection of one susceptible other animal. No further outbreaks in captive monkeys occurred after 1968, as conditions for monkeys in transit improved, and Europe and the US increasingly bred their own monkeys.

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2003 Midwest monkeypox outbreak

Beginning in May 2003, by July a total of 71 cases of human monkeypox were found in six Midwestern states including Wisconsin (39 cases), Indiana (16), Illinois (12), Kansas (1), Missouri (2), and Ohio (1). The cause of the outbreak was traced to three species of African rodents ( Gambian pouched rat , dormice , rope squirrels ) imported from Ghana on April 9, 2003, into the United States by an exotic animal importer in Texas. These were shipped from Texas to an Illinois distributor, who housed them with prairie dogs , which then became infected. The outbreak marked the first time monkeypox infection appeared in the United States, and the first time in the Western Hemisphere . No deaths were reported, and no human-to-human transmission was found. All cases involved direct contact with infected prairie dogs. Electron microscopy and testing by polymerase chain reaction and immunohistochemistry were used to confirm the causative agent was human monkeypox. In May, 2003, a three-year-old Wisconsin resident was bitten by a prairie dog purchased from a local pet store. The child was hospitalized after developing fever of unknown origin ( 103 °F (39 °C) ), swollen eyes, and a red vesicular skin rash. The child's parents also developed a rash, but no other symptoms. Physicians immediately associated the symptoms with the animal bite and reported the case to the Milwaukee Health Department. Testing of both the child and the prairie dog confirmed the monkeypox virus as the causative agent. [ citation needed ] Between May 15, 2003, when the three-year-old index patient was first diagnosed through June 20, the date of the last patient with a laboratory-confirmed case of monkeypox, a total of 71 people ranging in age from 1 to 51 were infected. On April 9, 2003, a Texas importer received a shipment of 762 African rodents from Accra, Ghana , which included rope squirrels (Funiscuirus sp.), tree squirrels (Heliosciurus sp.), Gambian pouched rats (Cricetomys sp.), African brush-tailed porcupine (Atherurus sp.), dormice (Graphiurus sp.), and striped mice (Hybomys sp.). Of these 762 rodents, 584 (77%) were shipped to distributors in six US states: Texas (9), New Jersey (1), Iowa (1), Japan (1), Illinois (2), Minnesota (1) and Wisconsin (1). The remaining 178 (23%) rodents could not be traced due to lack of documentation. CDC laboratory testing of animals from this shipment confirmed monkeypox by PCR and virus isolation in one Gambian rat, three dormice, and two rope squirrels. Illinois distributor number one received Gambian rats and dormice and housed the rodents with 200 prairie dogs. This distributor shipped prairie dogs to pet stores in Wisconsin, Illinois, Indiana, Missouri, Kansas, South Carolina, and Michigan. No human cases of monkeypox were reported in Japan, Michigan, and South Carolina. Laboratory-confirmed cases occurred only in Kansas (1), Missouri (2), Indiana (16), Illinois (12), and Wisconsin (22). Of the 200 prairie dogs housed with the Gambian rats and dormice, 94 tested positive for monkeypox virus, including prairie dogs in pet stores in Wisconsin (44 cases), Indiana (24), Illinois (19), Ohio (4), Kansas (1), Missouri (1), and one case in the eastern seaboard state of New Jersey . The Gambian rats and dormice housed with the prairie dogs at Illinois distributor number one tested positive for monkeypox virus. [ citation needed ] The most recent incidence of monkeypox prior to the Midwest outbreak occurred in the Democratic Republic of the Congo in 1996–1997, with a reported 88 cases. No deaths occurred in the Midwest outbreak. This was attributed to the prompt medical care received and the standard of living in the United States, which includes soap, running water, washing machines, sterile dressing materials, and hospital use of universal precautions , including isolation, gown, mask, gloves, and handwashing. No human-to-human transmission was found during this outbreak. All cases were found to be the direct result of contact with infected prairie dogs. Human-to-human transmission has been reported in Central and West Africa. [ citation needed ]The onset of the illness among affected persons in the United States began in early May 2003. People typically experienced fever, headaches, muscle aches, chills, and nonproductive coughs, followed 1–10 days later by a generalized papular rash which developed first on the trunk, then limbs and head. The papules evolved through phases of vesiculation , pustulation , umbilication , and crusting. All persons reported direct or close contact with recently acquired prairie dogs. As no direct antiviral treatment for monkeypox was known, only supportive care and prevention of secondary infection was recommended. Universal precautions in the care of those with the disease had been shown to prevent human-to-human transmission and inoculation with the smallpox vaccine has shown to be effective in abating the progression of the disease in those with active infection, and in the prevention of the disease in the general population. [ citation needed ] In the Midwest outbreak, the CDC issued guidance on the use of smallpox vaccine , Cidofovir , and Vaccinia immune globulin . Thirty residents in six states received the smallpox vaccination. This included 28 adults and two children. Vaccine was given before exposure to seven persons (three veterinarians, two laboratory workers, and two health-care workers) and after exposure to 23 persons (10 health-care workers, seven household contacts, three laboratory workers, one public health veterinarian, one public health epidemiologist, and one work contact). Three (10%) reported rash within 2 weeks of vaccination. One adult who was vaccinated as a child did not have a major vaccine reaction or "take" 7 days after vaccination and required revaccination. [ citation needed ] No adverse reactions to the smallpox vaccine were reported to the Vaccine Adverse Event Reporting System . [ citation needed ]In the Midwest outbreak, the CDC issued guidance on the use of smallpox vaccine , Cidofovir , and Vaccinia immune globulin . Thirty residents in six states received the smallpox vaccination. This included 28 adults and two children. Vaccine was given before exposure to seven persons (three veterinarians, two laboratory workers, and two health-care workers) and after exposure to 23 persons (10 health-care workers, seven household contacts, three laboratory workers, one public health veterinarian, one public health epidemiologist, and one work contact). Three (10%) reported rash within 2 weeks of vaccination. One adult who was vaccinated as a child did not have a major vaccine reaction or "take" 7 days after vaccination and required revaccination. [ citation needed ] No adverse reactions to the smallpox vaccine were reported to the Vaccine Adverse Event Reporting System . [ citation needed ]To prevent monkeypox virus from entering into the United States again, the Centers for Disease Control banned the importation of implicated African rodents. The U.S. Food and Drug Administration issued orders banning the interstate shipment of prairie dogs and all African rodents. [ citation needed ] These were lifted in 2008.

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2022–2023 mpox outbreak in Austria

The 2022–2023 mpox outbreak in Austria is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . Austria is the fifteenth country outside of Africa to experience an endemic mpox outbreak. The first case was reported in Vienna , Austria , on 22 May 2022. As of 2 December, Austria has confirmed a total of 327 cases. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on May 4, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis, an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . The first known case was detected in on 22 May 2022, with a 35-year-old man in Vienna , Austria . The person was hospitalized in Vienna . There, he tested positive for mpox, becoming the first case in Austria. Two weeks after the man tested positive, additional cases were reported in Austria days later and more are being quarantined. As of 10 August, there are 175 cases and no suspected cases. Till 22 August 2022, there have been 217 confirmed cases of mpox in Austria. Hospitals have also begun making their own preparations to help control the current mpox outbreak, including screening patients, increasing decontamination and cleaning procedures, and wearing appropriate safety gear ( Personal protective equipment / Medical gown ) when interacting with infected patients. Austria also published a set of guidelines in hopes of containing the disease in the country. A three-week quarantine was set into place for infected patients. Isolation can be performed at home or at hospital, depending on the state of health of the patient, according to the Ministry of Health.

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2022–2023 mpox outbreak in the United Kingdom

The 2022–2023 mpox outbreak in the United Kingdom is part of the larger outbreak of human mpox caused by the West African clade (type) of the monkeypox virus . The United Kingdom was the first country, outside of the endemic African areas, to experience an outbreak. As of 22 July 2022 [ update ] , there were 2,208 confirmed cases in the United Kingdom, with 2,115 in England, 54 in Scotland, 24 in Wales, and 15 in Northern Ireland. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on 4 May, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . The first known case was detected in the beginning of May 2022, in a British resident who had travelled to Lagos and Delta State in Nigeria, in areas where mpox is considered to be an endemic disease. The person developed a rash on 29 April while in Nigeria and flew back to the United Kingdom, arriving on 4 May, and presented to hospital later the same day. Mpox infection was immediately suspected, and the patient was hospitalised at Guy's Hospital and isolated, then tested positive for the virus on 6 May. In late May, cases started to be reported in the other constituent countries, with Public Health Scotland reporting its first case on 23 May. Public Health Wales and the Public Health Agency of Northern Ireland each reported one case on 26 May. On 1 June, a case was reported in Gibraltar , a British Overseas Territory . On 30 August 2022, 3413 cumulative cases (3,279 confirmed and 134 highly probable cases) of human mpox up to (and including) 29 August were reported for the UK. On 22 May, Education Secretary Nadhim Zahawi said "we're taking it very, very seriously" and that the UK government had already started purchasing smallpox vaccines. The UK Health Security Agency (UKHSA) advised people who have had close contact with a person infected with mpox to self-isolate for 21 days. Self-isolation is not mandatory. Furthermore, to combat the continued spread of the outbreak, the UKHSA has offered doses of the Imvanex smallpox vaccine, also effective against mpox, to people having had close contact with people confirmed to having been infected. On 30 May, the four main public health agencies published a consensus statement describing the principles they will put in use, with the aim of limiting community transmission.

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2022–2023 mpox outbreak in Singapore

The 2022–2023 mpox outbreak in Singapore is a part of the global outbreak of human mpox caused by the West African clade of the monkeypox virus . According to the Ministry of Health (MOH), Singapore's first imported mpox case was reported on 20 June 2022. It was the first ever confirmed case in Southeast Asia . Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. The Ministry of Health (MOH) detailed that the patient is a 42-year-old British man who works as a flight attendant . He was reportedly in Singapore between 15 and 17 June 2022 and again on 19 June as he flew in and out of Singapore. He tested positive for mpox on 20 June. On 6 July, it was confirmed that a 45-year-old Malaysian man tested positive becoming the first locally unlinked infection in the country. As of 5 August 2022, there are 10 locally transmitted cases and 5 imported cases in the country, all of whom are in stable conditions or ready to be discharged.

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ODE-CDV

InChI=1S/C28H54N3O7P/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-20-36-21-22-38-39(34,35)25-37-26(24-32)23-31-19-18-27(29)30-28(31)33/h18-19,26,32H,2-17,20-25H2,1H3,(H,34,35)(H2,29,30,33)/t26-/m0/s1 Key: BLYNHZVAZVOTGV-SANMLTNESA-N InChI=1/C28H54N3O7P/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-20-36-21-22-38-39(34,35)25-37-26(24-32)23-31-19-18-27(29)30-28(31)33/h18-19,26,32H,2-17,20-25H2,1H3,(H,34,35)(H2,29,30,33)/t26-/m0/s1 Key: BLYNHZVAZVOTGV-SANMLTNEBA CCCCCCCCCCCCCCCCCCOCCOP(=O)(CO[C@@H](Cn1ccc(nc1=O)N)CO)O ODE-CDV (octadecyloxyethyl-cidofovir) is a cidofovir derivative with antiviral activity.

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2022–2023 mpox outbreak in Brazil

The 2022–2023 mpox outbreak in Brazil is a part of the ongoing outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak was first reported in Brazil on 9 June 2022 when a man in São Paulo was registered as the country's index case . Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. In May 2022, the World Health Organization (WHO) made an emergency announcement of the existence of a multi-country outbreak of mpox , a viral disease then commonly known as "monkeypox" . The initial cluster of cases was found in the United Kingdom , where the first case was detected in London on 6 May 2022 in a patient with a recent travel history from Nigeria (where the disease is endemic ). On 16 May, the UK Health Security Agency ( UKHSA ) confirmed four new cases with no link to travel to a country where mpox is endemic. Subsequently, cases have been reported from many countries and regions. The outbreak marked the first time mpox had spread widely outside Central and West Africa . There is evidence that the disease had been circulating and evolving in human hosts over a number of years prior to the outbreak. The outbreak was of the Clade IIb variant of the virus. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . Three suspected mpox cases were reported in Brazil on 30 May 2022. On 9 June, a 41-year-old man, who had recently travelled to Spain and Portugal and had been admitted to a São Paulo hospital, tested positive for the virus. On 29 July, the first death was reported outside of Endemic african countries and the country's first mpox cases in children were confirmed in three kids from São Paulo city.

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2022–2023 mpox outbreak in Taiwan

The 2022–2023 mpox outbreak in Taiwan is a part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . According to the Centers for Disease Control , Taiwan's first mpox case was reported on 24 June 2022. As of November 2023, there have been 355 confirmed cases of mpox in Taiwan. 17 cases were imported, and 338 cases were domestically transmitted.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on 4 May, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. The first known case of the mpox outbreak in Taiwan was detected on 24 June 2022. According to the Centers for Disease Control, the case was a Taiwanese man in his 20s who had traveled to Germany for his studies. He returned to Taiwan on 16 June, started showing symptoms on 20 June, and tested positive for mpox on 24 June. On 12 July, Taiwan reported its second case of mpox in a man in his 30s who had gone on a business trip to the United States . On 6 August, a third case of imported mpox was reported, involving a man in his 20s who had returned to Taiwan from the United States. The fourth imported case, reported on 9 October, involved a man in his 40s who had visited Canada, and developed symptoms in the United States. The fifth case was reported on 15 February 2023. By March 2023, the disease was confirmed to have been domestically transmitted. In November 2023, the first death from mpox in Taiwan was reported. In February 2024, Taiwan's Ministry of Health and Welfare formally changed the Mandarin name of the disease from monkeypox ( 猴痘 ) to mpox ( M痘 ). This mirrored a change in the English-language name of the disease, originally proposed by the World Health Organization (WHO) on 28 November 2022. On 20 February, the Centers for Disease Control announced that Taiwan had avoided domestic transmission of mpox for fourteen consecutive weeks, thereby meeting the WHO criteria for the elimination of mpox from epidemic status. Subsequently, two men separately tested positive for mpox, and each was classified as a domestic case. In May 2022, the Taiwan Centers for Disease Control started increasing monitoring for mpox cases. Later that month, health minister Chen Shih-chung stated that Taiwan was not yet planning to purchase a mpox vaccine. As the global outbreak spread, Taiwan designated mpox as a category 2 communicable disease on 23 June. Two days after the index case was publicized, the CDC issued guidelines for risk assessment and control. By 27 June, the CDC had begun working to reverse the vaccine policy declared in May, stating that talks to acquire mpox medications and vaccines had started. Later on 30 June, the CDC issued a travel warning for 44 countries that had reported cases of mpox. On 2 July, the CDC announced that they are planning to receive third-generation smallpox vaccines and antiviral drugs in late 2022. The CDC said that frontline medical workers and researchers will be the first to receive the vaccine. On 24 July, the CDC announced that they signed a contract to purchase medication to treat mpox patients, and that a shipment will arrive in August at the earliest. The CDC also announced that they are in talks to purchase mpox vaccines, and that they are hoping to receive them by late August. On 27 July, 504 courses of mpox medications arrived in Taiwan, to be used by severe cases and immunocompromised individuals. On 1 September, Taiwan received its first doses of the mpox vaccine. New cases per day

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2022–2023 mpox outbreak in Ghana

The 2022–2023 mpox outbreak in Ghana is a part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . As opposed to its West African neighbours, Ghana had no endemic presence of mpox, only experiencing it during the 2022 outbreak. The first 5 cases of mpox in Ghana was detected on June 8, 2022. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on May 6, 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on April 29, 2022. The resident returned to the United Kingdom on May 4, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis, an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes .

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2022–2023 mpox outbreak in the Philippines

The 2022–2023 mpox outbreak in the Philippines was a part of the larger global outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak was first reported in the Philippines when a suspected case was confirmed on July 28, 2022, according to the Department of Health . Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. The first case of human mpox in the Philippines was confirmed on July 28, 2022. The case involved a 31-year-old Filipino national who arrived from abroad to the Philippines on July 19, 2022. He also had prior travel to countries with documented mpox cases. The individual's mpox infection was confirmed through a reverse transcription–polymerase chain reaction (RT-PCR) test at the Research Institute for Tropical Medicine in Muntinlupa which yielded a positive result on July 28, 2022. The patient had already recovered at the time of the health department's announcement but is undergoing isolation at home. Ten other people, including three people from the individual's household were identified as close contacts. Earlier on July 23, 2022, Director-General Tedros Adhanom Ghebreyesus of the World Health Organization declared the mpox global outbreak a public health emergency of international concern . On August 6, 2022, the patient was discharged after undergoing the 21-day quarantine isolation to which no other person was infected according to the Department of Health (DOH). Other close contacts tested negative too though they are still required to complete their 21 days of quarantine. On August 19, 2022, the DOH announced the detection of two more cases; those of a 34-year-old and a 29-year-old both of which has a history of travel abroad. The 34-year-old patient is undergoing home isolation and the 29-year-old patient is in isolation at a health facility. Contract tracing was conducted for both with the latter having 17 identified contacts. The PCR test conducted for both individuals returned positive results on August 18 and 19 respectively. All three cases at that time are unrelated to each other as they entered the Philippines from different countries and the DOH considered these cases as "imported" cases. They have exhibited typical symptoms associated with mpox like lesions on their faces and other parts of their bodies. DOH Technical Advisory Group (TAG) member Dr. Edsel Salvana says he expects more cases to be detected but allayed concerns of a local transmission or the disease becoming endemic in the country. He points out that mpox is less contagious than COVID-19 and that protocols in place for the COVID-19 pandemic is also mitigating the spread of mpox. On August 22, the DOH announced that the country has detected its fourth case that of a 25-year-old Filipino who have no travel history outside the country. The individual's PCR Test returned a positive result on August 19. The health department also stated that the fourth case is not related to the previous three. The following day the health department's Western Visayas regional office, released further details regarding the patient confined in a hospital; a male who works in Iloilo City and resides in Iloilo province. Iloilo City mayor Jerry Treñas in an interview with local radio stations said that the indicidual worked in a fast food chain in the city and added that he had a relative who recently came in from abroad. The DOH also asked the Western Visayas regional office to investigate the photos of the patient shared on social media as early as August 22 deeming such act as an unauthorized disclosure of private and confidential information. The second case was deemed recovered on August 31 while the third case was considered the same on September 8. The fourth case was discharged from the hospital on September 15 and is deemed to have recovered. The Philippines would not record any further case of the human mpox. In May 2023, the public health emergency of the WHO was declared over. Meanwhile, the country's health department never declared a health emergency. The first case of human mpox in the Philippines was confirmed on July 28, 2022. The case involved a 31-year-old Filipino national who arrived from abroad to the Philippines on July 19, 2022. He also had prior travel to countries with documented mpox cases. The individual's mpox infection was confirmed through a reverse transcription–polymerase chain reaction (RT-PCR) test at the Research Institute for Tropical Medicine in Muntinlupa which yielded a positive result on July 28, 2022. The patient had already recovered at the time of the health department's announcement but is undergoing isolation at home. Ten other people, including three people from the individual's household were identified as close contacts. Earlier on July 23, 2022, Director-General Tedros Adhanom Ghebreyesus of the World Health Organization declared the mpox global outbreak a public health emergency of international concern . On August 6, 2022, the patient was discharged after undergoing the 21-day quarantine isolation to which no other person was infected according to the Department of Health (DOH). Other close contacts tested negative too though they are still required to complete their 21 days of quarantine. On August 19, 2022, the DOH announced the detection of two more cases; those of a 34-year-old and a 29-year-old both of which has a history of travel abroad. The 34-year-old patient is undergoing home isolation and the 29-year-old patient is in isolation at a health facility. Contract tracing was conducted for both with the latter having 17 identified contacts. The PCR test conducted for both individuals returned positive results on August 18 and 19 respectively. All three cases at that time are unrelated to each other as they entered the Philippines from different countries and the DOH considered these cases as "imported" cases. They have exhibited typical symptoms associated with mpox like lesions on their faces and other parts of their bodies. DOH Technical Advisory Group (TAG) member Dr. Edsel Salvana says he expects more cases to be detected but allayed concerns of a local transmission or the disease becoming endemic in the country. He points out that mpox is less contagious than COVID-19 and that protocols in place for the COVID-19 pandemic is also mitigating the spread of mpox. On August 22, the DOH announced that the country has detected its fourth case that of a 25-year-old Filipino who have no travel history outside the country. The individual's PCR Test returned a positive result on August 19. The health department also stated that the fourth case is not related to the previous three. The following day the health department's Western Visayas regional office, released further details regarding the patient confined in a hospital; a male who works in Iloilo City and resides in Iloilo province. Iloilo City mayor Jerry Treñas in an interview with local radio stations said that the indicidual worked in a fast food chain in the city and added that he had a relative who recently came in from abroad. The DOH also asked the Western Visayas regional office to investigate the photos of the patient shared on social media as early as August 22 deeming such act as an unauthorized disclosure of private and confidential information. The second case was deemed recovered on August 31 while the third case was considered the same on September 8. The fourth case was discharged from the hospital on September 15 and is deemed to have recovered. The Philippines would not record any further case of the human mpox. In May 2023, the public health emergency of the WHO was declared over. Meanwhile, the country's health department never declared a health emergency. On September 5, 2022, the first ever case of mpox in Hong Kong was detected from a passenger who arrived from a flight from Manila. The individual concerned is a 30-year old Hong Konger. On May 24, 2022, the DOH expressed readiness to detect and contain mpox if it reaches the Philippines. It has classified mpox as a notifiable disease requiring health facilities in the country to report all patients under investigation and cases to its Epidemiology Bureau (EB) and Regional Epidemiology Surveillance Unit. It also announced that all suspected cases are to undergo reverse transcription–polymerase chain reaction (RT-PCR) tests for mpox. By June 20, 2022, the Research Institute for Tropical Medicine in Muntinlupa announced that it has optimized its real-time polymerase chain reaction (PCR) assay for the detection of monkeypox virus. As of July 2022, the RITM and the Philippine Genome Center in Quezon City are the only institutions in the Philippines capable of detecting mpox through RT-PCR tests. The DOH has aimed to expand capacity and capability to other institutional hospitals as well. Ninoy Aquino International Airport and several national airports ramped up their surveillance to detect the virus. In an explicit statement on August 2, 2022, DOH Officer in Charge Maria Rosario Vergeire said that borders and foreign entry are not to be shut down whilst not yet receiving recommendations from the World Health Organization (WHO). Furthermore, it was affirmed that the opening of classes and universities will still resume on August 22 accordingly along with the cooperation of DepEd and local LGUs . The DOH has also entered negotiations with the United States government in a bid to secure mpox vaccines for a limited demographic. Along with the WHO, the DOH has been proactively monitoring cases and revamping medical facilities in the country. Upon the detection of the first case, the Private Hospitals Association of the Philippines Inc. released a statement advising against home isolation for further suspected mpox cases.

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2022–2023 mpox outbreak in India

The 2022–2023 mpox outbreak in India is a part of the ongoing outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak was first reported in India on 14 July 2022 when Kerala 's State Health Minister Veena George announced a suspected imported case which was confirmed hours later by the NIV . India was the tenth country to report a mpox case in Asia and the first in South Asia . Currently, India has reported 23 cases of mpox. On 24 July, the first locally transmitted case was reported in Delhi . The individual, a middle-aged male who had no recent history of travelling abroad, was isolated in the Lok Nayak Hospital , New Delhi .Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. In May 2022, the World Health Organization (WHO) made an emergency announcement of the existence of a multi-country outbreak of mpox , a viral disease then commonly known as "monkeypox" . The initial cluster of cases was found in the United Kingdom , where the first case was detected in London on 6 May 2022 in a patient with a recent travel history from Nigeria (where the disease is endemic ). On 16 May, the UK Health Security Agency ( UKHSA ) confirmed four new cases with no link to travel to a country where mpox is endemic. Subsequently, cases have been reported from many countries and regions. The outbreak marked the first time mpox had spread widely outside Central and West Africa . There is evidence that the disease had been circulating and evolving in human hosts over a number of years prior to the outbreak. The outbreak was of the Clade IIb variant of the virus. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . On 14 July, a suspected mpox case was reported in the South-Indian state of Kerala by the State health minister Veena George . The patient was reportedly in close contact with a person who tested positive for mpox abroad in the United Arab Emirates , and arrived in India from UAE four days prior to the announcement. Hours later, minister Veena George announced that the patient was confirmed to be infected with the mpox disease by the NIV of Pune . [ citation needed ] No community transmission or locally transmitted cases were detected in India until on 24 July, Delhi reported their first case, and the patient had no history of travel from abroad. He recently attended a party in Himachal Pradesh . Although community transmission of the disease in India wasn't confirmed by the government health officials.On 14 July, a suspected mpox case was reported in the South-Indian state of Kerala by the State health minister Veena George . The patient was reportedly in close contact with a person who tested positive for mpox abroad in the United Arab Emirates , and arrived in India from UAE four days prior to the announcement. Hours later, minister Veena George announced that the patient was confirmed to be infected with the mpox disease by the NIV of Pune . [ citation needed ]No community transmission or locally transmitted cases were detected in India until on 24 July, Delhi reported their first case, and the patient had no history of travel from abroad. He recently attended a party in Himachal Pradesh . Although community transmission of the disease in India wasn't confirmed by the government health officials.14 July: A suspected mpox case was reported in Kerala . State health minister Veena George said that the patient was in close contact with a person who tested positive for mpox. The patient arrived in India from the United Arab Emirates four days earlier, according to the health minister, and was admitted to a hospital in the state after the patient showed symptoms, and samples were sent to the National Institute of Virology (NIV) . It was also reported that tests in local hospitals confirmed that the individual was affected with disease, but still samples were sent to the NIV for confirmation, as per the guideline given by the central government. 31 July: A 22-year-old man who had been in the United Arab Emirates came back to India. During his stay in the UAE, he had been in contact with another man who also tested positive for the virus. He then tested positive for mpox in the UAE but left the country following the test, he then arrived in his home-district in Thrissur , Kerala on 22 July. At first, he didn't have much symptoms with others in contact with him saying he was actively playing 'football' and other daily activities. On 26 July, he was admitted to a hospital with a fever and the authorities announced a suspected case. On 31 July, he died in the hospital of an unknown cause. It was then reported he died of mpox. 14 July: A suspected mpox case was reported in Kerala . State health minister Veena George said that the patient was in close contact with a person who tested positive for mpox. The patient arrived in India from the United Arab Emirates four days earlier, according to the health minister, and was admitted to a hospital in the state after the patient showed symptoms, and samples were sent to the National Institute of Virology (NIV) . It was also reported that tests in local hospitals confirmed that the individual was affected with disease, but still samples were sent to the NIV for confirmation, as per the guideline given by the central government. 31 July: A 22-year-old man who had been in the United Arab Emirates came back to India. During his stay in the UAE, he had been in contact with another man who also tested positive for the virus. He then tested positive for mpox in the UAE but left the country following the test, he then arrived in his home-district in Thrissur , Kerala on 22 July. At first, he didn't have much symptoms with others in contact with him saying he was actively playing 'football' and other daily activities. On 26 July, he was admitted to a hospital with a fever and the authorities announced a suspected case. On 31 July, he died in the hospital of an unknown cause. It was then reported he died of mpox. After the outbreak was highlighted on mid-May, Union Health Minister Mansukh Mandaviya directed the National Centre for Disease Control (NCDC) and the Indian Council of Medical Research (ICMR) to keep a close watch and monitor the situation. The Union Health Ministry has also directed airport and other port health officers to be vigilant and have been instructed to isolate and send samples to the National Institute of Virology (NIV) in Pune of any sick passenger with a travel history to infected countries. After the outbreak was highlighted on mid-May, Union Health Minister Mansukh Mandaviya directed the National Centre for Disease Control (NCDC) and the Indian Council of Medical Research (ICMR) to keep a close watch and monitor the situation. The Union Health Ministry has also directed airport and other port health officers to be vigilant and have been instructed to isolate and send samples to the National Institute of Virology (NIV) in Pune of any sick passenger with a travel history to infected countries.

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2022–2023 mpox outbreak in France

The 2022 – 2023 mpox outbreak in France is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . France had its first case on 20 May 2022.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. As of 2 August 2022, there were 2,171 confirmed cases of mpox reported in France, and as of 29 August 2022, there were 3,547 confirmed cases reported. As of 4 October 2022 there were 4,043 cases. Ref:

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2022–2023 mpox outbreak in Australia

The 2022–2023 mpox outbreak in Australia is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak reached Australia on 20 May 2022. By 28 October 2022 there were over 140 confirmed cases. The Chief Medical Officer of Australia stood down the country's Communicable Disease Incident of National Significance declaration on 25 November 2022. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. In May 2022, the World Health Organization (WHO) made an emergency announcement of the existence of a multi-country outbreak of mpox , a viral disease then commonly known as "monkeypox" . The initial cluster of cases was found in the United Kingdom , where the first case was detected in London on 6 May 2022 in a patient with a recent travel history from Nigeria (where the disease is endemic ). On 16 May, the UK Health Security Agency ( UKHSA ) confirmed four new cases with no link to travel to a country where mpox is endemic. Subsequently, cases have been reported from many countries and regions. The outbreak marked the first time mpox had spread widely outside Central and West Africa . There is evidence that the disease had been circulating and evolving in human hosts over a number of years prior to the outbreak. The outbreak was of the Clade IIb variant of the virus. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . The first case was detected on 20 May 2022 by a General Practitioner in Sydney. The patient, a male in his 40s, had recently returned from travelling in Europe and had developed symptoms. The man was placed in isolation while testing was carried out. Shortly afterward another male, in is 30s, who had recently returned from the United Kingdom to Victoria was diagnosed with the disease. By 26 June 2022 there were six cases in New South Wales and four in Victoria. By 30 June 2022 the first case of the virus was reported in South Australia , the man tested positive after returning from overseas and was placed in isolation. Queensland reported the first case on 11 July 2022 with one person testing positive and being placed in isolation and under virtual monitoring in Brisbane . On 24 July 2022 Australia had recorded a total of 44 cases, by 2 August the number of cases had increased to 53. The first case was detected in Western Australia on 4 August 2022 in a person who had travelled from overseas. The person was placed in isolation in Perth, Western Australia . On 5 August 2022 there had been 34 cases of mpox recorded in New South Wales and 57 cases had been recorded nationally. By 11 August there were 70 confirmed and probable cases in Australia with 33 in New South Wales, 30 in Victoria, 2 in Queensland, 2 in Western Australia, 2 in the Australian Capital Territory and 1 in South Australia. By 18 August there were 89 confirmed cases in Australia with 40 cases in Victoria, 39 in New South Wales, 3 in Queensland, 3 in Western Australia, 2 in both South Australia and the Australian Capital Territory. There were 106 confirmed cases of mpox in Australia on the 25th of August with 52 recorded cases in Victoria, 43 cases in New South Wales, 4 in Western Australia, 3 in Queensland, 2 in South Australia and the Australian Capital Territory. The Chief Medical Officer of Australia stood down the country's Communicable Disease Incident of National Significance declaration on 25 November 2022. At least 140 cases had been reported between May and late October 2022.

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2022–2023 mpox outbreak in Chile

The 2022–2023 mpox outbreak in Chile is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus. The outbreak reached Chile on 17 June 2022. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on May 6, 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on April 29, 2022. The resident returned to the United Kingdom on May 4, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis, an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . The first case of infection was recorded on June 17 in Santiago de Chile after an adult with a history of travel to Europe presented symptoms

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2022–2023 mpox outbreak in Canada

The 2022–2023 mpox outbreak in Canada is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak started in Canada on May 19, 2022, with the country since then becoming one of the most affected in the Americas .Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on May 6, 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on April 29, 2022. The resident returned to the United Kingdom on May 4, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. Symptoms such as fever, headache, swollen lymph nodes, and rashes or lesions are fairly common. Additionally some patients also have presented with proctitis . The Public Health Agency of Canada has noted that person to person transmission of mpox is possible from direct contact with bodily fluids including sexual contact. On May 18, the United States confirmed its first 2022 case of mpox and Canada reported 13 suspected cases. On May 19, the first confirmed case of mpox was reported in Toronto . On May 27, 500 people in Montreal , Quebec , received smallpox vaccinations. By July 6, 800 Montrealers had lined up at the clinic in the center of the Gay Village that was offering the initial vaccination. Canada currently has the 8th most mpox cases. This was the first time in history that mpox was in Canada .

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2022–2023 mpox outbreak in Spain

The 2022–2023 mpox outbreak in Spain is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus . Spain was the second country outside the African countries with endemic mpox, to experience an outbreak in 2022. The outbreak was first reported in Spain on 18 May 2022. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on 4 May, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . On 18 May 2022, the Community of Madrid regional government reported the first eight suspected cases of mpox, and seven of them were confirmed by the Ministry of Health on 20 May. On 20 May, the health authorities of Madrid closed the gay sauna Paraíso, which was under investigation as a possible high transmission point in Madrid. The sauna reopened again on 9 June after receiving an authorization from the regional health department. According to the Community of Madrid regional government on 6 June 2022, all cases in the region were men, except one woman who is cohabitant with one of the infected men. The most likely contagion event for most was sexual relations with strangers, usually at parties in private residences, a sauna, or the gay pride event at Maspalomas, Canary Islands. 48% of cases were also HIV -positive. On 10 June, the Ministry of Health disclosed that out of a sample of 78 cases, 21 had a previous smallpox vaccine dose. On 26 August, the Ministry of Health published additional data about 6,459 cases. 6,334 of them were men, and 125 were women. Age ranged between 7 months and 88 years, with a median age of 37 years. Out of 5,198 cases with recorded data, 5,022 were men who have sex with men . Out of 3,700 cases with recorded data, 92,6% had prolonged intimate contact during sexual relation as the most likely transmission mechanism. Several experts have raised concerns about stigmatization of LGBT people in connection to the mpox outbreak. In June 2022, the public prosecutor of Valencia opened an investigation of a publication about the mpox outbreak by the far-right political party España 2000 , which could constitute hate speech against the LGBT community.

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2022–2023 mpox outbreak in Germany

The 2022–2023 mpox outbreak in Germany is part of an ongoing global outbreak of human mpox caused by the West African clade of the monkeypox virus . At the beginning of September 2022, Spain , France , Germany and the United Kingdom are the countries with most cumulative cases (in absolute numbers) in Europe.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. German virologist Christian Drosten from the Charité – who was the main medical adviser for the German federal government for measures against the COVID-19 pandemic in Germany and who warned early that the SARS virus potential needed to be investigated – warned in May 2023 that the Mpox disease could aggravate: "Wir wissen aus der Geschichte, dass andere Pockenvirus-Infektionen mit milden Verläufen begannen und sich dann in der Anpassung an den Menschen verstärkt haben" [We know from history that other smallpox virus infections began with mild courses and then intensified as they adapted to humans]. German virologist Christian Drosten from the Charité – who was the main medical adviser for the German federal government for measures against the COVID-19 pandemic in Germany and who warned early that the SARS virus potential needed to be investigated – warned in May 2023 that the Mpox disease could aggravate: "Wir wissen aus der Geschichte, dass andere Pockenvirus-Infektionen mit milden Verläufen begannen und sich dann in der Anpassung an den Menschen verstärkt haben" [We know from history that other smallpox virus infections began with mild courses and then intensified as they adapted to humans]. On 20 May 2022, the first case of mpox was serologically detected in a man in Munich , who showed "characteristic skin changes" already the day before. Until the end of May 2022, 33 cases of mpox were confirmed, on 10 June the (cumulated) number of cases was 165, and as of 5 July the number rose to 1,242. As of 3 June 2022, the most affected federal state of Germany in terms of reported cases has been the city-state of Berlin − with 39 reported cases in Berlin and 65 in the whole country, and as of 28 June Berlin reported about two thirds of all cases (557 out of 838). The city-state planned to start vaccination during the week of 4 July. As of 1 July 2022 [ update ] there were 1,054 cases reported for the whole country, albeit the Robert Koch Institute (RKI) expounded that the situation was not worrisome ("nicht beunruhigend") for the general population. As of 5 July 2022 [ update ] there were 761 reported cases in city-state of Berlin alone; one article criticized that vaccinations had not yet started in Berlin, although 8,000 vaccine doses of non-replicating smallpox vaccine were already in stock. Vaccination in Berlin were going to start in the week of 11 July. As of 8 July 2022 [ update ] there were 1,490 reported cases in Germany. On 19, 2 July 033 (cumulative) cases were reported, with 1,140 cases in Berlin alone; on 22 July, the state of Berlin was applying for more vaccine allocations due to high demand. On 22 July 2022, the European Medicines Agency recommended the approval of Imvanex smallpox vaccine for the prevention of mpox disease, and the European Commission subsequently approved it. (The vaccinations with Imvanex started earlier, depending on the federal state; in Lower Saxony they started on 3 July 2022 and in Berlin on 13 July. ) Till July 2022, the Federal Republic has received 40,000 doses (of the Imvanex smallpox vaccine) and distributed them to the federal states. Another 200,000 vaccine doses are expected for September. At the end of July, the Deutsche Aidshilfe e.V. (de) appealed to the German government to order 1 million vaccine doses in order to enable the (full) vaccination of up to 500,000 people. Till 5 August 2022, 2887 confirmed cases were reported for the whole country and about half of the cases (1436) were reported from city-state of Berlin alone. In addition to the 9,500 vaccine doses Berlin already received, the federal government is expected give Berlin an additional 1,900 doses in the week of 8 August 2022. In Berlin where the highest number of reported new mpox infections occurred for a long time, this number has decreased significantly by mid-August. By 19 August 2022, 6417 vaccinations (including 90 second shots) against mpox had been administered at the 28 vaccination sites in Berlin. As of 9 September 2022, a total of 3530 cases of mpox have been reported to RKI, including 14 cases in females and 2 cases in children younger than 14 years. The weekly number of newly reported cases has been declining since early August. Since the number of cases reported each week has fallen to low numbers (quite persistently below 50), the RKI will provide information only once a week on Tuesday, starting in the second week of October 2022. Until the end of May 2022, 33 cases of mpox were confirmed, on 10 June the (cumulated) number of cases was 165, and as of 5 July the number rose to 1,242. As of 3 June 2022, the most affected federal state of Germany in terms of reported cases has been the city-state of Berlin − with 39 reported cases in Berlin and 65 in the whole country, and as of 28 June Berlin reported about two thirds of all cases (557 out of 838). The city-state planned to start vaccination during the week of 4 July. As of 1 July 2022 [ update ] there were 1,054 cases reported for the whole country, albeit the Robert Koch Institute (RKI) expounded that the situation was not worrisome ("nicht beunruhigend") for the general population. As of 5 July 2022 [ update ] there were 761 reported cases in city-state of Berlin alone; one article criticized that vaccinations had not yet started in Berlin, although 8,000 vaccine doses of non-replicating smallpox vaccine were already in stock. Vaccination in Berlin were going to start in the week of 11 July. As of 8 July 2022 [ update ] there were 1,490 reported cases in Germany. On 19, 2 July 033 (cumulative) cases were reported, with 1,140 cases in Berlin alone; on 22 July, the state of Berlin was applying for more vaccine allocations due to high demand. On 22 July 2022, the European Medicines Agency recommended the approval of Imvanex smallpox vaccine for the prevention of mpox disease, and the European Commission subsequently approved it. (The vaccinations with Imvanex started earlier, depending on the federal state; in Lower Saxony they started on 3 July 2022 and in Berlin on 13 July. ) Till July 2022, the Federal Republic has received 40,000 doses (of the Imvanex smallpox vaccine) and distributed them to the federal states. Another 200,000 vaccine doses are expected for September. At the end of July, the Deutsche Aidshilfe e.V. (de) appealed to the German government to order 1 million vaccine doses in order to enable the (full) vaccination of up to 500,000 people. Till 5 August 2022, 2887 confirmed cases were reported for the whole country and about half of the cases (1436) were reported from city-state of Berlin alone. In addition to the 9,500 vaccine doses Berlin already received, the federal government is expected give Berlin an additional 1,900 doses in the week of 8 August 2022. In Berlin where the highest number of reported new mpox infections occurred for a long time, this number has decreased significantly by mid-August. By 19 August 2022, 6417 vaccinations (including 90 second shots) against mpox had been administered at the 28 vaccination sites in Berlin. As of 9 September 2022, a total of 3530 cases of mpox have been reported to RKI, including 14 cases in females and 2 cases in children younger than 14 years. The weekly number of newly reported cases has been declining since early August. Since the number of cases reported each week has fallen to low numbers (quite persistently below 50), the RKI will provide information only once a week on Tuesday, starting in the second week of October 2022. On 30 June 2022 − with pre-publication on 21 June − the RKI recommended Imvanex smallpox vaccine for post-exposure prophylaxis (PEP), for people with high risk of infection and for people with risk of a severe course of the disease. Due to the limited resources of Imvanex there are priorisations. The Imvanex smallpox vaccine is administered subcutaneously. (Unlike the first and second generation smallpox vaccines .) On 21 July, the Standing Committee on Vaccination (STIKO) recommended to use only one dose per person (instead of two) of the Imvanex smallpox vaccine for the time being − so that more people can be vaccinated. Since 19 August 2022, the European Medicines Agency (EMA) also allows intradermal administration of the vaccine, which requires only one-fifth the dose amount (compared with subcutaneous administration) to induce similar antibody levels. The RKI recommends that persons with diagnosed mpox isolate themselves at home for at least 21 days. Isolation can be mandatory by ordinance of the "Gesundheitsamt" (local health authority). This mandatory isolation period can also apply to close contacts that are vaccinated and show no signs of infection. On 30 June 2022 − with pre-publication on 21 June − the RKI recommended Imvanex smallpox vaccine for post-exposure prophylaxis (PEP), for people with high risk of infection and for people with risk of a severe course of the disease. Due to the limited resources of Imvanex there are priorisations. The Imvanex smallpox vaccine is administered subcutaneously. (Unlike the first and second generation smallpox vaccines .) On 21 July, the Standing Committee on Vaccination (STIKO) recommended to use only one dose per person (instead of two) of the Imvanex smallpox vaccine for the time being − so that more people can be vaccinated. Since 19 August 2022, the European Medicines Agency (EMA) also allows intradermal administration of the vaccine, which requires only one-fifth the dose amount (compared with subcutaneous administration) to induce similar antibody levels. The RKI recommends that persons with diagnosed mpox isolate themselves at home for at least 21 days. Isolation can be mandatory by ordinance of the "Gesundheitsamt" (local health authority). This mandatory isolation period can also apply to close contacts that are vaccinated and show no signs of infection. In order to restrict the links for mere case numbers there are perhaps only some links for special days (like the end of a month or days that are not archived by the Wayback machine). The RKI reports data from Monday to Friday and German press relies on this data for the overall number, so there are no new cases on Saturday or Sunday. The data can be verified with the Internet Archive ("Wayback Machine") of the webpage from the RKI, see #RKI & CDC data . References:

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2022–2023 mpox outbreak in Mexico

The 2022–2023 mpox outbreak in Mexico is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . Mexico is the twenty-fourth country outside of Africa to experience an endemic mpox outbreak. The first case was reported in Mexico City , Mexico , on May 28, 2022. As of December 8th 2022, Mexico had confirmed a total of 3455 cases in all 32 states and 4 deaths.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on May 6, 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on April 29, 2022. The resident returned to the United Kingdom on May 4, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis, an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . The first known case was detected in on May 28, 2022, in a 50-year-old male who resides permanently in the city of New York City , New York . He was diagnosed and hospitalized in Mexico City . There, he tested positive for mpox, becoming the first case in Mexico. On June 14, 4 more cases were reported in Mexico in the course of a week which brought the total number of cases in the country up to 5. There were 4 cases reported in Mexico City and 1 confirmed in Jalisco . On July 5, over the course of 3 weeks, 22 more cases were reported, which brought the total number of cases in the country up to 27. The only counties that reported cases were Mexico City and Jalisco . Other counties were not affected at the time. On July 27, after 3 weeks, 33 more infections were confirmed, which increased the total number of cases in the country up to 60. Cases had been reported across 11 regions in Mexico. On August 2, after 1 week, 31 more cases were confirmed, which rose the total number of cases from 60 to 91. Cases had been reported in 4 more regions, which brought the overall number of regions and territories affected by mpox up to 15. On August 9, over the course of 1 week, 56 more mpox cases were reported, which brought the total number of cases in the country up to 147. Cases had been reported in 3 more regions, which rose the overall number of regions and territories affected by mpox up to 18. On August 15, in the course of just 6 days, 105 greater mpox cases had been confirmed, which rose the overall number of infections from 147 to 252. Mpox infections had been reported in 2 more regions, which brought the total number of regions and territories affected by mpox up to 20. As of August 18, there is currently 252 confirmed cases with 107 suspected cases in the country. Hospitals have also begun making their own preparations to help control the current mpox outbreak, including screening patients, increasing decontamination and cleaning procedures, and wearing appropriate safety gear ( Personal protective equipment / Medical gown ) when interacting with infected patients. Mexico has also responded to the outbreak. Mexican health authorities have posted notices in clinics and hospitals for the purpose of identifying suspected cases and infections in the country. In addition, the Ministry of Health has issued an epidemiological alert on 26 May 2022.

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2022–2023 mpox outbreak in the Republic of Ireland

The 2022-2023 mpox outbreak in the Republic of Ireland is part of the larger ongoing global outbreak of human mpox caused by Clade II of the monkeypox virus . The first case in the Republic was confirmed on 27 May 2022. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . As of 28 June 2023, the Health Protection Surveillance Centre (HPSC) had been notified of 228 cases of mpox, no deaths have been recorded so far. Median age: 35; Mean age: 37; Total = 228 Total = 228

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2022–2023 mpox outbreak in North America

The 2022–2023 mpox outbreak in North America is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak reached North America on 18 May 2022, when the United States reported their first case of mpox. As of 23 August 2022 , [ update ] 20 North American countries and territories have confirmed cases.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on May 6, 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on May 4, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . An index case was imported into the United States on 18 May 2022, by a man who had recently travelled to Canada. He was admitted to a hospital in Massachusetts , likely on 17 May. The day after, the man was confirmed to have contracted mpox. The following day, another mpox case was confirmed, and the United States reported these cases to the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). On 19 May, Canada confirmed the first two cases of mpox. Health officials revealed that there was a link between the U.S. case of mpox in Massachusetts and a few of the suspected cases in the Montreal region. The patient of unknown gender or age, may have been infected when recently traveling to Canada. The spread was likely through skin-to-skin contact picked up abroad. On 28 May, Mexico registered its first case of mpox. It was in a 50-year-old male who resides in the city of New York City and is being treated at Mexico City . It was noted that he may have contracted the disease abroad, from the Netherlands , where there it had already been affected by mpox. It was likely picked up by skin-to-skin contact picked up abroad. On 29 June, Puerto Rico , a US Territory , confirmed its first case of mpox. It was likely in a male, age between 20 and 50 years old. It is unknown how it was contracted, but likely skin-to-skin contact picked up abroad. On 30 June, the Bahamas confirmed its first mpox case in a male visitor in his 40s who had most likely contracted the disease from a trip to London, UK, which had already been affected by the mpox outbreak on 9 June. It was likely picked up from skin-to-skin contact abroad. On 5 July, Panama received its first mpox infection in a resident of unknown gender and age who most likely contracted the disease via contact with tourists from Europe, which had already been affected by the mpox outbreak. It was likely skin-to-skin contact rather than sexual contact. On 6 July, Jamaica registered its first mpox case. It was in a male of unknown age who had most likely contracted the disease from a trip to London, UK, which had already been affected by the mpox outbreak. It was likely picked up from skin-to-skin contact abroad. On the same day, the Dominican Republic also confirmed its first case of mpox. It was in a 25-year-old male who had most likely contracted the disease via contact with a person who was infected with mpox in the United States. It was likely skin-to-skin contact rather than sexual contact. On 16 July, Barbados confirmed its first mpox infection. It was in a Barbadian patient of unknown gender in his 30s. It is unknown how the patient contracted the disease, but likely via skin-to-skin contact abroad. On 17 July, Martinique , part of Overseas France and a Single territorial collectivity and an Overseas Department of France, received its first mpox case. It was in an adult of unknown exact age and gender who most likely contracted the disease from a trip to a country which had been affected by the mpox outbreak. It was likely picked up via skin-to-skin contact abroad. On 20 July, Costa Rica recorded its first mpox infection. It was in a 34-year-old male from the United States who resided in Costa Rica for 2 years. He most likely contracted it from a trip to the United States abroad and is considered an imported case. It was likely picked up via skin-to-skin contact. On 22 July, Bermuda , a British Overseas Territory , although technically part of North America, registered its first mpox case. It is unknown what the patient's gender and age is and how the patient contracted the disease, but it was likely via skin-to-skin contact abroad. On 25 July, Guadeloupe , part of Overseas France and an Overseas Department of France, confirmed its first case of mpox. It was in a patient of unknown gender or age who resides in Guadeloupe. The patient recently travelled to France and likely contracted the disease via contact with someone in France. It was likely skin-to-skin contact rather than sexual contact. On 1 August, Collectivity of Saint Martin , part of Overseas France , confirmed its first case of mpox. It was in a patient of unknown gender or age who's residence is unknown. It is unknown how it was contracted, however it may be likely that it was picked up via skin-to-skin contact abroad. On 3 August, Guatemala registered its first case of mpox. It was in a 31-year-old male who had likely contracted the disease via contact with foreigners/tourists from another country. It was likely skin-to-skin contact rather than sexual contact. On 9 August, Greenland reported its first two cases of mpox. It was in patients of unknown genders and ages who likely contracted the disease via skin-to-skin contact picked up abroad. On 12 August, Honduras reported its first case of mpox in an adult male under 50 years of age. It is unknown how the male contracted the disease, although it was likely picked up via contact with other infected abroad. On 19 August, Curaçao confirmed its first case of mpox in a patient of unknown gender and age who likely contracted the disease abroad, via skin-to-skin contact or sexual contact with others. On 20 August, Cuba reported its first mpox infection. It was in a male Italian tourist of unknown gender. He most likely contracted the disease from a trip to Italy and other various destinations in the Caribbean . It is unknown how the disease was contracted, but likely via skin-to-skin contact rather than sexual contact. The man fell into cardiac arrest, likely on the same day he was diagnosed, which he recovered from, but remained in critical condition at the time. He later died on 21 August after rapidly deteriorating. This marked Cuba's first death, as well as North America's first death during the ongoing outbreak. On 22 August, Aruba reported its first case of mpox. It was in a patient of unknown age and gender who resides in Aruba. It is unknown how the patient contracted the disease, but likely contracted the disease abroad, via skin-to-skin contact or sexual contact with others. An index case was imported into the United States on 18 May 2022, by a man who had recently travelled to Canada. He was admitted to a hospital in Massachusetts , likely on 17 May. The day after, the man was confirmed to have contracted mpox. The following day, another mpox case was confirmed, and the United States reported these cases to the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). On 19 May, Canada confirmed the first two cases of mpox. Health officials revealed that there was a link between the U.S. case of mpox in Massachusetts and a few of the suspected cases in the Montreal region. The patient of unknown gender or age, may have been infected when recently traveling to Canada. The spread was likely through skin-to-skin contact picked up abroad. On 28 May, Mexico registered its first case of mpox. It was in a 50-year-old male who resides in the city of New York City and is being treated at Mexico City . It was noted that he may have contracted the disease abroad, from the Netherlands , where there it had already been affected by mpox. It was likely picked up by skin-to-skin contact picked up abroad. On 29 June, Puerto Rico , a US Territory , confirmed its first case of mpox. It was likely in a male, age between 20 and 50 years old. It is unknown how it was contracted, but likely skin-to-skin contact picked up abroad. On 30 June, the Bahamas confirmed its first mpox case in a male visitor in his 40s who had most likely contracted the disease from a trip to London, UK, which had already been affected by the mpox outbreak on 9 June. It was likely picked up from skin-to-skin contact abroad. On 5 July, Panama received its first mpox infection in a resident of unknown gender and age who most likely contracted the disease via contact with tourists from Europe, which had already been affected by the mpox outbreak. It was likely skin-to-skin contact rather than sexual contact. On 6 July, Jamaica registered its first mpox case. It was in a male of unknown age who had most likely contracted the disease from a trip to London, UK, which had already been affected by the mpox outbreak. It was likely picked up from skin-to-skin contact abroad. On the same day, the Dominican Republic also confirmed its first case of mpox. It was in a 25-year-old male who had most likely contracted the disease via contact with a person who was infected with mpox in the United States. It was likely skin-to-skin contact rather than sexual contact. On 16 July, Barbados confirmed its first mpox infection. It was in a Barbadian patient of unknown gender in his 30s. It is unknown how the patient contracted the disease, but likely via skin-to-skin contact abroad. On 17 July, Martinique , part of Overseas France and a Single territorial collectivity and an Overseas Department of France, received its first mpox case. It was in an adult of unknown exact age and gender who most likely contracted the disease from a trip to a country which had been affected by the mpox outbreak. It was likely picked up via skin-to-skin contact abroad. On 20 July, Costa Rica recorded its first mpox infection. It was in a 34-year-old male from the United States who resided in Costa Rica for 2 years. He most likely contracted it from a trip to the United States abroad and is considered an imported case. It was likely picked up via skin-to-skin contact. On 22 July, Bermuda , a British Overseas Territory , although technically part of North America, registered its first mpox case. It is unknown what the patient's gender and age is and how the patient contracted the disease, but it was likely via skin-to-skin contact abroad. On 25 July, Guadeloupe , part of Overseas France and an Overseas Department of France, confirmed its first case of mpox. It was in a patient of unknown gender or age who resides in Guadeloupe. The patient recently travelled to France and likely contracted the disease via contact with someone in France. It was likely skin-to-skin contact rather than sexual contact. On 1 August, Collectivity of Saint Martin , part of Overseas France , confirmed its first case of mpox. It was in a patient of unknown gender or age who's residence is unknown. It is unknown how it was contracted, however it may be likely that it was picked up via skin-to-skin contact abroad. On 3 August, Guatemala registered its first case of mpox. It was in a 31-year-old male who had likely contracted the disease via contact with foreigners/tourists from another country. It was likely skin-to-skin contact rather than sexual contact. On 9 August, Greenland reported its first two cases of mpox. It was in patients of unknown genders and ages who likely contracted the disease via skin-to-skin contact picked up abroad. On 12 August, Honduras reported its first case of mpox in an adult male under 50 years of age. It is unknown how the male contracted the disease, although it was likely picked up via contact with other infected abroad. On 19 August, Curaçao confirmed its first case of mpox in a patient of unknown gender and age who likely contracted the disease abroad, via skin-to-skin contact or sexual contact with others. On 20 August, Cuba reported its first mpox infection. It was in a male Italian tourist of unknown gender. He most likely contracted the disease from a trip to Italy and other various destinations in the Caribbean . It is unknown how the disease was contracted, but likely via skin-to-skin contact rather than sexual contact. The man fell into cardiac arrest, likely on the same day he was diagnosed, which he recovered from, but remained in critical condition at the time. He later died on 21 August after rapidly deteriorating. This marked Cuba's first death, as well as North America's first death during the ongoing outbreak. On 22 August, Aruba reported its first case of mpox. It was in a patient of unknown age and gender who resides in Aruba. It is unknown how the patient contracted the disease, but likely contracted the disease abroad, via skin-to-skin contact or sexual contact with others. On 19 May, Canada confirmed the first two cases of mpox. Health officials revealed that there was a link between the U.S. case of mpox in Massachusetts and a few of the suspected cases in the Montreal region. The patient of unknown gender or age, may have been infected when recently traveling to Canada. The spread was likely through skin-to-skin contact picked up abroad. On 28 May, Mexico registered its first case of mpox. It was in a 50-year-old male who resides in the city of New York City and is being treated at Mexico City . It was noted that he may have contracted the disease abroad, from the Netherlands , where there it had already been affected by mpox. It was likely picked up by skin-to-skin contact picked up abroad. On 19 May, Canada confirmed the first two cases of mpox. Health officials revealed that there was a link between the U.S. case of mpox in Massachusetts and a few of the suspected cases in the Montreal region. The patient of unknown gender or age, may have been infected when recently traveling to Canada. The spread was likely through skin-to-skin contact picked up abroad. On 28 May, Mexico registered its first case of mpox. It was in a 50-year-old male who resides in the city of New York City and is being treated at Mexico City . It was noted that he may have contracted the disease abroad, from the Netherlands , where there it had already been affected by mpox. It was likely picked up by skin-to-skin contact picked up abroad. On 29 June, Puerto Rico , a US Territory , confirmed its first case of mpox. It was likely in a male, age between 20 and 50 years old. It is unknown how it was contracted, but likely skin-to-skin contact picked up abroad. On 30 June, the Bahamas confirmed its first mpox case in a male visitor in his 40s who had most likely contracted the disease from a trip to London, UK, which had already been affected by the mpox outbreak on 9 June. It was likely picked up from skin-to-skin contact abroad. On 29 June, Puerto Rico , a US Territory , confirmed its first case of mpox. It was likely in a male, age between 20 and 50 years old. It is unknown how it was contracted, but likely skin-to-skin contact picked up abroad. On 30 June, the Bahamas confirmed its first mpox case in a male visitor in his 40s who had most likely contracted the disease from a trip to London, UK, which had already been affected by the mpox outbreak on 9 June. It was likely picked up from skin-to-skin contact abroad. On 5 July, Panama received its first mpox infection in a resident of unknown gender and age who most likely contracted the disease via contact with tourists from Europe, which had already been affected by the mpox outbreak. It was likely skin-to-skin contact rather than sexual contact. On 6 July, Jamaica registered its first mpox case. It was in a male of unknown age who had most likely contracted the disease from a trip to London, UK, which had already been affected by the mpox outbreak. It was likely picked up from skin-to-skin contact abroad. On the same day, the Dominican Republic also confirmed its first case of mpox. It was in a 25-year-old male who had most likely contracted the disease via contact with a person who was infected with mpox in the United States. It was likely skin-to-skin contact rather than sexual contact. On 16 July, Barbados confirmed its first mpox infection. It was in a Barbadian patient of unknown gender in his 30s. It is unknown how the patient contracted the disease, but likely via skin-to-skin contact abroad. On 17 July, Martinique , part of Overseas France and a Single territorial collectivity and an Overseas Department of France, received its first mpox case. It was in an adult of unknown exact age and gender who most likely contracted the disease from a trip to a country which had been affected by the mpox outbreak. It was likely picked up via skin-to-skin contact abroad. On 20 July, Costa Rica recorded its first mpox infection. It was in a 34-year-old male from the United States who resided in Costa Rica for 2 years. He most likely contracted it from a trip to the United States abroad and is considered an imported case. It was likely picked up via skin-to-skin contact. On 22 July, Bermuda , a British Overseas Territory , although technically part of North America, registered its first mpox case. It is unknown what the patient's gender and age is and how the patient contracted the disease, but it was likely via skin-to-skin contact abroad. On 25 July, Guadeloupe , part of Overseas France and an Overseas Department of France, confirmed its first case of mpox. It was in a patient of unknown gender or age who resides in Guadeloupe. The patient recently travelled to France and likely contracted the disease via contact with someone in France. It was likely skin-to-skin contact rather than sexual contact. On 5 July, Panama received its first mpox infection in a resident of unknown gender and age who most likely contracted the disease via contact with tourists from Europe, which had already been affected by the mpox outbreak. It was likely skin-to-skin contact rather than sexual contact. On 6 July, Jamaica registered its first mpox case. It was in a male of unknown age who had most likely contracted the disease from a trip to London, UK, which had already been affected by the mpox outbreak. It was likely picked up from skin-to-skin contact abroad. On the same day, the Dominican Republic also confirmed its first case of mpox. It was in a 25-year-old male who had most likely contracted the disease via contact with a person who was infected with mpox in the United States. It was likely skin-to-skin contact rather than sexual contact. On 16 July, Barbados confirmed its first mpox infection. It was in a Barbadian patient of unknown gender in his 30s. It is unknown how the patient contracted the disease, but likely via skin-to-skin contact abroad. On 17 July, Martinique , part of Overseas France and a Single territorial collectivity and an Overseas Department of France, received its first mpox case. It was in an adult of unknown exact age and gender who most likely contracted the disease from a trip to a country which had been affected by the mpox outbreak. It was likely picked up via skin-to-skin contact abroad. On 20 July, Costa Rica recorded its first mpox infection. It was in a 34-year-old male from the United States who resided in Costa Rica for 2 years. He most likely contracted it from a trip to the United States abroad and is considered an imported case. It was likely picked up via skin-to-skin contact. On 22 July, Bermuda , a British Overseas Territory , although technically part of North America, registered its first mpox case. It is unknown what the patient's gender and age is and how the patient contracted the disease, but it was likely via skin-to-skin contact abroad. On 25 July, Guadeloupe , part of Overseas France and an Overseas Department of France, confirmed its first case of mpox. It was in a patient of unknown gender or age who resides in Guadeloupe. The patient recently travelled to France and likely contracted the disease via contact with someone in France. It was likely skin-to-skin contact rather than sexual contact. On 1 August, Collectivity of Saint Martin , part of Overseas France , confirmed its first case of mpox. It was in a patient of unknown gender or age who's residence is unknown. It is unknown how it was contracted, however it may be likely that it was picked up via skin-to-skin contact abroad. On 3 August, Guatemala registered its first case of mpox. It was in a 31-year-old male who had likely contracted the disease via contact with foreigners/tourists from another country. It was likely skin-to-skin contact rather than sexual contact. On 9 August, Greenland reported its first two cases of mpox. It was in patients of unknown genders and ages who likely contracted the disease via skin-to-skin contact picked up abroad. On 12 August, Honduras reported its first case of mpox in an adult male under 50 years of age. It is unknown how the male contracted the disease, although it was likely picked up via contact with other infected abroad. On 19 August, Curaçao confirmed its first case of mpox in a patient of unknown gender and age who likely contracted the disease abroad, via skin-to-skin contact or sexual contact with others. On 20 August, Cuba reported its first mpox infection. It was in a male Italian tourist of unknown gender. He most likely contracted the disease from a trip to Italy and other various destinations in the Caribbean . It is unknown how the disease was contracted, but likely via skin-to-skin contact rather than sexual contact. The man fell into cardiac arrest, likely on the same day he was diagnosed, which he recovered from, but remained in critical condition at the time. He later died on 21 August after rapidly deteriorating. This marked Cuba's first death, as well as North America's first death during the ongoing outbreak. On 22 August, Aruba reported its first case of mpox. It was in a patient of unknown age and gender who resides in Aruba. It is unknown how the patient contracted the disease, but likely contracted the disease abroad, via skin-to-skin contact or sexual contact with others. On 1 August, Collectivity of Saint Martin , part of Overseas France , confirmed its first case of mpox. It was in a patient of unknown gender or age who's residence is unknown. It is unknown how it was contracted, however it may be likely that it was picked up via skin-to-skin contact abroad. On 3 August, Guatemala registered its first case of mpox. It was in a 31-year-old male who had likely contracted the disease via contact with foreigners/tourists from another country. It was likely skin-to-skin contact rather than sexual contact. On 9 August, Greenland reported its first two cases of mpox. It was in patients of unknown genders and ages who likely contracted the disease via skin-to-skin contact picked up abroad. On 12 August, Honduras reported its first case of mpox in an adult male under 50 years of age. It is unknown how the male contracted the disease, although it was likely picked up via contact with other infected abroad. On 19 August, Curaçao confirmed its first case of mpox in a patient of unknown gender and age who likely contracted the disease abroad, via skin-to-skin contact or sexual contact with others. On 20 August, Cuba reported its first mpox infection. It was in a male Italian tourist of unknown gender. He most likely contracted the disease from a trip to Italy and other various destinations in the Caribbean . It is unknown how the disease was contracted, but likely via skin-to-skin contact rather than sexual contact. The man fell into cardiac arrest, likely on the same day he was diagnosed, which he recovered from, but remained in critical condition at the time. He later died on 21 August after rapidly deteriorating. This marked Cuba's first death, as well as North America's first death during the ongoing outbreak. On 22 August, Aruba reported its first case of mpox. It was in a patient of unknown age and gender who resides in Aruba. It is unknown how the patient contracted the disease, but likely contracted the disease abroad, via skin-to-skin contact or sexual contact with others. On 20 May, the WHO convened an emergency meeting of independent advisers to discuss the outbreak and assess the threat level. Its European chief, Hans Kluge , expressed concern that infections could accelerate in Europe as people gather for parties and festivals over the summer. On 14 June, the WHO announced plans to rename the disease from monkeypox to mpox in order to combat stigma and racism surrounding the disease. Another meeting convened on 23 June determined that the outbreak does not constitute a Public Health Emergency of International Concern for the time being. The majority of North American countries responded to the outbreak, and the responses of some are listed below. We were unable to record Overseas and Dependant territories' response to the outbreak.On 20 May, the WHO convened an emergency meeting of independent advisers to discuss the outbreak and assess the threat level. Its European chief, Hans Kluge , expressed concern that infections could accelerate in Europe as people gather for parties and festivals over the summer. On 14 June, the WHO announced plans to rename the disease from monkeypox to mpox in order to combat stigma and racism surrounding the disease. Another meeting convened on 23 June determined that the outbreak does not constitute a Public Health Emergency of International Concern for the time being. The majority of North American countries responded to the outbreak, and the responses of some are listed below. We were unable to record Overseas and Dependant territories' response to the outbreak.This is a table of confirmed and suspected mpox cases in North American countries during the ongoing 2022–2023 mpox outbreak. It does not include countries where suspected cases were reported but later discarded. ( As of 24 August 2022 [ update ] ) Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases. Countries listed several times reported suspected cases again after they discarded suspected cases before. As of 22 August 2022 , [ update ] 20 North American countries and territories have been affected by the outbreak.Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases. Countries listed several times reported suspected cases again after they discarded suspected cases before.Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases. Countries listed several times reported suspected cases again after they discarded suspected cases before.As of 22 August 2022 , [ update ] 20 North American countries and territories have been affected by the outbreak.

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2022–2023 mpox outbreak in South Africa

The 2022–2023 mpox outbreak in South Africa is a part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . South Africa was the forty-seventh country, outside of the African countries with endemic mpox, to experience an outbreak in 2022. The first case of mpox in South Africa was on June 23, 2022. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on 4 May, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . The first known case of mpox in South Africa was detected on Thursday, 23 June 2022 declared by the health minister of South Africa Joe Phaahla . The first victim was a 30-year-old man who had no recent travel history, meaning that he has not contacted the disease outside the country. 5 days later on the 28th of June, South Africa confirmed its second case of mpox. The victim also had no recent travel history. On 11 July 2022 South Africa confirmed third case of mpox, the 42 year old is a tourist from Switzerland who came to South Africa to enjoy his holidays. On the second week of August 2022 Minister of Health South Africa announced the 4th case of mpox in South Africa the victim recently arrived from Spain .

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2022–2023 mpox outbreak in the Netherlands

The 2022–2023 mpox outbreak in the Netherlands is an ongoing global outbreak which has also spread in the Netherlands. The RIVM declared the disease an A-disease which makes it mandatory to report suspected cases to the GGD . The first human case of mpox in the Netherlands has been identified at the 21 May 2022. The outbreak does have a noticeable impact at the society, especially with people spreading misinformation related to the virus. The ongoing COVID-19 pandemic in the Netherlands has increased the fear among the community for a new pandemic like mpox. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on 4 May, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . As of 4 July 2022, there are 818 cases of the mpox virus in the Netherlands and zero deaths. The RIVM does update their mpox statistics two times per week, usually at Monday and Thursday. [ citation needed ]

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2022–2023 mpox outbreak in Italy

The 2022–2023 mpox outbreak in Italy is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . Italy was the sixth country, outside of the African countries with endemic mpox, to experience an outbreak in 2022. The first case was documented in Rome , Italy , on May 19, 2022. As of August 5th, Italy has 505 cases. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on May 6, 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on April 29, 2022. The resident returned to the United Kingdom on May 4, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis, an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . The first case in Italy was reported on 19 May 2022 at the Spallanzani hospital in Rome the person who got mpox was kept in isolation.

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2022–2023 mpox outbreak in Portugal

The 2022–2023 mpox outbreak in Portugal is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . Portugal was the third country, outside of the African countries with endemic mpox, to experience an outbreak in 2022.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on 4 May, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . On 18 May 2022, Portugal reported five cases in men and 15 suspected cases. At the end of May, 96 people were confirmed to have mpox, before the amount reached 153 after the first week of June. As of 7 July, there were 433 confirmed cases in the country.

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2022–2023 mpox outbreak in Israel

The 2022–2023 mpox outbreak in Israel is a part of the ongoing outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak was first reported in Israel on 20 May 2022 when the Health Ministry announced a suspected case which was confirmed on 21 May 2022. One month later, on 21 June, the first locally transmitted case was reported. Currently, Israel is the most affected country in Asia and the 14th most affected country in the world. Israel was also the first in Asia to report a case.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. In May 2022, the World Health Organization (WHO) made an emergency announcement of the existence of a multi-country outbreak of mpox , a viral disease then commonly known as "monkeypox" . The initial cluster of cases was found in the United Kingdom , where the first case was detected in London on 6 May 2022 in a patient with a recent travel history from Nigeria (where the disease is endemic ). On 16 May, the UK Health Security Agency ( UKHSA ) confirmed four new cases with no link to travel to a country where mpox is endemic. Subsequently, cases have been reported from many countries and regions. The outbreak marked the first time mpox had spread widely outside Central and West Africa . There is evidence that the disease had been circulating and evolving in human hosts over a number of years prior to the outbreak. The outbreak was of the Clade IIb variant of the virus. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . In 2018, an imported case was detected in Israel. A 38-year-old man came from Rivers State , Nigeria in late September. He showed the symptoms of the disease on that month. Later on October the patient sought medical attention at Shaare-Zedek Medical Center in Jerusalem . He was confirmed to be infected with the West African Clade of monkeypox virus that month. All of the patient's contacts were traced and followed up but no virus transmission were detected. As the outbreak was spreading in Europe in the middle of May 2022, the Israeli Health Ministry reported a suspected mpox case in the country on 20 May. The case was confirmed by testing on 21 May, becoming the first case in Israel during the outbreak. The 30-year-old man returned from Western Europe and contracted the disease from there. The ministry reported that he was in isolation in the Ichilov General Hospital in Tel Aviv . The Ministry of Health reported the first case of community transmission on 21 June 2022. In 2018, an imported case was detected in Israel. A 38-year-old man came from Rivers State , Nigeria in late September. He showed the symptoms of the disease on that month. Later on October the patient sought medical attention at Shaare-Zedek Medical Center in Jerusalem . He was confirmed to be infected with the West African Clade of monkeypox virus that month. All of the patient's contacts were traced and followed up but no virus transmission were detected. As the outbreak was spreading in Europe in the middle of May 2022, the Israeli Health Ministry reported a suspected mpox case in the country on 20 May. The case was confirmed by testing on 21 May, becoming the first case in Israel during the outbreak. The 30-year-old man returned from Western Europe and contracted the disease from there. The ministry reported that he was in isolation in the Ichilov General Hospital in Tel Aviv . The Ministry of Health reported the first case of community transmission on 21 June 2022.

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2022–2023 mpox outbreak in Europe

The 2022–2023 mpox outbreak in Europe is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak reached Europe on 6 May 2022 when the United Kingdom reported their first case of mpox. As of 13 July 2022 , [ update ] 35 European countries and territories have confirmed cases.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . An index case was imported into the United Kingdom in late April 2022, by a man who had travelled to Nigeria, where the disease is endemic. He had already showed symptoms since 29 April, and was admitted to hospital in London on 6 May. On 12 May, the man was confirmed to have contracted mpox. The following day, another mpox case was confirmed, and the United Kingdom reported these cases to the World Health Organization (WHO). On 18 May, Spain and Portugal both confirmed their first cases of mpox following the confirmation of mpox in the United Kingdom starting an outbreak in the countries. It is unknown how it was contracted, but most likely via travel or skin-to-skin contact abroad. On 19 May, Belgium confirmed its first cases of mpox in two Belgian men, it was later confirmed by Reuters that the men had gone to the same party. Later, Italy confirmed its first case of mpox in an Italian man in Rome, the man was isolated at the Spallanzani Hospital . The disease was likely contracted from a stay in the Canary Islands. There were 2 suspected cases, which later became confirmed cases. Sweden then confirmed its first case of mpox in Stockholm , the Swedish Health Agency confirmed it later. The person was not reported to be a woman or a man, but it was most likely a man. It is unknown how it was contracted, but likely via travel or skin-to-skin contact abroad. On 20 May, France reported their first case of mpox. The patient had no travel history, meaning he didn't contract the disease abroad. On the same day, Germany and the Netherlands reported their first cases of mpox. It was unknown how it was contracted in both stories, but likely via travel or skin-to-skin contact abroad. On 21 May, Switzerland confirmed its first case of mpox. It was in a person of undisclosed gender, contracted through "close physical contact" abroad, according to Reuters. On 22 May, Austria confirmed its first case of mpox. It is unknown how it was contracted or who contracted it, but likely via travel or skin-to-skin contact abroad. On 23 May, Denmark detected its first mpox infection. It was in an adult male, likely contracted from a trip to Spain, according to Reuters. No cases of mpox were detected in Greenland , a Danish constituent country in North America. On 24 May, the Czech Republic registered its first case of mpox in a woman, likely picked up from a festival in Belgium, according to Reuters. On the same day, Slovenia also registered its first case of mpox. It was in a traveller of undisclosed gender who likely contracted mpox from a trip to the Canary Islands, according to Reuters. On 27 May, Ireland confirmed its first case of mpox in the east of the country. The Health Protection Surveillance Centre (HPSC) commenced publication of a weekly report on the epidemiology of human mpox in Ireland on 9 June. On the same day, Finland also confirmed its first case of mpox. It was in a man who likely had contracted the disease from a trip to another European country, according to Reuters. On 28 May, Malta registered its first case of mpox. It was in an adult male, who most likely picked up the disease abroad from one of the countries affected by the outbreak, according to the Malta Times. On 31 May, Hungary confirmed its first case of mpox, in an adult male. It is still being investigated whether or not he recently travelled, though it is unknown how the man contracted the disease. On the same day, Norway confirmed its first case of mpox. It was in a person of undisclosed gender who most likely contracted the disease from travelling abroad. The case was linked to the ongoing outbreak in Europe, meaning that the patient may have travelled to a European country that was affected by the outbreak. On 1 June, Gibraltar, a British Overseas Territory , registered its first case of mpox in a Spanish resident of undisclosed gender working in Gibraltar. The patient likely contracted the disease from close contact with another Spanish national also working in Gibraltar. On 3 June, Latvia confirmed its first mpox infection. It was in an elderly person of undisclosed gender who most likely contracted the disease abroad. On 8 June, Greece confirmed the country's first mpox case. It was in a person of undisclosed gender who likely contracted the disease from a trip to Portugal. On 9 June, Iceland confirmed its first mpox case. It was in two men who most likely contracted the disease from a trip to Europe. On 10 June, Poland confirmed its first mpox case. It is unknown who the patient is or how it was contracted, but it is possible it was picked up via travel or skin-to-skin contact. On 13 June, Romania confirmed its first monkempoxypox infection. It was in an adult male who most likely contracted the disease from his partner who travelled in several different European countries that have been affected by mpox at the time. On 15 June, Luxembourg confirmed its first mpox case. It is unknown how it was contracted, though it is being investigated. The disease was likely picked up via travelling abroad or skin-to-skin contact. On the same day, Georgia also confirmed its first case of mpox. It was in a patient of undisclosed gender who likely contracted the disease from a trip to Europe. On 17 June, Serbia confirmed its first case of mpox. It was in a patient of undisclosed gender. It was revealed that it was an "imported case", meaning that the patient may have contracted the disease abroad. On 23 June, Bulgaria confirmed its first mpox case. It was in two men who most likely contracted the disease from a trip to Spain and the United Kingdom but don't reckon any contact with infected persons. On the same day, Croatia also received its first case of mpox. It was in an adult man who most likely contracted the disease from a stay in Italy and Spain. On 28 June, Estonia confirmed its first case of mpox. It was in a middle-aged man who most likely contracted the disease abroad. He had no close contacts with anyone in Estonia. On 2 July, Andorra registered its first mpox case in a woman of unknown age. It is unknown how it was contracted, but it may likely have been picked up either abroad via travel or via skin-to-skin contact. On July 7, Slovakia received its first case of mpox. It was in a person of undisclosed gender in the 20-59 age group who most likely contracted the disease abroad. On 12 July, Russia confirmed its first case of mpox. It was in a man probably in his 20-25 age group who likely contracted the disease from a trip to Europe where the outbreak had started. The man then tested positive for the virus and was isolated in a hospital, most likely in Saint Petersburg . On 13 July, Bosnia and Herzegovina registered its first mpox case. It is unknown how it was contracted, although the disease was likely picked up abroad via travel or skin-to-skin contact. On 22 July, Monaco confirmed its first case of mpox, in a man who most likely had travelled to France where the disease was spreading. The Princess Grace Hospital Centre later reported that the first case of the disease had been confirmed in the residential area of La Colle . [ citation needed ] On 15 September, Ukraine's Ministry of Health reported the country's first case of mpox. The Ministry noted that the patient, who did not travel abroad, was experiencing "mild symptoms" and undergoing hospital treatment. The region where the case was reported was not disclosed. An index case was imported into the United Kingdom in late April 2022, by a man who had travelled to Nigeria, where the disease is endemic. He had already showed symptoms since 29 April, and was admitted to hospital in London on 6 May. On 12 May, the man was confirmed to have contracted mpox. The following day, another mpox case was confirmed, and the United Kingdom reported these cases to the World Health Organization (WHO). On 18 May, Spain and Portugal both confirmed their first cases of mpox following the confirmation of mpox in the United Kingdom starting an outbreak in the countries. It is unknown how it was contracted, but most likely via travel or skin-to-skin contact abroad. On 19 May, Belgium confirmed its first cases of mpox in two Belgian men, it was later confirmed by Reuters that the men had gone to the same party. Later, Italy confirmed its first case of mpox in an Italian man in Rome, the man was isolated at the Spallanzani Hospital . The disease was likely contracted from a stay in the Canary Islands. There were 2 suspected cases, which later became confirmed cases. Sweden then confirmed its first case of mpox in Stockholm , the Swedish Health Agency confirmed it later. The person was not reported to be a woman or a man, but it was most likely a man. It is unknown how it was contracted, but likely via travel or skin-to-skin contact abroad. On 20 May, France reported their first case of mpox. The patient had no travel history, meaning he didn't contract the disease abroad. On the same day, Germany and the Netherlands reported their first cases of mpox. It was unknown how it was contracted in both stories, but likely via travel or skin-to-skin contact abroad. On 21 May, Switzerland confirmed its first case of mpox. It was in a person of undisclosed gender, contracted through "close physical contact" abroad, according to Reuters. On 22 May, Austria confirmed its first case of mpox. It is unknown how it was contracted or who contracted it, but likely via travel or skin-to-skin contact abroad. On 23 May, Denmark detected its first mpox infection. It was in an adult male, likely contracted from a trip to Spain, according to Reuters. No cases of mpox were detected in Greenland , a Danish constituent country in North America. On 24 May, the Czech Republic registered its first case of mpox in a woman, likely picked up from a festival in Belgium, according to Reuters. On the same day, Slovenia also registered its first case of mpox. It was in a traveller of undisclosed gender who likely contracted mpox from a trip to the Canary Islands, according to Reuters. On 27 May, Ireland confirmed its first case of mpox in the east of the country. The Health Protection Surveillance Centre (HPSC) commenced publication of a weekly report on the epidemiology of human mpox in Ireland on 9 June. On the same day, Finland also confirmed its first case of mpox. It was in a man who likely had contracted the disease from a trip to another European country, according to Reuters. On 28 May, Malta registered its first case of mpox. It was in an adult male, who most likely picked up the disease abroad from one of the countries affected by the outbreak, according to the Malta Times. On 31 May, Hungary confirmed its first case of mpox, in an adult male. It is still being investigated whether or not he recently travelled, though it is unknown how the man contracted the disease. On the same day, Norway confirmed its first case of mpox. It was in a person of undisclosed gender who most likely contracted the disease from travelling abroad. The case was linked to the ongoing outbreak in Europe, meaning that the patient may have travelled to a European country that was affected by the outbreak. On 1 June, Gibraltar, a British Overseas Territory , registered its first case of mpox in a Spanish resident of undisclosed gender working in Gibraltar. The patient likely contracted the disease from close contact with another Spanish national also working in Gibraltar. On 3 June, Latvia confirmed its first mpox infection. It was in an elderly person of undisclosed gender who most likely contracted the disease abroad. On 8 June, Greece confirmed the country's first mpox case. It was in a person of undisclosed gender who likely contracted the disease from a trip to Portugal. On 9 June, Iceland confirmed its first mpox case. It was in two men who most likely contracted the disease from a trip to Europe. On 10 June, Poland confirmed its first mpox case. It is unknown who the patient is or how it was contracted, but it is possible it was picked up via travel or skin-to-skin contact. On 13 June, Romania confirmed its first monkempoxypox infection. It was in an adult male who most likely contracted the disease from his partner who travelled in several different European countries that have been affected by mpox at the time. On 15 June, Luxembourg confirmed its first mpox case. It is unknown how it was contracted, though it is being investigated. The disease was likely picked up via travelling abroad or skin-to-skin contact. On the same day, Georgia also confirmed its first case of mpox. It was in a patient of undisclosed gender who likely contracted the disease from a trip to Europe. On 17 June, Serbia confirmed its first case of mpox. It was in a patient of undisclosed gender. It was revealed that it was an "imported case", meaning that the patient may have contracted the disease abroad. On 23 June, Bulgaria confirmed its first mpox case. It was in two men who most likely contracted the disease from a trip to Spain and the United Kingdom but don't reckon any contact with infected persons. On the same day, Croatia also received its first case of mpox. It was in an adult man who most likely contracted the disease from a stay in Italy and Spain. On 28 June, Estonia confirmed its first case of mpox. It was in a middle-aged man who most likely contracted the disease abroad. He had no close contacts with anyone in Estonia. On 2 July, Andorra registered its first mpox case in a woman of unknown age. It is unknown how it was contracted, but it may likely have been picked up either abroad via travel or via skin-to-skin contact. On July 7, Slovakia received its first case of mpox. It was in a person of undisclosed gender in the 20-59 age group who most likely contracted the disease abroad. On 12 July, Russia confirmed its first case of mpox. It was in a man probably in his 20-25 age group who likely contracted the disease from a trip to Europe where the outbreak had started. The man then tested positive for the virus and was isolated in a hospital, most likely in Saint Petersburg . On 13 July, Bosnia and Herzegovina registered its first mpox case. It is unknown how it was contracted, although the disease was likely picked up abroad via travel or skin-to-skin contact. On 22 July, Monaco confirmed its first case of mpox, in a man who most likely had travelled to France where the disease was spreading. The Princess Grace Hospital Centre later reported that the first case of the disease had been confirmed in the residential area of La Colle . [ citation needed ] On 15 September, Ukraine's Ministry of Health reported the country's first case of mpox. The Ministry noted that the patient, who did not travel abroad, was experiencing "mild symptoms" and undergoing hospital treatment. The region where the case was reported was not disclosed. On 18 May, Spain and Portugal both confirmed their first cases of mpox following the confirmation of mpox in the United Kingdom starting an outbreak in the countries. It is unknown how it was contracted, but most likely via travel or skin-to-skin contact abroad. On 19 May, Belgium confirmed its first cases of mpox in two Belgian men, it was later confirmed by Reuters that the men had gone to the same party. Later, Italy confirmed its first case of mpox in an Italian man in Rome, the man was isolated at the Spallanzani Hospital . The disease was likely contracted from a stay in the Canary Islands. There were 2 suspected cases, which later became confirmed cases. Sweden then confirmed its first case of mpox in Stockholm , the Swedish Health Agency confirmed it later. The person was not reported to be a woman or a man, but it was most likely a man. It is unknown how it was contracted, but likely via travel or skin-to-skin contact abroad. On 20 May, France reported their first case of mpox. The patient had no travel history, meaning he didn't contract the disease abroad. On the same day, Germany and the Netherlands reported their first cases of mpox. It was unknown how it was contracted in both stories, but likely via travel or skin-to-skin contact abroad. On 21 May, Switzerland confirmed its first case of mpox. It was in a person of undisclosed gender, contracted through "close physical contact" abroad, according to Reuters. On 22 May, Austria confirmed its first case of mpox. It is unknown how it was contracted or who contracted it, but likely via travel or skin-to-skin contact abroad. On 23 May, Denmark detected its first mpox infection. It was in an adult male, likely contracted from a trip to Spain, according to Reuters. No cases of mpox were detected in Greenland , a Danish constituent country in North America. On 24 May, the Czech Republic registered its first case of mpox in a woman, likely picked up from a festival in Belgium, according to Reuters. On the same day, Slovenia also registered its first case of mpox. It was in a traveller of undisclosed gender who likely contracted mpox from a trip to the Canary Islands, according to Reuters. On 27 May, Ireland confirmed its first case of mpox in the east of the country. The Health Protection Surveillance Centre (HPSC) commenced publication of a weekly report on the epidemiology of human mpox in Ireland on 9 June. On the same day, Finland also confirmed its first case of mpox. It was in a man who likely had contracted the disease from a trip to another European country, according to Reuters. On 28 May, Malta registered its first case of mpox. It was in an adult male, who most likely picked up the disease abroad from one of the countries affected by the outbreak, according to the Malta Times. On 31 May, Hungary confirmed its first case of mpox, in an adult male. It is still being investigated whether or not he recently travelled, though it is unknown how the man contracted the disease. On the same day, Norway confirmed its first case of mpox. It was in a person of undisclosed gender who most likely contracted the disease from travelling abroad. The case was linked to the ongoing outbreak in Europe, meaning that the patient may have travelled to a European country that was affected by the outbreak. On 18 May, Spain and Portugal both confirmed their first cases of mpox following the confirmation of mpox in the United Kingdom starting an outbreak in the countries. It is unknown how it was contracted, but most likely via travel or skin-to-skin contact abroad.On 19 May, Belgium confirmed its first cases of mpox in two Belgian men, it was later confirmed by Reuters that the men had gone to the same party. Later, Italy confirmed its first case of mpox in an Italian man in Rome, the man was isolated at the Spallanzani Hospital . The disease was likely contracted from a stay in the Canary Islands. There were 2 suspected cases, which later became confirmed cases. Sweden then confirmed its first case of mpox in Stockholm , the Swedish Health Agency confirmed it later. The person was not reported to be a woman or a man, but it was most likely a man. It is unknown how it was contracted, but likely via travel or skin-to-skin contact abroad.On 20 May, France reported their first case of mpox. The patient had no travel history, meaning he didn't contract the disease abroad. On the same day, Germany and the Netherlands reported their first cases of mpox. It was unknown how it was contracted in both stories, but likely via travel or skin-to-skin contact abroad.On 21 May, Switzerland confirmed its first case of mpox. It was in a person of undisclosed gender, contracted through "close physical contact" abroad, according to Reuters. On 22 May, Austria confirmed its first case of mpox. It is unknown how it was contracted or who contracted it, but likely via travel or skin-to-skin contact abroad.On 23 May, Denmark detected its first mpox infection. It was in an adult male, likely contracted from a trip to Spain, according to Reuters. No cases of mpox were detected in Greenland , a Danish constituent country in North America.On 24 May, the Czech Republic registered its first case of mpox in a woman, likely picked up from a festival in Belgium, according to Reuters. On the same day, Slovenia also registered its first case of mpox. It was in a traveller of undisclosed gender who likely contracted mpox from a trip to the Canary Islands, according to Reuters. On 27 May, Ireland confirmed its first case of mpox in the east of the country. The Health Protection Surveillance Centre (HPSC) commenced publication of a weekly report on the epidemiology of human mpox in Ireland on 9 June. On the same day, Finland also confirmed its first case of mpox. It was in a man who likely had contracted the disease from a trip to another European country, according to Reuters. On 28 May, Malta registered its first case of mpox. It was in an adult male, who most likely picked up the disease abroad from one of the countries affected by the outbreak, according to the Malta Times. On 31 May, Hungary confirmed its first case of mpox, in an adult male. It is still being investigated whether or not he recently travelled, though it is unknown how the man contracted the disease. On the same day, Norway confirmed its first case of mpox. It was in a person of undisclosed gender who most likely contracted the disease from travelling abroad. The case was linked to the ongoing outbreak in Europe, meaning that the patient may have travelled to a European country that was affected by the outbreak. On 1 June, Gibraltar, a British Overseas Territory , registered its first case of mpox in a Spanish resident of undisclosed gender working in Gibraltar. The patient likely contracted the disease from close contact with another Spanish national also working in Gibraltar. On 3 June, Latvia confirmed its first mpox infection. It was in an elderly person of undisclosed gender who most likely contracted the disease abroad. On 8 June, Greece confirmed the country's first mpox case. It was in a person of undisclosed gender who likely contracted the disease from a trip to Portugal. On 9 June, Iceland confirmed its first mpox case. It was in two men who most likely contracted the disease from a trip to Europe. On 10 June, Poland confirmed its first mpox case. It is unknown who the patient is or how it was contracted, but it is possible it was picked up via travel or skin-to-skin contact. On 13 June, Romania confirmed its first monkempoxypox infection. It was in an adult male who most likely contracted the disease from his partner who travelled in several different European countries that have been affected by mpox at the time. On 15 June, Luxembourg confirmed its first mpox case. It is unknown how it was contracted, though it is being investigated. The disease was likely picked up via travelling abroad or skin-to-skin contact. On the same day, Georgia also confirmed its first case of mpox. It was in a patient of undisclosed gender who likely contracted the disease from a trip to Europe. On 17 June, Serbia confirmed its first case of mpox. It was in a patient of undisclosed gender. It was revealed that it was an "imported case", meaning that the patient may have contracted the disease abroad. On 23 June, Bulgaria confirmed its first mpox case. It was in two men who most likely contracted the disease from a trip to Spain and the United Kingdom but don't reckon any contact with infected persons. On the same day, Croatia also received its first case of mpox. It was in an adult man who most likely contracted the disease from a stay in Italy and Spain. On 28 June, Estonia confirmed its first case of mpox. It was in a middle-aged man who most likely contracted the disease abroad. He had no close contacts with anyone in Estonia. On 1 June, Gibraltar, a British Overseas Territory , registered its first case of mpox in a Spanish resident of undisclosed gender working in Gibraltar. The patient likely contracted the disease from close contact with another Spanish national also working in Gibraltar. On 3 June, Latvia confirmed its first mpox infection. It was in an elderly person of undisclosed gender who most likely contracted the disease abroad. On 8 June, Greece confirmed the country's first mpox case. It was in a person of undisclosed gender who likely contracted the disease from a trip to Portugal. On 9 June, Iceland confirmed its first mpox case. It was in two men who most likely contracted the disease from a trip to Europe. On 10 June, Poland confirmed its first mpox case. It is unknown who the patient is or how it was contracted, but it is possible it was picked up via travel or skin-to-skin contact. On 13 June, Romania confirmed its first monkempoxypox infection. It was in an adult male who most likely contracted the disease from his partner who travelled in several different European countries that have been affected by mpox at the time. On 15 June, Luxembourg confirmed its first mpox case. It is unknown how it was contracted, though it is being investigated. The disease was likely picked up via travelling abroad or skin-to-skin contact. On the same day, Georgia also confirmed its first case of mpox. It was in a patient of undisclosed gender who likely contracted the disease from a trip to Europe. On 17 June, Serbia confirmed its first case of mpox. It was in a patient of undisclosed gender. It was revealed that it was an "imported case", meaning that the patient may have contracted the disease abroad. On 23 June, Bulgaria confirmed its first mpox case. It was in two men who most likely contracted the disease from a trip to Spain and the United Kingdom but don't reckon any contact with infected persons. On the same day, Croatia also received its first case of mpox. It was in an adult man who most likely contracted the disease from a stay in Italy and Spain. On 28 June, Estonia confirmed its first case of mpox. It was in a middle-aged man who most likely contracted the disease abroad. He had no close contacts with anyone in Estonia. On 2 July, Andorra registered its first mpox case in a woman of unknown age. It is unknown how it was contracted, but it may likely have been picked up either abroad via travel or via skin-to-skin contact. On July 7, Slovakia received its first case of mpox. It was in a person of undisclosed gender in the 20-59 age group who most likely contracted the disease abroad. On 12 July, Russia confirmed its first case of mpox. It was in a man probably in his 20-25 age group who likely contracted the disease from a trip to Europe where the outbreak had started. The man then tested positive for the virus and was isolated in a hospital, most likely in Saint Petersburg . On 13 July, Bosnia and Herzegovina registered its first mpox case. It is unknown how it was contracted, although the disease was likely picked up abroad via travel or skin-to-skin contact. On 22 July, Monaco confirmed its first case of mpox, in a man who most likely had travelled to France where the disease was spreading. The Princess Grace Hospital Centre later reported that the first case of the disease had been confirmed in the residential area of La Colle . [ citation needed ]On 2 July, Andorra registered its first mpox case in a woman of unknown age. It is unknown how it was contracted, but it may likely have been picked up either abroad via travel or via skin-to-skin contact. On July 7, Slovakia received its first case of mpox. It was in a person of undisclosed gender in the 20-59 age group who most likely contracted the disease abroad. On 12 July, Russia confirmed its first case of mpox. It was in a man probably in his 20-25 age group who likely contracted the disease from a trip to Europe where the outbreak had started. The man then tested positive for the virus and was isolated in a hospital, most likely in Saint Petersburg . On 13 July, Bosnia and Herzegovina registered its first mpox case. It is unknown how it was contracted, although the disease was likely picked up abroad via travel or skin-to-skin contact. On 22 July, Monaco confirmed its first case of mpox, in a man who most likely had travelled to France where the disease was spreading. The Princess Grace Hospital Centre later reported that the first case of the disease had been confirmed in the residential area of La Colle . [ citation needed ]On 15 September, Ukraine's Ministry of Health reported the country's first case of mpox. The Ministry noted that the patient, who did not travel abroad, was experiencing "mild symptoms" and undergoing hospital treatment. The region where the case was reported was not disclosed. On 15 September, Ukraine's Ministry of Health reported the country's first case of mpox. The Ministry noted that the patient, who did not travel abroad, was experiencing "mild symptoms" and undergoing hospital treatment. The region where the case was reported was not disclosed. On 20 May, the WHO convened an emergency meeting of independent advisers to discuss the outbreak and assess the threat level. Its European chief, Hans Kluge , expressed concern that infections could accelerate in Europe as people gather for parties and festivals over the summer. On 14 June, the WHO announced plans to rename the disease from monkeypox to mpox in order to combat stigma and racism surrounding the disease. Another meeting convened on 23 June determined that the outbreak does not constitute a Public Health Emergency of International Concern for the time being. The majority of European countries responded to the outbreak, and the responses of some are listed below.On 20 May, the WHO convened an emergency meeting of independent advisers to discuss the outbreak and assess the threat level. Its European chief, Hans Kluge , expressed concern that infections could accelerate in Europe as people gather for parties and festivals over the summer. On 14 June, the WHO announced plans to rename the disease from monkeypox to mpox in order to combat stigma and racism surrounding the disease. Another meeting convened on 23 June determined that the outbreak does not constitute a Public Health Emergency of International Concern for the time being. The majority of European countries responded to the outbreak, and the responses of some are listed below.This is a table of confirmed and suspected mpox cases in European countries during the ongoing 2022–2023 mpox outbreak. It does not include countries where suspected cases were reported but later discarded. ( As of 13 July 2022 [ update ] ) Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases. Countries listed several times reported suspected cases again after they discarded suspected cases before. As of 11 July 2022 , [ update ] 33 European countries and territories have been affected by the pandemic.Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases. Countries listed several times reported suspected cases again after they discarded suspected cases before. As of 11 July 2022 , [ update ] 33 European countries and territories have been affected by the pandemic.Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases. Countries listed several times reported suspected cases again after they discarded suspected cases before. As of 11 July 2022 , [ update ] 33 European countries and territories have been affected by the pandemic.

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Orthopoxvirus

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List of virus genera

This is an alphabetical list of genera of biological viruses. It includes all genera and subgenera of viruses listed by the International Committee on Taxonomy of Viruses (ICTV) 2022 release.

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2022–2023 mpox outbreak in Colombia

The 2022–2023 mpox outbreak in Colombia is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak reached Colombia on 23 June 2022. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. In May 2022, the World Health Organization (WHO) made an emergency announcement of the existence of a multi-country outbreak of mpox , a viral disease then commonly known as "monkeypox" . The initial cluster of cases was found in the United Kingdom , where the first case was detected in London on 6 May 2022 in a patient with a recent travel history from Nigeria (where the disease is endemic ). On 16 May, the UK Health Security Agency ( UKHSA ) confirmed four new cases with no link to travel to a country where mpox is endemic. Subsequently, cases have been reported from many countries and regions. The outbreak marked the first time mpox had spread widely outside Central and West Africa . There is evidence that the disease had been circulating and evolving in human hosts over a number of years prior to the outbreak. The outbreak was of the Clade IIb variant of the virus. As of May, the Colombian Ministry of Health was taking follow-up and control measures. The Director of Epidemiology and Demography of the Ministry of Health, Claudia Cuellar, informed the Colombian population about how mpox is spread through people, and she spoke about the clinical presentation of the virus and international health regulations. Health authorities in the Department of Norte de Santander have been on alert, since the department is a border area where people pass between Colombia and Venezuela. On June 23, 2022, the Colombian Ministry of Health confirmed three cases of mpox, specifically two in the city of Bogotá and one in Medellín . The two cases reported in Bogota were of people who had traveled to Europe. The first case identified in Medellin was a person who had been infected while traveling to the European city of Barcelona in Spain. On July 8, the National Institute of Health confirmed a new case of the disease in Bogota from a person who had been in contact with an infected person from Italy when they had traveled to Europe. On July 23, following the follow-up of several cases, health authorities began an extensive surveillance phase. On the same day, the National Institute of Health confirmed that the number of cases in the country reached 10. On July 25, the first case of a person who had been in Argentina was reported in the department of Cundinamarca , specifically in the municipality of Cajicá . On July 29, the first case was detected in Pereira , capital of the department of Risaralda . On July 30, the National Institute of Health confirmed the first case in the department of Valle del Cauca , specifically in the city of Cartago located in the north of the department. On August 1, the Mayor's Office of Cali City opened a hotline to receive information when a person reports suspected cases of this disease. On August 3, the first case was confirmed in the Department of La Guajira of a man who had traveled to Bogotá. The case was detected in the municipality of Albania , which is located in the center of the department. After the first case was detected in La Guajira, health authorities in the neighboring department of Cesar increased their alert. The department's health secretary, Guillermo Girón, indicated that prevention measures should be increased due to the proximity to La Guajira. On August 4, the first case was confirmed in the city of Bucaramanga , capital of the department of Santander . On the same day, the first case was registered in the department of Tolima , specifically in the capital city of Ibagué , of a person who had traveled to the United States. On August 5, the first case was confirmed in the capital of the department of Bolívar , Cartagena . On August 11, the first case of this disease was detected in Popayán , capital of the Cauca department . On August 12, the first case of mpox in Riohacha , capital of La Guajira, was confirmed. On August 15, the first case was confirmed in the city of Cúcuta , capital of the department of Norte de Santander , in a man who had traveled to Mexico and the United States. On the same day, the first case was reported in Barranquilla , capital city of the Atlántico department . On August 16, the first case was reported in Cali, capital city of the Valle del Cauca department. On August 17, the first case was confirmed in the capital of the department of Quindío , Armenia . On August 20, the first case was reported in the city of Villavicencio, capital of the Meta department . On August 31, the José María Córdova airport carried out the first simulation in the country in order to deal with contagions of the disease. On August 26, the first one was confirmed in the department of Sucre , specifically in the municipality of Tolú in the western part of the department. On August 29, the first case was confirmed in Tunja , capital of the department of Boyacá . On September 7, the health authorities of the department of Cesar confirmed the first case in the department, specifically in Valledupar . On September 9, the first case was confirmed in the capital of Putumayo , Mocoa, according to Adriana Medicis, health secretary of the departmental government, explained that the case was a person residing in Mocoa . Also on the same day, the first case was confirmed in the city of Neiva , the capital of the Huila department . As of May, the Colombian Ministry of Health was taking follow-up and control measures. The Director of Epidemiology and Demography of the Ministry of Health, Claudia Cuellar, informed the Colombian population about how mpox is spread through people, and she spoke about the clinical presentation of the virus and international health regulations. Health authorities in the Department of Norte de Santander have been on alert, since the department is a border area where people pass between Colombia and Venezuela. On June 23, 2022, the Colombian Ministry of Health confirmed three cases of mpox, specifically two in the city of Bogotá and one in Medellín . The two cases reported in Bogota were of people who had traveled to Europe. The first case identified in Medellin was a person who had been infected while traveling to the European city of Barcelona in Spain. On July 8, the National Institute of Health confirmed a new case of the disease in Bogota from a person who had been in contact with an infected person from Italy when they had traveled to Europe. On July 23, following the follow-up of several cases, health authorities began an extensive surveillance phase. On the same day, the National Institute of Health confirmed that the number of cases in the country reached 10. On July 25, the first case of a person who had been in Argentina was reported in the department of Cundinamarca , specifically in the municipality of Cajicá . On July 29, the first case was detected in Pereira , capital of the department of Risaralda . On July 30, the National Institute of Health confirmed the first case in the department of Valle del Cauca , specifically in the city of Cartago located in the north of the department. On August 1, the Mayor's Office of Cali City opened a hotline to receive information when a person reports suspected cases of this disease. On August 3, the first case was confirmed in the Department of La Guajira of a man who had traveled to Bogotá. The case was detected in the municipality of Albania , which is located in the center of the department. After the first case was detected in La Guajira, health authorities in the neighboring department of Cesar increased their alert. The department's health secretary, Guillermo Girón, indicated that prevention measures should be increased due to the proximity to La Guajira. On August 4, the first case was confirmed in the city of Bucaramanga , capital of the department of Santander . On the same day, the first case was registered in the department of Tolima , specifically in the capital city of Ibagué , of a person who had traveled to the United States. On August 5, the first case was confirmed in the capital of the department of Bolívar , Cartagena . On August 11, the first case of this disease was detected in Popayán , capital of the Cauca department . On August 12, the first case of mpox in Riohacha , capital of La Guajira, was confirmed. On August 15, the first case was confirmed in the city of Cúcuta , capital of the department of Norte de Santander , in a man who had traveled to Mexico and the United States. On the same day, the first case was reported in Barranquilla , capital city of the Atlántico department . On August 16, the first case was reported in Cali, capital city of the Valle del Cauca department. On August 17, the first case was confirmed in the capital of the department of Quindío , Armenia . On August 20, the first case was reported in the city of Villavicencio, capital of the Meta department . On August 31, the José María Córdova airport carried out the first simulation in the country in order to deal with contagions of the disease. On August 26, the first one was confirmed in the department of Sucre , specifically in the municipality of Tolú in the western part of the department. On August 29, the first case was confirmed in Tunja , capital of the department of Boyacá . On September 7, the health authorities of the department of Cesar confirmed the first case in the department, specifically in Valledupar . On September 9, the first case was confirmed in the capital of Putumayo , Mocoa, according to Adriana Medicis, health secretary of the departmental government, explained that the case was a person residing in Mocoa . Also on the same day, the first case was confirmed in the city of Neiva , the capital of the Huila department . In August 2022, the Colombian government requested from the Pan American Health Organization the vaccines to immunize the country's population. Doctor Gina Tambini, who is Colombia's representative for both the World Health Organization and the Pan American Health Organization, explained about the vaccination scheme that will be implemented in the country, which will first prioritize people who have presented symptoms of the disease or have been close to positive cases.

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2022–2023 mpox outbreak in South America

The 2022–2023 mpox outbreak in South America is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak reached South America on 27 May 2022 when Argentina reported their first case of mpox. As of 14 August 2022 , [ update ] 8 South American countries and territories have confirmed cases.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on 4 May, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . An index case was imported into Argentina on 27 May. It was unknown how the disease was contracted, but likely abroad in mpox-affected countries. The patient had likely showed symptoms since 25 May, and was admitted to a hospital on 26 May. The next day, the patient was confirmed to have contracted mpox. The following day, another mpox case was confirmed, and Argentina reported these cases to Reliefweb . On 9 June, Brazil confirmed its first case of mpox. It was in a 41-year-old male who may have been infected from recently traveling to Spain and Portugal, which had already been affected by the mpox outbreak. It was likely contracted via skin-to-skin contact. On 12 June, Venezuela registered its first case of mpox. It was in a male of unknown age who had likely contracted the disease via skin-to-skin contact in Madrid , Spain which had already been affected by the mpox outbreak. On 17 June, Chile confirmed its first mpox infection. It was in a young male of unknown specific age from the Metropolitan Region . It was likely contracted via skin-to-skin contact from a trip to Europe . On 23 June, Colombia confirmed its first three cases of mpox in adults of unknown genders and ages. Two of the cases were found in the capital Bogota , and the third was found in Colombia's second city, Medellin . It was unknown how those cases were contracted, although it was likely skin-to-skin contact picked up abroad. On 26 June, Peru reported its first case of mpox. It was in a foreign citizen of unknown gender or age who resides in Lima , Peru . The patient likely got infected via while being in contact with people from abroad. It was likely skin-to-skin contact rather than sexual contact. On 6 July, Ecuador reported its first mpox infection. It was in a 30-year-old male who resides in the Southwest coastal province of Guayas , Ecuador . It is unknown how the patient contracted the disease, but likely skin-to-skin contact picked up abroad. [ citation needed ] On 29 July, Uruguay registered its first case of mpox. It was in a patient of unknown age and gender. It is unknown how the disease was contracted, but likely skin-to-skin contact abroad. On 1 August, Bolivia confirmed its first case of mpox. It was in a 38-year-old male. It is unknown how the disease was contracted, but likely skin-to-skin contact picked up abroad. An index case was imported into Argentina on 27 May. It was unknown how the disease was contracted, but likely abroad in mpox-affected countries. The patient had likely showed symptoms since 25 May, and was admitted to a hospital on 26 May. The next day, the patient was confirmed to have contracted mpox. The following day, another mpox case was confirmed, and Argentina reported these cases to Reliefweb . On 9 June, Brazil confirmed its first case of mpox. It was in a 41-year-old male who may have been infected from recently traveling to Spain and Portugal, which had already been affected by the mpox outbreak. It was likely contracted via skin-to-skin contact. On 12 June, Venezuela registered its first case of mpox. It was in a male of unknown age who had likely contracted the disease via skin-to-skin contact in Madrid , Spain which had already been affected by the mpox outbreak. On 17 June, Chile confirmed its first mpox infection. It was in a young male of unknown specific age from the Metropolitan Region . It was likely contracted via skin-to-skin contact from a trip to Europe . On 23 June, Colombia confirmed its first three cases of mpox in adults of unknown genders and ages. Two of the cases were found in the capital Bogota , and the third was found in Colombia's second city, Medellin . It was unknown how those cases were contracted, although it was likely skin-to-skin contact picked up abroad. On 26 June, Peru reported its first case of mpox. It was in a foreign citizen of unknown gender or age who resides in Lima , Peru . The patient likely got infected via while being in contact with people from abroad. It was likely skin-to-skin contact rather than sexual contact. On 6 July, Ecuador reported its first mpox infection. It was in a 30-year-old male who resides in the Southwest coastal province of Guayas , Ecuador . It is unknown how the patient contracted the disease, but likely skin-to-skin contact picked up abroad. [ citation needed ] On 29 July, Uruguay registered its first case of mpox. It was in a patient of unknown age and gender. It is unknown how the disease was contracted, but likely skin-to-skin contact abroad. On 1 August, Bolivia confirmed its first case of mpox. It was in a 38-year-old male. It is unknown how the disease was contracted, but likely skin-to-skin contact picked up abroad. On 9 June, Brazil confirmed its first case of mpox. It was in a 41-year-old male who may have been infected from recently traveling to Spain and Portugal, which had already been affected by the mpox outbreak. It was likely contracted via skin-to-skin contact. On 12 June, Venezuela registered its first case of mpox. It was in a male of unknown age who had likely contracted the disease via skin-to-skin contact in Madrid , Spain which had already been affected by the mpox outbreak. On 17 June, Chile confirmed its first mpox infection. It was in a young male of unknown specific age from the Metropolitan Region . It was likely contracted via skin-to-skin contact from a trip to Europe . On 23 June, Colombia confirmed its first three cases of mpox in adults of unknown genders and ages. Two of the cases were found in the capital Bogota , and the third was found in Colombia's second city, Medellin . It was unknown how those cases were contracted, although it was likely skin-to-skin contact picked up abroad. On 26 June, Peru reported its first case of mpox. It was in a foreign citizen of unknown gender or age who resides in Lima , Peru . The patient likely got infected via while being in contact with people from abroad. It was likely skin-to-skin contact rather than sexual contact. On 9 June, Brazil confirmed its first case of mpox. It was in a 41-year-old male who may have been infected from recently traveling to Spain and Portugal, which had already been affected by the mpox outbreak. It was likely contracted via skin-to-skin contact. On 12 June, Venezuela registered its first case of mpox. It was in a male of unknown age who had likely contracted the disease via skin-to-skin contact in Madrid , Spain which had already been affected by the mpox outbreak. On 17 June, Chile confirmed its first mpox infection. It was in a young male of unknown specific age from the Metropolitan Region . It was likely contracted via skin-to-skin contact from a trip to Europe . On 23 June, Colombia confirmed its first three cases of mpox in adults of unknown genders and ages. Two of the cases were found in the capital Bogota , and the third was found in Colombia's second city, Medellin . It was unknown how those cases were contracted, although it was likely skin-to-skin contact picked up abroad. On 26 June, Peru reported its first case of mpox. It was in a foreign citizen of unknown gender or age who resides in Lima , Peru . The patient likely got infected via while being in contact with people from abroad. It was likely skin-to-skin contact rather than sexual contact. On 6 July, Ecuador reported its first mpox infection. It was in a 30-year-old male who resides in the Southwest coastal province of Guayas , Ecuador . It is unknown how the patient contracted the disease, but likely skin-to-skin contact picked up abroad. [ citation needed ] On 29 July, Uruguay registered its first case of mpox. It was in a patient of unknown age and gender. It is unknown how the disease was contracted, but likely skin-to-skin contact abroad. On 6 July, Ecuador reported its first mpox infection. It was in a 30-year-old male who resides in the Southwest coastal province of Guayas , Ecuador . It is unknown how the patient contracted the disease, but likely skin-to-skin contact picked up abroad. [ citation needed ]On 29 July, Uruguay registered its first case of mpox. It was in a patient of unknown age and gender. It is unknown how the disease was contracted, but likely skin-to-skin contact abroad. On 1 August, Bolivia confirmed its first case of mpox. It was in a 38-year-old male. It is unknown how the disease was contracted, but likely skin-to-skin contact picked up abroad. On 1 August, Bolivia confirmed its first case of mpox. It was in a 38-year-old male. It is unknown how the disease was contracted, but likely skin-to-skin contact picked up abroad. On 20 May, the WHO convened an emergency meeting of independent advisers to discuss the outbreak and assess the threat level. Its European chief, Hans Kluge , expressed concern that infections could accelerate in Europe as people gather for parties and festivals over the summer. On 14 June, the WHO announced plans to rename disease from monkeypox to mpox in order to combat stigma and racism surrounding the disease. Another meeting convened on 23 June determined that the outbreak does not constitute a Public Health Emergency of International Concern for the time being. The majority of South American countries responded to the outbreak, and the responses of some are listed below.On 20 May, the WHO convened an emergency meeting of independent advisers to discuss the outbreak and assess the threat level. Its European chief, Hans Kluge , expressed concern that infections could accelerate in Europe as people gather for parties and festivals over the summer. On 14 June, the WHO announced plans to rename disease from monkeypox to mpox in order to combat stigma and racism surrounding the disease. Another meeting convened on 23 June determined that the outbreak does not constitute a Public Health Emergency of International Concern for the time being. The majority of South American countries responded to the outbreak, and the responses of some are listed below.This is a table of confirmed and suspected mpox cases in South American countries during the ongoing 2022–2023 mpox outbreak. It does not include countries where suspected cases were reported but later discarded. ( As of 31 July 2023 [ update ] ) Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases. Countries listed several times reported suspected cases again after they discarded suspected cases before.Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases. Countries listed several times reported suspected cases again after they discarded suspected cases before.Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases. Countries listed several times reported suspected cases again after they discarded suspected cases before.

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2022–2023 mpox outbreak in Japan

The 2022–2023 mpox outbreak in Japan is a part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus . According to the Ministry of Health , Japan's first mpox case was reported in Tokyo on 25 July 2022.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on 4 May, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. The first known case of the mpox outbreak in Japan was detected on 25 July 2022. According to the Ministry of Health , the index case was a man in his 30s who had recently traveled to Europe, and he had contact with someone who was later diagnosed with mpox. On 28 July 2022, Japan confirmed its second case of mpox, from a man in his 30s in Tokyo and he had recently traveled abroad. It was officially said one victim had no contact with the other victim. On 5 August 2022, Japan confirmed an additional mpox case. On August 11, a fourth case was reported. On October 6, 2 new cases were reported. One day later, a 7th case was reported. On December 29, an 8th case was reported.

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B13R (virus protein)

B13R (sometimes called SPI-2 ) is a protein expressed by vaccinia virus . Vaccinia virus is member of Orthopoxvirus family. These viruses contain approximately 200 genes in their genome . About one third of the genome is not necessary for the viral replication itself. These viral products interfere with the host immune response . SPI-2 is one of these immunomodulatory factors. SPI-2 is a nonglycosylated peptide with size of 38,5 kDa. It is expressed in an early phase of infection . The initiation site for transcription was identified about 72 nucleotides upstream from the open reading frame . The translated protein stays in the cytoplasm of the host cell. SPI-2 shares 92% of its amino acid sequence with the cowpox virus modifier of the cytokine response – known as crmA . SPI-2 belongs in superfamily of the inhibitors of serine proteases (serpins). Serpins are the most broadly distributed family of inhibitors of proteases . They were identified in all multicellular eukaryotic organisms . In mammals serpins are secreted in plasma where they serve as inhibitors of proteases involved in blood coagulation , inflammation and complement activation. SPI-2 inhibits processing of an inactive precursor of interleukin-1β (pro-IL-1β) to active form of this cytokine . It does so by binding to caspase 1 (or ICE – interleukin-1 converting enzyme) which is under normal circumstances activated by the formation of inflammasome . SPI-2 expression also inhibits the apoptotic pathway activated by Fas-ligand and TNFα . Deletion of SPI-2 leads to virus attenuation in vivo (observed in mice model after intranasal infection) but without any remarkable influence on the host immune response. That was one of the reasons this gene was targeted during search for more safe and efficient vaccine against smallpox . It was shown that immunization with vaccinia virus with deleted SPI-2 and 1 and coexpressing IFNγ leads to strong attenuation but without decreasing host immune response. Host reaction was comparable to that on MVA virus (modified virus Ankara ) which serves as a smallpox vaccine nowadays. The Copenhagen strain of vaccinia virus only has a truncated version of this protein. Vaccinia virus encodes two more serpin - SPI-1 and SPI-3. SPI-1 influences the host range and SPI-3 stops infected cells from fusing together.

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2022–2023 mpox outbreak in Peru

The 2022–2023 mpox outbreak in Peru is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak reached Peru on 26 June 2022. Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. In May 2022, the World Health Organization (WHO) made an emergency announcement of the existence of a multi-country outbreak of mpox , a viral disease then commonly known as "monkeypox" . The initial cluster of cases was found in the United Kingdom , where the first case was detected in London on 6 May 2022 in a patient with a recent travel history from Nigeria (where the disease is endemic ). On 16 May, the UK Health Security Agency ( UKHSA ) confirmed four new cases with no link to travel to a country where mpox is endemic. Subsequently, cases have been reported from many countries and regions. The outbreak marked the first time mpox had spread widely outside Central and West Africa . There is evidence that the disease had been circulating and evolving in human hosts over a number of years prior to the outbreak. The outbreak was of the Clade IIb variant of the virus. The first suspected case of infection in the country was reported on 30 May 2022, when health authorities in the department of Piura reported the identification of a 70-year-old patient who presented symptoms compatible with mpox and was isolated in the intensive care unit (ICU) of the Santa Rosa Hospital ( Piura ).

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2022–2023 mpox outbreak in Asia

The 2022 mpox outbreak in Asia is a part of the ongoing outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak was reported in Asia on 20 May 2022 when Israel reported a suspected case of mpox, which was confirmed on 21 May. As of 10 August 2022 , [ update ] seven West Asian , three Southeast Asian , three East Asian and one South Asian country, along with Russia , have reported confirmed cases. As of 10 August 2022 , [ update ] a total of 162 cases were confirmed. Most of them were concentrated in the region of West Asia, with 141 of the total 156 cases (≈90.38%) being reported in the region. Israel alone has reported 114 cases (≈73.07%). Israel reported the first community transmission of the disease on 21 June 2022.Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. In May 2022, the World Health Organization (WHO) made an emergency announcement of the existence of a multi-country outbreak of mpox , a viral disease then commonly known as "monkeypox" . The initial cluster of cases was found in the United Kingdom , where the first case was detected in London on 6 May 2022 in a patient with a recent travel history from Nigeria (where the disease is endemic ). On 16 May, the UK Health Security Agency ( UKHSA ) confirmed four new cases with no link to travel to a country where mpox is endemic. Subsequently, cases have been reported from many countries and regions. The outbreak marked the first time mpox had spread widely outside Central and West Africa . There is evidence that the disease had been circulating and evolving in human hosts over a number of years prior to the outbreak. The outbreak was of the Clade IIb variant of the virus. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis , an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . According to the World Health Organization , imported cases of mpox from Nigeria was detected in Israel and Singapore in September 2018 and May 2019, respectively. In 2018, an imported case was detected in Israel. A 38-year-old man came from Rivers State , Nigeria in late September. He showed the symptoms of the disease on that month. Later on October the patient sought medical attention at Shaare-Zedek Medical Center in Jerusalem . He was confirmed to be infected with the West African Clade of monkeypox virus that month. All of the patient's contacts were traced and followed up but no virus transmission were detected. As the outbreak was spreading in Europe in the middle of May 2022, the Israeli Health Ministry reported a suspected mpox case in the country on 20 May. The case was confirmed by testing on 21 May, becoming the first case in Israel during the outbreak, which also became the first in Asia. The 30-year-old man returned from Western Europe and contracted the disease from there. The ministry reported that he was in isolation in the Ichilov General Hospital in Tel Aviv . In May and June 2022, two Australians tested positive for mpox in Australia, but before that they stayed in transit in airports for some hours in Southeast Asia . On 30 May, Thai health authorities confirmed that an Australian who stayed in transit in Suvarnabhumi Airport for two hours that week had tested positive for mpox in Australia. On 6 June, the Singaporean Ministry of Health announced that a mpox case in New South Wales in Australia stayed in transit in Singapore on 2 June. 13 people who had casual contact were isolated. A study from the Faculty of Medicine, Chulalongkorn University, Thailand led by Dr Dhammika Leshan Wannigama reported Multiple traces of monkeypox virus were detected in non-sewered wastewater with sparse sampling collected from both the Bangkok, Thailand with increasing concentrations from June to August 2022. This is the first dataset related to monkeypox viral DNA in wastewater in Bangkok. Monkeypox viral DNA was first detected in wastewater in the second week of June 2022. From the first week of July, the number of viral DNA copies increased. Sanger sequencing confirmed the identification of the monkeypox virus and its relation to the 2022–2023 mpox outbreak. The same group later released findings from wastewater surveillance in six Southeast Asian countries (Thailand, Lao PDR, Myanmar, Cambodia, Vietnam, and Indonesia), which showed the presence of Monkeypox virus (MPXV) DNA, suggesting local transmission. This information serves as a vital notification for healthcare professionals and aids in the distribution of resources such as testing, vaccines, and treatments in regions with limited resources. Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases (i.e. Turkey ). Countries listed several times reported suspected cases again after they discarded suspected cases before.According to the World Health Organization , imported cases of mpox from Nigeria was detected in Israel and Singapore in September 2018 and May 2019, respectively. In 2018, an imported case was detected in Israel. A 38-year-old man came from Rivers State , Nigeria in late September. He showed the symptoms of the disease on that month. Later on October the patient sought medical attention at Shaare-Zedek Medical Center in Jerusalem . He was confirmed to be infected with the West African Clade of monkeypox virus that month. All of the patient's contacts were traced and followed up but no virus transmission were detected. As the outbreak was spreading in Europe in the middle of May 2022, the Israeli Health Ministry reported a suspected mpox case in the country on 20 May. The case was confirmed by testing on 21 May, becoming the first case in Israel during the outbreak, which also became the first in Asia. The 30-year-old man returned from Western Europe and contracted the disease from there. The ministry reported that he was in isolation in the Ichilov General Hospital in Tel Aviv . In May and June 2022, two Australians tested positive for mpox in Australia, but before that they stayed in transit in airports for some hours in Southeast Asia . On 30 May, Thai health authorities confirmed that an Australian who stayed in transit in Suvarnabhumi Airport for two hours that week had tested positive for mpox in Australia. On 6 June, the Singaporean Ministry of Health announced that a mpox case in New South Wales in Australia stayed in transit in Singapore on 2 June. 13 people who had casual contact were isolated. A study from the Faculty of Medicine, Chulalongkorn University, Thailand led by Dr Dhammika Leshan Wannigama reported Multiple traces of monkeypox virus were detected in non-sewered wastewater with sparse sampling collected from both the Bangkok, Thailand with increasing concentrations from June to August 2022. This is the first dataset related to monkeypox viral DNA in wastewater in Bangkok. Monkeypox viral DNA was first detected in wastewater in the second week of June 2022. From the first week of July, the number of viral DNA copies increased. Sanger sequencing confirmed the identification of the monkeypox virus and its relation to the 2022–2023 mpox outbreak. The same group later released findings from wastewater surveillance in six Southeast Asian countries (Thailand, Lao PDR, Myanmar, Cambodia, Vietnam, and Indonesia), which showed the presence of Monkeypox virus (MPXV) DNA, suggesting local transmission. This information serves as a vital notification for healthcare professionals and aids in the distribution of resources such as testing, vaccines, and treatments in regions with limited resources. Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases (i.e. Turkey ). Countries listed several times reported suspected cases again after they discarded suspected cases before.Countries listed below had only suspected cases at the time of reporting. Some countries reported confirmed cases after reporting suspected cases (i.e. Turkey ). Countries listed several times reported suspected cases again after they discarded suspected cases before.Several countries have responded to the outbreak. The responses of some of them are listed below.Georgia was the first Caucasian and the third Asian and West Asian country to report confirmed cases of mpox. The first case was reported by the Ministry of Health on 15 June 2022. Israel was the first in both Asia and West Asia to report a case. On 20 May, Israel reported a suspected mpox infected patient who was in isolation in Ichilov Hospital and tested positive on 21 May. On the same day, another suspected case was reported but the case was ruled out the next day, on 22 May. Israel reported a single case each on 28 May and 7, 9, 15 and 16 June until the authorities reported three cases on 20 June. In a press statement released on 21 June, the ministry stated that one of them was infected locally, confirming community transmission of the disease in Israel. The total reached 9 on that day. The case figure was updated regularly and press releases were released on the ministry 's website whenever cases where reported. But after 21 June, the ministry started to release weekly report of the situation on the website. On 15 July, Health Minister Nitzan Horowitz announced that 2,000 mpox vaccines will arrive in Israel, adding that he spoke with biotech company Bavarian Nordic CEO Paul Chaplin. He also said that a total of 90 cases were registered till then, and none of them needed hospitalisation. As of 17 July 2022, 96 confirmed cases were reported in Israel. On 20 June, the first case of mpox in Lebanon was reported by the National News Agency (NNA) stating the Ministry of Health, thus Lebanon became the fourth country in both Asia and West Asia and the third in the Middle East to report a mpox case. On 14 July, the first mpox case was detected in the capital city of Riyadh . The person came from abroad. On 29 May, the Islamic Republic News Agency and other news agencies reported two suspected cases of mpox who came back from Iran in Nimruz Province citing local newspapers and the Ministry of Health and provincial health authorities. On 30 May, one case was reported in Herat Province . On 31 May, ministry spokesperson Javid Hazhir denied reports of confirmed cases and stated that suspected cases in Nimruz and Kabul provinces tested negative. He also said that Afghanistan has the capability to test mpox cases. On 5 June, it was reported that the WHO will give test kits to the Taliban-controlled Ministry of Public Health , as they were lacking kits. Ministry spokesperson stated that suspected cases in Herat , Maidan Wardak and Nangarhar provinces along with other provinces which were stated earlier tested negative and the country is free of mpox. Bangladeshi health authorities declared alert on every ports in the country in mid-May. Shahjalal International Airport in Dhaka was in high alert. On 7 June, a 32-year-old Turkish citizen was detected with mpox symptoms at the airport while screening. He was taken to the Infectious Diseases Hospital in Dhaka's Mohakhali and isolated. Although, on the same day the Ministry of Health and Family Welfare published a press release denying reports of mpox 'confirmed' in a foreigner. On the next day, the DGHS director stated that he investigated the Turkish citizen himself, and his symptoms were not due to mpox, and he was suffering from a skin disease for a long time. On 9 June, the suspected case tested negative. On 10 June, a 60-year-old woman was isolated in Chuadanga after local doctors detected symptoms of mpox on her on 9 June. On the same day, a 42-year-old man who came back from India through Benapole Border Crossing on 3 June, was sent to Jashore Hospital after he showed pox like symptoms. Although, the district civil surgeon said on the next day that he was very probably infected with chickenpox. [ citation needed ] On 12 June, the case in Chuandanga was discarded. Bangladesh was the first country bar shore passes. On late May, Chittagong Seaport authority barred shore passes for all crew unless in the case of an emergency, while signed-off crew will have to undergo health checks. On 21 May, Union Health Minister Mansukh Mandaviya directed the National Centre for Disease Control and the ICMR to keep a close watch and monitor the situation and directed airport and port health officers to be vigilant. They have been instructed to isolate and send samples to the National Institute of Virology (NIV) of any sick passenger with a travel history to infected countries. Many other states also responded individually, including Karnataka , Kerala , Madhya Pradesh , Maharashtra , Rajasthan , Tamil Nadu , Uttar Pradesh , and West Bengal . On 3 June, a sample of a 5-year-old girl of Ghaziabad in Uttar Pradesh who showed some symptoms of mpox were sent to the National Institute of Virology in Pune. The test came back negative on 7 June. [ citation needed ] On 14 July, the health minister of Kerala Veena George announced a suspected case in Kerala . The patient was a male who came back from the United Arab Emirates three days earlier. The patient reportedly died on 31 July, making it the first mpox casualty in India. On 21 June 2022, Singaporean officials reported that a British flight attendant in the country had tested positive for the virus on 20 June. Singapore was the fifth Asian and first Southeast Asian country to report an mpox case during this outbreak. On 6 July, Singaporean authorities confirmed the first case of local transmission. One more imported case was reported each on 7 and 8 July 2022, of which both are conveyed to the National Centre for Infectious Diseases (NCID) . [ citation needed ] On 13 July, the Ministry of Health reported another locally transmitted case, taking the total tally to 5. The patient was a 48-year-old British national residing in Singapore and was also warded in the NCID. Another local case was reported on the next day on 14 July. The patient was a male in his 40s, and was also warded in the NCID. On 21 July 2022, the Thai health ministry reported the first case of mpox in the country. The patient was a 21-year-old Nigerian who stayed in Phuket before crossing the border into Cambodia and subsequently arrested in Phnom Penh . A week later, a second confirmed case was found in Bangkok in a 47-year-old local man who admitted to had engaged in sexual contact with foreign men. On 3 August, a third confirmed case was reported by the Department of Disease Control . The patient was a 25-year-old German man who arrived in Phuket on July 18 as a tourist. On 5 August, the first confirmed case of a female in the country was announced. The patient was a 22-year-old Thai woman who frequented Bangkok night spots. On 15 August, it was reported that the fifth confirmed mpox patient in the country was a 25-year-old Thai woman returning from Dubai. A study from the Faculty of Medicine, Chulalongkorn University, Thailand led by Dr Dhammika Leshan Wannigama reported  Multiple traces of monkeypox virus were detected in non-sewered wastewater in Thailand with increasing concentrations from June to August 2022. On 16 September, China reported its first case of mpox in Chongqing municipality. On 25 July, Japan reported its first case of mpox in a man in his 30s. On 28 July, a second case was reported from a man in his 30s. On 5 August, a third case was reported. On 10 August, a fourth case was reported. On 22 June, South Korea reported its first mpox case. On 24 June 2022, Taiwan reported its first confirmed case of mpox in a 25-year-old Taiwanese man who came back to Taiwan on 16 June after studying in Germany . Domestic transmission of mpox was reported in March 2023, followed by the first Taiwanese death from mpox in November 2023. Taiwan avoided domestic transmission of the disease for fourteen consecutive weeks, until late February 2024. The first mpox case in Russia, and by extension North Asia, was confirmed on 12 July 2022, in a young man who returned from a trip to Europe. Georgia was the first Caucasian and the third Asian and West Asian country to report confirmed cases of mpox. The first case was reported by the Ministry of Health on 15 June 2022. Israel was the first in both Asia and West Asia to report a case. On 20 May, Israel reported a suspected mpox infected patient who was in isolation in Ichilov Hospital and tested positive on 21 May. On the same day, another suspected case was reported but the case was ruled out the next day, on 22 May. Israel reported a single case each on 28 May and 7, 9, 15 and 16 June until the authorities reported three cases on 20 June. In a press statement released on 21 June, the ministry stated that one of them was infected locally, confirming community transmission of the disease in Israel. The total reached 9 on that day. The case figure was updated regularly and press releases were released on the ministry 's website whenever cases where reported. But after 21 June, the ministry started to release weekly report of the situation on the website. On 15 July, Health Minister Nitzan Horowitz announced that 2,000 mpox vaccines will arrive in Israel, adding that he spoke with biotech company Bavarian Nordic CEO Paul Chaplin. He also said that a total of 90 cases were registered till then, and none of them needed hospitalisation. As of 17 July 2022, 96 confirmed cases were reported in Israel. On 20 June, the first case of mpox in Lebanon was reported by the National News Agency (NNA) stating the Ministry of Health, thus Lebanon became the fourth country in both Asia and West Asia and the third in the Middle East to report a mpox case. On 14 July, the first mpox case was detected in the capital city of Riyadh . The person came from abroad. Georgia was the first Caucasian and the third Asian and West Asian country to report confirmed cases of mpox. The first case was reported by the Ministry of Health on 15 June 2022. Israel was the first in both Asia and West Asia to report a case. On 20 May, Israel reported a suspected mpox infected patient who was in isolation in Ichilov Hospital and tested positive on 21 May. On the same day, another suspected case was reported but the case was ruled out the next day, on 22 May. Israel reported a single case each on 28 May and 7, 9, 15 and 16 June until the authorities reported three cases on 20 June. In a press statement released on 21 June, the ministry stated that one of them was infected locally, confirming community transmission of the disease in Israel. The total reached 9 on that day. The case figure was updated regularly and press releases were released on the ministry 's website whenever cases where reported. But after 21 June, the ministry started to release weekly report of the situation on the website. On 15 July, Health Minister Nitzan Horowitz announced that 2,000 mpox vaccines will arrive in Israel, adding that he spoke with biotech company Bavarian Nordic CEO Paul Chaplin. He also said that a total of 90 cases were registered till then, and none of them needed hospitalisation. As of 17 July 2022, 96 confirmed cases were reported in Israel. On 20 June, the first case of mpox in Lebanon was reported by the National News Agency (NNA) stating the Ministry of Health, thus Lebanon became the fourth country in both Asia and West Asia and the third in the Middle East to report a mpox case.On 14 July, the first mpox case was detected in the capital city of Riyadh . The person came from abroad. On 29 May, the Islamic Republic News Agency and other news agencies reported two suspected cases of mpox who came back from Iran in Nimruz Province citing local newspapers and the Ministry of Health and provincial health authorities. On 30 May, one case was reported in Herat Province . On 31 May, ministry spokesperson Javid Hazhir denied reports of confirmed cases and stated that suspected cases in Nimruz and Kabul provinces tested negative. He also said that Afghanistan has the capability to test mpox cases. On 5 June, it was reported that the WHO will give test kits to the Taliban-controlled Ministry of Public Health , as they were lacking kits. Ministry spokesperson stated that suspected cases in Herat , Maidan Wardak and Nangarhar provinces along with other provinces which were stated earlier tested negative and the country is free of mpox. Bangladeshi health authorities declared alert on every ports in the country in mid-May. Shahjalal International Airport in Dhaka was in high alert. On 7 June, a 32-year-old Turkish citizen was detected with mpox symptoms at the airport while screening. He was taken to the Infectious Diseases Hospital in Dhaka's Mohakhali and isolated. Although, on the same day the Ministry of Health and Family Welfare published a press release denying reports of mpox 'confirmed' in a foreigner. On the next day, the DGHS director stated that he investigated the Turkish citizen himself, and his symptoms were not due to mpox, and he was suffering from a skin disease for a long time. On 9 June, the suspected case tested negative. On 10 June, a 60-year-old woman was isolated in Chuadanga after local doctors detected symptoms of mpox on her on 9 June. On the same day, a 42-year-old man who came back from India through Benapole Border Crossing on 3 June, was sent to Jashore Hospital after he showed pox like symptoms. Although, the district civil surgeon said on the next day that he was very probably infected with chickenpox. [ citation needed ] On 12 June, the case in Chuandanga was discarded. Bangladesh was the first country bar shore passes. On late May, Chittagong Seaport authority barred shore passes for all crew unless in the case of an emergency, while signed-off crew will have to undergo health checks. On 21 May, Union Health Minister Mansukh Mandaviya directed the National Centre for Disease Control and the ICMR to keep a close watch and monitor the situation and directed airport and port health officers to be vigilant. They have been instructed to isolate and send samples to the National Institute of Virology (NIV) of any sick passenger with a travel history to infected countries. Many other states also responded individually, including Karnataka , Kerala , Madhya Pradesh , Maharashtra , Rajasthan , Tamil Nadu , Uttar Pradesh , and West Bengal . On 3 June, a sample of a 5-year-old girl of Ghaziabad in Uttar Pradesh who showed some symptoms of mpox were sent to the National Institute of Virology in Pune. The test came back negative on 7 June. [ citation needed ] On 14 July, the health minister of Kerala Veena George announced a suspected case in Kerala . The patient was a male who came back from the United Arab Emirates three days earlier. The patient reportedly died on 31 July, making it the first mpox casualty in India. On 29 May, the Islamic Republic News Agency and other news agencies reported two suspected cases of mpox who came back from Iran in Nimruz Province citing local newspapers and the Ministry of Health and provincial health authorities. On 30 May, one case was reported in Herat Province . On 31 May, ministry spokesperson Javid Hazhir denied reports of confirmed cases and stated that suspected cases in Nimruz and Kabul provinces tested negative. He also said that Afghanistan has the capability to test mpox cases. On 5 June, it was reported that the WHO will give test kits to the Taliban-controlled Ministry of Public Health , as they were lacking kits. Ministry spokesperson stated that suspected cases in Herat , Maidan Wardak and Nangarhar provinces along with other provinces which were stated earlier tested negative and the country is free of mpox. Bangladeshi health authorities declared alert on every ports in the country in mid-May. Shahjalal International Airport in Dhaka was in high alert. On 7 June, a 32-year-old Turkish citizen was detected with mpox symptoms at the airport while screening. He was taken to the Infectious Diseases Hospital in Dhaka's Mohakhali and isolated. Although, on the same day the Ministry of Health and Family Welfare published a press release denying reports of mpox 'confirmed' in a foreigner. On the next day, the DGHS director stated that he investigated the Turkish citizen himself, and his symptoms were not due to mpox, and he was suffering from a skin disease for a long time. On 9 June, the suspected case tested negative. On 10 June, a 60-year-old woman was isolated in Chuadanga after local doctors detected symptoms of mpox on her on 9 June. On the same day, a 42-year-old man who came back from India through Benapole Border Crossing on 3 June, was sent to Jashore Hospital after he showed pox like symptoms. Although, the district civil surgeon said on the next day that he was very probably infected with chickenpox. [ citation needed ] On 12 June, the case in Chuandanga was discarded. Bangladesh was the first country bar shore passes. On late May, Chittagong Seaport authority barred shore passes for all crew unless in the case of an emergency, while signed-off crew will have to undergo health checks. On 21 May, Union Health Minister Mansukh Mandaviya directed the National Centre for Disease Control and the ICMR to keep a close watch and monitor the situation and directed airport and port health officers to be vigilant. They have been instructed to isolate and send samples to the National Institute of Virology (NIV) of any sick passenger with a travel history to infected countries. Many other states also responded individually, including Karnataka , Kerala , Madhya Pradesh , Maharashtra , Rajasthan , Tamil Nadu , Uttar Pradesh , and West Bengal . On 3 June, a sample of a 5-year-old girl of Ghaziabad in Uttar Pradesh who showed some symptoms of mpox were sent to the National Institute of Virology in Pune. The test came back negative on 7 June. [ citation needed ] On 14 July, the health minister of Kerala Veena George announced a suspected case in Kerala . The patient was a male who came back from the United Arab Emirates three days earlier. The patient reportedly died on 31 July, making it the first mpox casualty in India. On 21 June 2022, Singaporean officials reported that a British flight attendant in the country had tested positive for the virus on 20 June. Singapore was the fifth Asian and first Southeast Asian country to report an mpox case during this outbreak. On 6 July, Singaporean authorities confirmed the first case of local transmission. One more imported case was reported each on 7 and 8 July 2022, of which both are conveyed to the National Centre for Infectious Diseases (NCID) . [ citation needed ] On 13 July, the Ministry of Health reported another locally transmitted case, taking the total tally to 5. The patient was a 48-year-old British national residing in Singapore and was also warded in the NCID. Another local case was reported on the next day on 14 July. The patient was a male in his 40s, and was also warded in the NCID. On 21 July 2022, the Thai health ministry reported the first case of mpox in the country. The patient was a 21-year-old Nigerian who stayed in Phuket before crossing the border into Cambodia and subsequently arrested in Phnom Penh . A week later, a second confirmed case was found in Bangkok in a 47-year-old local man who admitted to had engaged in sexual contact with foreign men. On 3 August, a third confirmed case was reported by the Department of Disease Control . The patient was a 25-year-old German man who arrived in Phuket on July 18 as a tourist. On 5 August, the first confirmed case of a female in the country was announced. The patient was a 22-year-old Thai woman who frequented Bangkok night spots. On 15 August, it was reported that the fifth confirmed mpox patient in the country was a 25-year-old Thai woman returning from Dubai. A study from the Faculty of Medicine, Chulalongkorn University, Thailand led by Dr Dhammika Leshan Wannigama reported  Multiple traces of monkeypox virus were detected in non-sewered wastewater in Thailand with increasing concentrations from June to August 2022. On 21 June 2022, Singaporean officials reported that a British flight attendant in the country had tested positive for the virus on 20 June. Singapore was the fifth Asian and first Southeast Asian country to report an mpox case during this outbreak. On 6 July, Singaporean authorities confirmed the first case of local transmission. One more imported case was reported each on 7 and 8 July 2022, of which both are conveyed to the National Centre for Infectious Diseases (NCID) . [ citation needed ] On 13 July, the Ministry of Health reported another locally transmitted case, taking the total tally to 5. The patient was a 48-year-old British national residing in Singapore and was also warded in the NCID. Another local case was reported on the next day on 14 July. The patient was a male in his 40s, and was also warded in the NCID. On 21 July 2022, the Thai health ministry reported the first case of mpox in the country. The patient was a 21-year-old Nigerian who stayed in Phuket before crossing the border into Cambodia and subsequently arrested in Phnom Penh . A week later, a second confirmed case was found in Bangkok in a 47-year-old local man who admitted to had engaged in sexual contact with foreign men. On 3 August, a third confirmed case was reported by the Department of Disease Control . The patient was a 25-year-old German man who arrived in Phuket on July 18 as a tourist. On 5 August, the first confirmed case of a female in the country was announced. The patient was a 22-year-old Thai woman who frequented Bangkok night spots. On 15 August, it was reported that the fifth confirmed mpox patient in the country was a 25-year-old Thai woman returning from Dubai. A study from the Faculty of Medicine, Chulalongkorn University, Thailand led by Dr Dhammika Leshan Wannigama reported  Multiple traces of monkeypox virus were detected in non-sewered wastewater in Thailand with increasing concentrations from June to August 2022. On 16 September, China reported its first case of mpox in Chongqing municipality. On 25 July, Japan reported its first case of mpox in a man in his 30s. On 28 July, a second case was reported from a man in his 30s. On 5 August, a third case was reported. On 10 August, a fourth case was reported. On 22 June, South Korea reported its first mpox case. On 24 June 2022, Taiwan reported its first confirmed case of mpox in a 25-year-old Taiwanese man who came back to Taiwan on 16 June after studying in Germany . Domestic transmission of mpox was reported in March 2023, followed by the first Taiwanese death from mpox in November 2023. Taiwan avoided domestic transmission of the disease for fourteen consecutive weeks, until late February 2024.On 16 September, China reported its first case of mpox in Chongqing municipality. On 25 July, Japan reported its first case of mpox in a man in his 30s. On 28 July, a second case was reported from a man in his 30s. On 5 August, a third case was reported. On 10 August, a fourth case was reported.On 22 June, South Korea reported its first mpox case.On 24 June 2022, Taiwan reported its first confirmed case of mpox in a 25-year-old Taiwanese man who came back to Taiwan on 16 June after studying in Germany . Domestic transmission of mpox was reported in March 2023, followed by the first Taiwanese death from mpox in November 2023. Taiwan avoided domestic transmission of the disease for fourteen consecutive weeks, until late February 2024.The first mpox case in Russia, and by extension North Asia, was confirmed on 12 July 2022, in a young man who returned from a trip to Europe. This is a table of confirmed and suspected mpox cases in Asian countries during the ongoing 2022–2023 mpox outbreak . It does not include countries where suspected cases were reported but later discarded such as Afghanistan. (These graphs excludes the cases reported in Russia) (A week is considered Saturday to Friday here) (A week is considered Saturday to Friday here)This is a table of confirmed and suspected mpox cases in Asian countries during the ongoing 2022–2023 mpox outbreak . It does not include countries where suspected cases were reported but later discarded such as Afghanistan. (These graphs excludes the cases reported in Russia) (A week is considered Saturday to Friday here) (A week is considered Saturday to Friday here)(A week is considered Saturday to Friday here)(A week is considered Saturday to Friday here)

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Orthopoxvirus

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2022–2023 mpox outbreak in Switzerland

The 2022–2023 mpox outbreak in Switzerland is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus . The outbreak started in Switzerland on 19 May 2022, with the country since then becoming one of the most affected in Europe .Mpox (formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes . The illness is usually mild and most of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems. An ongoing outbreak of mpox was confirmed on 6 May 2022, beginning with a British resident who, after travelling to Nigeria (where the disease is endemic ), presented symptoms consistent with mpox on 29 April 2022. The resident returned to the United Kingdom on 4 May, creating the country's index case of the outbreak. The origin of several of the cases of mpox in the United Kingdom is unknown. Some monitors saw community transmission taking place in the London area as of mid-May, but it has been suggested that cases were already spreading in Europe in the previous months. A large portion of those infected were believed to have not recently traveled to areas of Africa where mpox is normally found, such as Nigeria , the Democratic Republic of the Congo as well as central and western Africa . It is believed to be transmitted by close contact with sick people, with extra caution for those individuals with lesions on their skin or genitals, along with their bedding and clothing. The CDC has also stated that individuals should avoid contact and consumption of dead animals such as rats, squirrels, monkeys and apes along with wild game or lotions derived from animals in Africa. In addition to more common symptoms, such as fever, headache, swollen lymph nodes, and rashes or lesions, some patients have also experienced proctitis, an inflammation of the rectum lining. CDC has also warned clinicians to not rule out mpox in patients with sexually transmitted infections since there have been reports of co-infections with syphilis , gonorrhea , chlamydia , and herpes . As of 22 August 2022, there have been 416 laboratory-confirmed cases of mpox in Switzerland. On 24 August 2022, the Swiss Federal Council decided to order 40,000 vaccine doses from Bavarian Nordic .

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Orthopoxvirus

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Isao Arita

Isao Arita ( 蟻田 功 , Arita Isao , 1926 – 17 March 2023) was a Japanese physician, virologist and vaccination specialist who headed the World Health Organization (WHO) Smallpox Eradication Unit in 1977–85. During this period, smallpox became the first infectious disease of humans to be eradicated globally. For this work, he and his colleagues were awarded the Japan Prize in 1988. He also advised the successful programme to eradicate poliovirus from the Western Pacific region.Arita was born in Kumamoto , southern Japan, in 1926. After gaining his medical degree from Kumamoto Medical School in 1950, he spent a decade working for the Japanese Ministry of Health and Welfare as a medical officer in the Infectious Disease Control section. For part of this time he worked on vaccine control and standardisation, an area in which he received training at the Paul Ehrlich Institute in Germany. Arita's work for the WHO smallpox eradication programme started in 1962. He spent around 2 years working on eradication in Liberia, Africa. When American epidemiologist Donald A. Henderson joined the programme in 1966, Arita was the only remaining WHO technical staff member. He was a part of the WHO Smallpox Eradication Unit from its inception in 1966, serving as its deputy director under Henderson's leadership. He was responsible for developing the programme's "surveillance and containment" strategy (which replaced the unsuccessful strategy of attempting to vaccinate at least 80% of the population), as well as for increasing the supply of smallpox vaccine used by the eradication programme, and for monitoring and improving vaccine quality. He also undertook research into poxviruses , particularly monkeypox virus . After Henderson left WHO in 1976 or 1977, Arita went on to direct the unit. Under his leadership an outbreak of variola minor in the Horn of Africa during the Ethiopian–Somali war was successfully contained, and the final case of naturally transmitted smallpox occurred in October 1977. He administered the process by which smallpox was formally certified by WHO as having been eradicated globally in May 1980. After certification, he managed the implementation of the certifying commission's recommendations. He continued to direct the unit's international surveillance activities. He was also involved in formulating policies on issues including ongoing vaccination and laboratory stocks of variola virus , and in archiving WHO's data on the eradication programme. In 1999, he was one of several scientists to argue for the destruction of the remaining stocks of variola virus. Arita was one of the lead authors, with Frank Fenner and Henderson, of the WHO publication Smallpox and its Eradication , an exhaustive 1460-page volume which was published in January 1988. Arita also wrote his own personal account in the 2010 book, The Smallpox Eradication Saga. An Insider's View . In 1985, Arita left WHO to direct the Kumamoto National Hospital in Japan, a position he retained until his retirement in 1992. He advised Morihiro Hosokawa (then governor of the Kumamoto prefecture) on the foundation of the Agency for Cooperation in International Health (ACIH) in 1990, and became its chair in 1993. The ACIH's aim is to promote disease prevention in developing countries, and the body has organised international conferences on vaccines and other topics. In the early 1990s, Arita called international attention to the issues surrounding the supply of vaccines and vaccine quality in developing countries, and advocated for these countries to move towards being self-sufficient in vaccine production. From 1990 until 2004, he chaired the Technical Advisory Group to WHO's Expanded Programme on Immunization and Poliomyelitis Eradication in the Western Pacific Region. The programme was successful in eradicating wild poliovirus from this region in 1997. He also served on the expert committee that certified the eradication of wild poliovirus from North and South America in 1997. Despite these regional successes, the global eradication of polio – planned for 2000 – has yet to be achieved. In 2006, with Fenner and Miyuki Nakane, Arita published an opinion piece in the journal Science that questioned whether it was feasible to eradicate polio globally, and suggested that control might be a preferable option. Arita also published on severe acute respiratory syndrome , measles , hepatitis B , hepatitis C and other viral diseases. Arita died on 17 March 2023, at the age of 96. In 1988, Arita, together with Henderson and Fenner, was awarded the Japan Prize – considered the Japanese equivalent of the Nobel Prize – for his work on smallpox eradication. The Japanese government conferred on him the title of "national treasure". Books Articles

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Orthopoxvirus

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List of MeSH codes (B04)

The following is a partial list of the "B" codes for Medical Subject Headings (MeSH), as defined by the United States National Library of Medicine (NLM). This list continues the information at List of MeSH codes (B03) . Codes following these are found at List of MeSH codes (B05) . For other MeSH codes, see List of MeSH codes . The source for this content is the set of 2006 MeSH Trees from the NLM.The list continues at List of MeSH codes (B05) .The list continues at List of MeSH codes (B05) .The list continues at List of MeSH codes (B05) .

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Acute hemorrhagic fever syndrome

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Hantavirus hemorrhagic fever with renal syndrome

Hantavirus hemorrhagic fever with renal syndrome ( HFRS ) is a group of clinically similar illnesses caused by species of hantaviruses . It is also known as Korean hemorrhagic fever and epidemic hemorrhagic fever . It is found in Europe, Asia, and Africa. The species that cause HFRS include Hantaan orthohantavirus , Dobrava-Belgrade orthohantavirus , Saaremaa virus , Seoul orthohantavirus , Puumala orthohantavirus and other orthohantaviruses. Of these species, Hantaan River virus and Dobrava-Belgrade virus cause the most severe form of the syndrome and have the highest morbidity rates. When caused by the Puumala virus, it is also called nephropathia epidemica . This infection is known as sorkfeber (vole fever) in Swedish, myyräkuume (vole fever) in Finnish, and musepest (mouse plague) in Norwegian. Both HFRS and hantavirus pulmonary syndrome (HPS) are caused by hantaviruses, specifically when humans inhale aerosolized excrements of infected rodents. Both diseases appear to be immunopathologic , and inflammatory mediators are important in causing the clinical manifestations. Symptoms of HFRS usually develop within one to two weeks after exposure to infectious material, but in rare cases, they may take up to eight weeks to develop. In Nephropathia epidemica, the incubation period is three weeks. Initial symptoms begin suddenly and include intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision. Individuals may have flushing of the face, inflammation or redness of the eyes, or a rash. Later symptoms can include low blood pressure, acute shock, vascular leakage, and acute kidney failure, which can cause severe fluid overload. The severity of the disease varies depending upon the virus causing the infection. Hantaan and Dobrava virus infections usually cause severe symptoms, while Seoul, Saaremaa, and Puumala virus infections are usually more moderate. Complete recovery can take weeks or months. The course of the illness can be split into five phases: This syndrome can also be fatal. In some cases, it has been known to cause permanent renal failure. Hantaviruses infect various rodents, generally without causing disease. Transmission by aerosolized rodent excreta still remains the only known way the virus is transmitted to humans. In general, droplet and/or fomite transfer has not been shown in the hantaviruses in either the pulmonary or hemorrhagic forms. For Nephropathia epidemica, the bank vole is the reservoir for the virus, which humans contract through inhalation of aerosolised vole droppings. HFRS is difficult to diagnose on clinical grounds alone and serological evidence is often needed. A fourfold rise in IgG antibody titer in a one-week interval and the presence of the IgM type of antibodies against hantaviruses are good evidence for an acute hantavirus infection. HFRS should be suspected in patients with acute febrile flu-like illness, kidney failure of unknown origin and sometimes liver dysfunction. Rodent control in and around the home remains the primary prevention strategy, as well as eliminating contact with rodents in the workplace and campsite. Closed storage sheds and cabins are often ideal sites for rodent infestations. Airing out of such spaces prior to use is recommended. Avoid direct contact with rodent droppings and wear a mask to avoid inhalation of aerosolized rodent secretions. There is no cure for HFRS. Treatment involves supportive therapy including renal dialysis. Treatment with ribavirin in China and Korea, administered within seven days of onset of fever, resulted in a reduced mortality as well as shortened course of illness. HFRS is primarily a Eurasian disease, whereas HPS appears to be confined to the Americas. The geography is directly related to the indigenous rodent hosts and the viruses that coevolved with them. Although fatal in a small percentage of cases, nephropathia epidemica is generally milder than the HFRS that is caused by hantaviruses in other parts of the world. HFRS was the subject of an episode of the television series M*A*S*H. In season 8, episode 9 the 4077th dealt with a condition, with similar symptoms to HFRS, called "Korean Hemorrhagic Fever".

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Acute hemorrhagic fever syndrome

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Viral hemorrhagic fever

Viral hemorrhagic fevers ( VHFs ) are a diverse group of animal and human illnesses . VHFs may be caused by five distinct families of RNA viruses : the families Filoviridae , Flaviviridae , Rhabdoviridae , and several member families of the Bunyavirales order such as Arenaviridae , and Hantaviridae . All types of VHF are characterized by fever and bleeding disorders and all can progress to high fever, shock and death in many cases. Some of the VHF agents cause relatively mild illnesses, such as the Scandinavian nephropathia epidemica (a hantavirus ), while others, such as Ebola virus , can cause severe, life-threatening disease.Signs and symptoms of VHFs include (by definition) fever and bleeding: The severity of symptoms varies with the type of virus. The "VHF syndrome" (capillary leak, bleeding diathesis , and circulatory compromise leading to shock) appears in a majority of people with filoviral hemorrhagic fevers (e.g., Ebola and Marburg virus ), Crimean–Congo hemorrhagic fever (CCHF), and the South American hemorrhagic fevers caused by arenaviruses , but only in a small minority of patients with dengue or Rift Valley fever .Five families of RNA viruses have been recognised as being able to cause hemorrhagic fevers. [ citation needed ] The pathogen that caused the cocoliztli epidemics in Mexico of 1545 and 1576 is still unknown, and the 1545 epidemic may have been bacterial rather than viral. Different hemorrhagic fever viruses act on the body in different ways, resulting in different symptoms. In most VHFs, it is likely that several mechanisms contribute to symptoms, including liver damage, disseminated intravascular coagulation (DIC), and bone marrow dysfunction. In DIC, small blood clots form in blood vessels throughout the body, removing platelets necessary for clotting from the bloodstream and reducing clotting ability. DIC is thought to cause bleeding in Rift Valley, Marburg, and Ebola fevers. For filoviral hemorrhagic fevers, there are four general mechanisms of pathogenesis. The first mechanism is dissemination of virus due to suppressed responses by macrophages and dendritic cell (antigen presenting cells). The second mechanism is prevention of antigen specific immune response. The third mechanism is apoptosis of lymphocytes. The fourth mechanism is when infected macrophages interact with toxic cytokines , leading to diapedesis and coagulation deficiency. From the vascular perspective, the virus will infect vascular endothelial cells, leading to the reorganization of the VE-cadherin catenin complex (a protein important in cell adhesion). This reorganization creates intercellular gaps in endothelial cells. The gaps lead to increased endothelial permeability and allow blood to escape from the vascular circulatory system. [ citation needed ] The reasons for variation among patients infected with the same virus are unknown but stem from a complex system of virus-host interactions. Dengue fever becomes more virulent during a second infection by means of antibody-dependent enhancement . After the first infection, macrophages display antibodies on their cell membranes specific to the dengue virus. By attaching to these antibodies, dengue viruses from a second infection are better able to infect the macrophages, thus reducing the immune system's ability to fight off infection. [ citation needed ]Definitive diagnosis is usually made at a reference laboratory with advanced biocontainment capabilities. The findings of laboratory investigation vary somewhat between the viruses but in general, there is a decrease in the total white cell count (particularly the lymphocytes ), a decrease in the platelet count, an increase in the blood serum liver enzymes , and reduced blood clotting ability measured as an increase in both the prothrombin (PT) and activated partial thromboplastin times (PTT). The hematocrit may be elevated. The serum urea and creatine may be raised but this is dependent on the hydration status of the patient. The bleeding time tends to be prolonged. [ citation needed ]With the exception of yellow fever vaccine and Ebola vaccines , vaccines for VHF-associated viruses are generally not available. Post-exposure prophylactic (preventive) ribavirin may be effective for some bunyavirus and arenavirus infections. VHF isolation guidelines dictate that all VHF patients (with the exception of dengue patients) should be cared for using strict contact precautions, including hand hygiene, double gloves, gowns, shoe and leg coverings, and face shield or goggles. Lassa, CCHF, Ebola, and Marburg viruses may be particularly prone to nosocomial (hospital-based) spread. Airborne precautions should be utilized including, at a minimum, a fit-tested , HEPA filter-equipped respirator (such as an N95 mask ), a battery-powered, air-purifying respirator, or a positive pressure supplied air respirator to be worn by personnel coming within 1.8 meter (six feet) of a VHF patient. Groups of patients should be cohorted (sequestered) to a separate building or a ward with an isolated air-handling system. Environmental decontamination is typically accomplished with hypochlorite (e.g. bleach) or phenolic disinfectants . Medical management of VHF patients may require intensive supportive care. Antiviral therapy with intravenous ribavirin may be useful in Bunyaviridae and Arenaviridae infections (specifically Lassa fever, RVF, CCHF, and HFRS due to Old World Hantavirus infection) and can be used only under an experimental protocol as IND approved by the U.S. Food and Drug Administration (FDA). Interferon may be effective in Argentine or Bolivian hemorrhagic fevers (also available only as IND). [ citation needed ]The VHF viruses are spread in a variety of ways. Some may be transmitted to humans through a respiratory route. [ citation needed ] The virus is considered by military medical planners to have a potential for aerosol dissemination, weaponization, or likelihood for confusion with similar agents that might be weaponized.

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Acute hemorrhagic fever syndrome

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Marburg virus disease

Marburg virus disease ( MVD ; formerly Marburg hemorrhagic fever ) is a viral hemorrhagic fever in human and non-human primates caused by either of the two Marburgviruses : Marburg virus (MARV) and Ravn virus (RAVV). Its clinical symptoms are very similar to those of Ebola virus disease (EVD). Egyptian fruit bats are believed to be the normal carrier in nature and Marburg virus RNA has been isolated from them. The most detailed study on the frequency, onset, and duration of MVD clinical signs and symptoms was performed during the 1998–2000 mixed MARV/RAVV disease outbreak. A skin rash , red or purple spots (e.g. petechiae or purpura ), bruises , and hematomas (especially around needle injection sites) are typical hemorrhagic manifestations. However, contrary to popular belief, hemorrhage does not lead to hypovolemia and is not the cause of death (total blood loss is minimal except during labor ). Instead, death occurs due to multiple organ dysfunction syndrome (MODS) due to fluid redistribution, hypotension , disseminated intravascular coagulation , and focal tissue necroses . Clinical phases of Marburg hemorrhagic fever's presentation are described below. Note that phases overlap due to variability between cases.MVD is caused by two viruses; Marburg virus (MARV) and Ravn virus (RAVV) , family Filoviridae. : 458 Marburgviruses are endemic in arid woodlands of equatorial Africa . Most marburgvirus infections were repeatedly associated with people visiting natural caves or working in mines . In 2009, the successful isolation of infectious MARV and RAVV was reported from healthy Egyptian fruit bat caught in caves. This isolation strongly suggests that Old World fruit bats are involved in the natural maintenance of marburgviruses and that visiting bat-infested caves is a risk factor for acquiring marburgvirus infections. Further studies are necessary to establish whether Egyptian rousettes are the actual hosts of MARV and RAVV or whether they get infected via contact with another animal and therefore serve only as intermediate hosts. Another risk factor is contact with nonhuman primates, although only one outbreak of MVD (in 1967) was due to contact with infected monkeys. Contrary to Ebola virus disease (EVD) , which has been associated with heavy rains after long periods of dry weather, triggering factors for spillover of marburgviruses into the human population have not yet been described.MVD is clinically indistinguishable from Ebola virus disease (EVD) , and it can also easily be confused with many other diseases prevalent in Equatorial Africa , such as other viral hemorrhagic fevers , falciparum malaria , typhoid fever , shigellosis , rickettsial diseases such as typhus , cholera , gram-negative sepsis , borreliosis such as relapsing fever or EHEC enteritis . Other infectious diseases that ought to be included in the differential diagnosis include leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , hemorrhagic smallpox , measles , and fulminant viral hepatitis . Non-infectious diseases that can be confused with MVD are acute promyelocytic leukemia , hemolytic uremic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary hemorrhagic telangiectasia , Kawasaki disease , and even warfarin intoxication. The most important indicator that may lead to the suspicion of MVD at clinical examination is the medical history of the patient, in particular the travel and occupational history (which countries and caves were visited?) and the patient's exposure to wildlife (exposure to bats or bat excrements?). MVD can be confirmed by isolation of marburgviruses from or by detection of marburgvirus antigen or genomic or subgenomic RNAs in patient blood or serum samples during the acute phase of MVD. Marburgvirus isolation is usually performed by inoculation of grivet kidney epithelial Vero E6 or MA-104 cell cultures or by inoculation of human adrenal carcinoma SW-13 cells, all of which react to infection with characteristic cytopathic effects . Filovirions can easily be visualized and identified in cell culture by electron microscopy due to their unique filamentous shapes, but electron microscopy cannot differentiate the various filoviruses alone despite some overall length differences. Immunofluorescence assays are used to confirm marburgvirus presence in cell cultures. During an outbreak, virus isolation and electron microscopy are most often not feasible options. The most common diagnostic methods are therefore RT-PCR in conjunction with antigen-capture ELISA , which can be performed in field or mobile hospitals and laboratories. Indirect immunofluorescence assays (IFAs) are not used for diagnosis of MVD in the field anymore. [ citation needed ] Marburg virus disease (MVD) is the official name listed in the World Health Organization 's International Statistical Classification of Diseases and Related Health Problems 10 (ICD-10) for the human disease caused by any of the two marburgviruses Marburg virus (MARV) and Ravn virus (RAVV). In the scientific literature, Marburg hemorrhagic fever (MHF) is often used as an unofficial alternative name for the same disease. Both disease names are derived from the German city Marburg , where MARV was first discovered. Marburg virus disease (MVD) is the official name listed in the World Health Organization 's International Statistical Classification of Diseases and Related Health Problems 10 (ICD-10) for the human disease caused by any of the two marburgviruses Marburg virus (MARV) and Ravn virus (RAVV). In the scientific literature, Marburg hemorrhagic fever (MHF) is often used as an unofficial alternative name for the same disease. Both disease names are derived from the German city Marburg , where MARV was first discovered. The details of the initial transmission of MVD to humans remain incompletely understood. Transmission most likely occurs from Egyptian fruit bats or another natural host, such as non-human primates or through the consumption of bushmeat , but the specific routes and body fluids involved are unknown. Human-to-human transmission of MVD occurs through direct contact with infected bodily fluids such as blood. Transmission events are relatively rare – there have been only 11 recorded outbreaks of MARV between 1975 and 2011, with one event involving both MARV and RAVV. There are currently no Food and Drug Administration -approved vaccines for the prevention of MVD. Many candidate vaccines have been developed and tested in various animal models. Of those, the most promising ones are DNA vaccines or based on Venezuelan equine encephalitis virus replicons , vesicular stomatitis Indiana virus (VSIV) or filovirus-like particles (VLPs) as all of these candidates could protect nonhuman primates from marburgvirus-induced disease. DNA vaccines have entered clinical trials. Marburgviruses are highly infectious , but not very contagious . They do not get transmitted by aerosol during natural MVD outbreaks. Due to the absence of an approved vaccine, prevention of MVD therefore relies predominantly on quarantine of confirmed or high probability cases, proper personal protective equipment , and sterilization and disinfection . [ citation needed ] The natural maintenance hosts of marburgviruses remain to be identified unequivocally. However, the isolation of both MARV and RAVV from bats and the association of several MVD outbreaks with bat-infested mines or caves strongly suggests that bats are involved in Marburg virus transmission to humans. Avoidance of contact with bats and abstaining from visits to caves is highly recommended, but may not be possible for those working in mines or people dependent on bats as a food source. [ citation needed ] Since marburgviruses are not spread via aerosol, the most straightforward prevention method during MVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids , and any possibly contaminated materials and utensils. Patients should be isolated, but still are safe to be visited by family members. Medical staff should be trained in and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, should be discouraged or modified, ideally with the help of local traditional healers . Marburgviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment , laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.The natural maintenance hosts of marburgviruses remain to be identified unequivocally. However, the isolation of both MARV and RAVV from bats and the association of several MVD outbreaks with bat-infested mines or caves strongly suggests that bats are involved in Marburg virus transmission to humans. Avoidance of contact with bats and abstaining from visits to caves is highly recommended, but may not be possible for those working in mines or people dependent on bats as a food source. [ citation needed ]Since marburgviruses are not spread via aerosol, the most straightforward prevention method during MVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids , and any possibly contaminated materials and utensils. Patients should be isolated, but still are safe to be visited by family members. Medical staff should be trained in and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, should be discouraged or modified, ideally with the help of local traditional healers . Marburgviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment , laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.There is currently no effective marburgvirus-specific therapy for MVD. Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and electrolytes to counter dehydration , administration of anticoagulants early in infection to prevent or control disseminated intravascular coagulation , administration of procoagulants late in infection to control hemorrhaging , maintaining oxygen levels, pain management , and administration of antibiotics or antifungals to treat secondary infections. Although supportive care can improve survival chances, marburg virus disease is fatal in the majority of cases. As of 2023 [ update ] the case fatality rate was assessed to be 61.9%. The WHO identifies marburg virus disease as having pandemic potential. Below is a table of outbreaks concerning MVD from 1967 to 2023: MVD was first documented in 1967, when 31 people became ill in the German towns of Marburg and Frankfurt am Main , and in Belgrade , Yugoslavia . The outbreak involved 25 primary MARV infections and seven deaths, and six nonlethal secondary cases. The outbreak was traced to infected grivets (species Chlorocebus aethiops ) imported from an undisclosed location in Uganda and used in developing poliomyelitis vaccines . The monkeys were received by Behringwerke, a Marburg company founded by the first winner of the Nobel Prize in Medicine , Emil von Behring . The company, which at the time was owned by Hoechst , was originally set up to develop sera against tetanus and diphtheria . Primary infections occurred in Behringwerke laboratory staff while working with grivet tissues or tissue cultures without adequate personal protective equipment . Secondary cases involved two physicians , a nurse , a post-mortem attendant, and the wife of a veterinarian . All secondary cases had direct contact, usually involving blood, with a primary case. Both physicians became infected through accidental skin pricks when drawing blood from patients. In 1975, an Australian tourist became infected with MARV in Rhodesia (today Zimbabwe ). He died in a hospital in Johannesburg , South Africa . His girlfriend and an attending nurse were subsequently infected with MVD, but survived. A case of MARV infection occurred in 1980 in Kenya . A French man, who worked as an electrical engineer in a sugar factory in Nzoia (close to Bungoma ) at the base of Mount Elgon (which contains Kitum Cave ), became infected by unknown means and died on 15 January shortly after admission to Nairobi Hospital. The attending physician contracted MVD, but survived. A popular science account of these cases can be found in Richard Preston 's book The Hot Zone (the French man is referred to under the pseudonym "Charles Monet", whereas the physician is identified under his real name, Shem Musoke). In 1987, a single lethal case of RAVV infection occurred in a 15-year-old Danish boy, who spent his vacation in Kisumu , Kenya . He had visited Kitum Cave on Mount Elgon prior to travelling to Mombasa , where he developed clinical signs of infection. The boy died after transfer to Nairobi Hospital. A popular science account of this case can be found in Richard Preston 's book The Hot Zone (the boy is referred to under the pseudonym "Peter Cardinal"). In 1988, researcher Nikolai Ustinov infected himself lethally with MARV after accidentally pricking himself with a syringe used for inoculation of guinea pigs . The accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR (today Russia ). Very little information is publicly available about this MVD case because Ustinov's experiments were classified. A popular science account of this case can be found in Ken Alibek 's book Biohazard . Another laboratory accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR , when a scientist contracted MARV by unknown means. A major MVD outbreak occurred among illegal gold miners around Goroumbwa mine in Durba and Watsa , Democratic Republic of Congo from 1998 to 2000, when co-circulating MARV and RAVV caused 154 cases of MVD and 128 deaths. The outbreak ended with the flooding of the mine. In early 2005, the World Health Organization (WHO) began investigating an outbreak of viral hemorrhagic fever in Angola , which was centered in the northeastern Uíge Province but also affected many other provinces. The Angolan government had to ask for international assistance, pointing out that there were only approximately 1,200 doctors in the entire country, with some provinces having as few as two. Health care workers also complained about a shortage of personal protective equipment such as gloves, gowns, and masks. Médecins Sans Frontières (MSF) reported that when their team arrived at the provincial hospital at the center of the outbreak, they found it operating without water and electricity . Contact tracing was complicated by the fact that the country's roads and other infrastructure were devastated after nearly three decades of civil war and the countryside remained littered with land mines . Americo Boa Vida Hospital in the Angolan capital Luanda set up a special isolation ward to treat infected people from the countryside. Unfortunately, because MVD often results in death, some people came to view hospitals and medical workers with suspicion and treated helpers with hostility. For instance, a specially-equipped isolation ward at the provincial hospital in Uíge was reported to be empty during much of the epidemic, even though the facility was at the center of the outbreak. WHO was forced to implement what it described as a "harm reduction strategy", which entailed distributing disinfectants to affected families who refused hospital care. Of the 252 people who contracted MVD during outbreak, 227 died. In 2007, four miners became infected with marburgviruses in Kamwenge District , Uganda . The first case, a 29-year-old man, became symptomatic on July 4, 2007, was admitted to a hospital on July 7, and died on July 13. Contact tracing revealed that the man had had prolonged close contact with two colleagues (a 22-year-old man and a 23-year-old man), who experienced clinical signs of infection before his disease onset. Both men had been admitted to hospitals in June and survived their infections, which were proven to be due to MARV. A fourth, 25-year-old man, developed MVD clinical signs in September and was shown to be infected with RAVV. He also survived the infection. On July 10, 2008, the Netherlands National Institute for Public Health and the Environment reported that a 41-year-old Dutch woman, who had visited Python Cave in Maramagambo Forest during her holiday in Uganda , had MVD due to MARV infection, and had been admitted to a hospital in the Netherlands . The woman died under treatment in the Leiden University Medical Centre in Leiden on July 11. The Ugandan Ministry of Health closed the cave after this case. On January 9 of that year an infectious diseases physician notified the Colorado Department of Public Health and the Environment that a 44-year-old American woman who had returned from Uganda had been hospitalized with a fever of unknown origin . At the time, serologic testing was negative for viral hemorrhagic fever . She was discharged on January 19, 2008. After the death of the Dutch patient and the discovery that the American woman had visited Python Cave, further testing confirmed the patient demonstrated MARV antibodies and RNA . In October 2017 an outbreak of Marburg virus disease was detected in Kween District , Eastern Uganda. All three initial cases (belonging to one family – two brothers and one sister) had died by 3 November. The fourth case – a health care worker – developed symptoms on 4 November and was admitted to a hospital. The first confirmed case traveled to Kenya before the death. A close contact of the second confirmed case traveled to Kampala . It is reported that several hundred people may have been exposed to infection. In August 2021, two months after the re-emergent Ebola epidemic in the Guéckédou prefecture was declared over, a case of the Marburg disease was confirmed by health authorities through laboratory analysis. Other potential case of the disease in a contact awaits official results. This was the first case of the Marburg hemorrhagic fever confirmed to happen in West Africa. The case of Marburg also has been identified in Guéckédou . During the outbreak, a total of one confirmed case, who died ( CFR =100%), and 173 contacts were identified, including 14 high-risk contacts based on exposure. Among them, 172 were followed for a period of 21 days, of which none developed symptoms. One high-risk contact was lost to follow up. Sequencing of an isolate from the Guinean patient showed that this outbreak was caused by the Angola-like Marburg virus. A colony of Egyptian rousettus bats ( reservoir host of Marburg virus ) was found in close proximity (4.5 km) to the village, where the Marburg virus disease outbreak emerged in 2021. Two sampled fruit bats from this colony were PCR-positive on the Marburg virus. In July 2022, preliminary analysis of samples taken from two patients – both deceased – in Ghana indicated the cases were positive for Marburg. However, per standard procedure, the samples were sent to the Pasteur Institute of Dakar for confirmation. On 17 July 2022 the two cases were confirmed by Ghana, which caused the country to declare a Marburg virus disease outbreak. An additional case was identified, bringing the total to three. A disease outbreak was first reported in Equatorial Guinea on 7 February 2023, and on 13 February 2023, it was identified as being Marburg virus disease. It was the first time the disease was detected in the country. Neighbouring Cameroon detected two suspected cases of Marburg virus disease on 13 February 2023, but they were later ruled out. On 25 February, a suspected case of Marburg was reported in the Spanish city of Valencia , however this case was subsequently discounted. As of 4 April 2023, there were 14 confirmed cases and 28 suspected cases, including ten confirmed deaths from the disease in Equatorial Guinea. On 8 June 2023, the World Health Organization declared the outbreak over. In total, 17 laboratory-confirmed cases and 12 deaths were recorded. All the 23 probable cases reportedly died. Four patients recovered from the virus and have been enrolled in a survivors programme to receive psychosocial and other post-recovery support. A Marburg virus disease outbreak in Tanzania was first reported on 21 March 2023 by the Ministry of Health of Tanzania. This was the first time that Tanzania had reported an outbreak of the disease. On 2 June 2023, Tanzania declared the outbreak over. There were 9 total infections, resulting in 6 total deaths. The WHO identifies marburg virus disease as having pandemic potential. Below is a table of outbreaks concerning MVD from 1967 to 2023:MVD was first documented in 1967, when 31 people became ill in the German towns of Marburg and Frankfurt am Main , and in Belgrade , Yugoslavia . The outbreak involved 25 primary MARV infections and seven deaths, and six nonlethal secondary cases. The outbreak was traced to infected grivets (species Chlorocebus aethiops ) imported from an undisclosed location in Uganda and used in developing poliomyelitis vaccines . The monkeys were received by Behringwerke, a Marburg company founded by the first winner of the Nobel Prize in Medicine , Emil von Behring . The company, which at the time was owned by Hoechst , was originally set up to develop sera against tetanus and diphtheria . Primary infections occurred in Behringwerke laboratory staff while working with grivet tissues or tissue cultures without adequate personal protective equipment . Secondary cases involved two physicians , a nurse , a post-mortem attendant, and the wife of a veterinarian . All secondary cases had direct contact, usually involving blood, with a primary case. Both physicians became infected through accidental skin pricks when drawing blood from patients. In 1975, an Australian tourist became infected with MARV in Rhodesia (today Zimbabwe ). He died in a hospital in Johannesburg , South Africa . His girlfriend and an attending nurse were subsequently infected with MVD, but survived. A case of MARV infection occurred in 1980 in Kenya . A French man, who worked as an electrical engineer in a sugar factory in Nzoia (close to Bungoma ) at the base of Mount Elgon (which contains Kitum Cave ), became infected by unknown means and died on 15 January shortly after admission to Nairobi Hospital. The attending physician contracted MVD, but survived. A popular science account of these cases can be found in Richard Preston 's book The Hot Zone (the French man is referred to under the pseudonym "Charles Monet", whereas the physician is identified under his real name, Shem Musoke). In 1987, a single lethal case of RAVV infection occurred in a 15-year-old Danish boy, who spent his vacation in Kisumu , Kenya . He had visited Kitum Cave on Mount Elgon prior to travelling to Mombasa , where he developed clinical signs of infection. The boy died after transfer to Nairobi Hospital. A popular science account of this case can be found in Richard Preston 's book The Hot Zone (the boy is referred to under the pseudonym "Peter Cardinal"). In 1988, researcher Nikolai Ustinov infected himself lethally with MARV after accidentally pricking himself with a syringe used for inoculation of guinea pigs . The accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR (today Russia ). Very little information is publicly available about this MVD case because Ustinov's experiments were classified. A popular science account of this case can be found in Ken Alibek 's book Biohazard . Another laboratory accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR , when a scientist contracted MARV by unknown means. A major MVD outbreak occurred among illegal gold miners around Goroumbwa mine in Durba and Watsa , Democratic Republic of Congo from 1998 to 2000, when co-circulating MARV and RAVV caused 154 cases of MVD and 128 deaths. The outbreak ended with the flooding of the mine. In early 2005, the World Health Organization (WHO) began investigating an outbreak of viral hemorrhagic fever in Angola , which was centered in the northeastern Uíge Province but also affected many other provinces. The Angolan government had to ask for international assistance, pointing out that there were only approximately 1,200 doctors in the entire country, with some provinces having as few as two. Health care workers also complained about a shortage of personal protective equipment such as gloves, gowns, and masks. Médecins Sans Frontières (MSF) reported that when their team arrived at the provincial hospital at the center of the outbreak, they found it operating without water and electricity . Contact tracing was complicated by the fact that the country's roads and other infrastructure were devastated after nearly three decades of civil war and the countryside remained littered with land mines . Americo Boa Vida Hospital in the Angolan capital Luanda set up a special isolation ward to treat infected people from the countryside. Unfortunately, because MVD often results in death, some people came to view hospitals and medical workers with suspicion and treated helpers with hostility. For instance, a specially-equipped isolation ward at the provincial hospital in Uíge was reported to be empty during much of the epidemic, even though the facility was at the center of the outbreak. WHO was forced to implement what it described as a "harm reduction strategy", which entailed distributing disinfectants to affected families who refused hospital care. Of the 252 people who contracted MVD during outbreak, 227 died. In 2007, four miners became infected with marburgviruses in Kamwenge District , Uganda . The first case, a 29-year-old man, became symptomatic on July 4, 2007, was admitted to a hospital on July 7, and died on July 13. Contact tracing revealed that the man had had prolonged close contact with two colleagues (a 22-year-old man and a 23-year-old man), who experienced clinical signs of infection before his disease onset. Both men had been admitted to hospitals in June and survived their infections, which were proven to be due to MARV. A fourth, 25-year-old man, developed MVD clinical signs in September and was shown to be infected with RAVV. He also survived the infection. On July 10, 2008, the Netherlands National Institute for Public Health and the Environment reported that a 41-year-old Dutch woman, who had visited Python Cave in Maramagambo Forest during her holiday in Uganda , had MVD due to MARV infection, and had been admitted to a hospital in the Netherlands . The woman died under treatment in the Leiden University Medical Centre in Leiden on July 11. The Ugandan Ministry of Health closed the cave after this case. On January 9 of that year an infectious diseases physician notified the Colorado Department of Public Health and the Environment that a 44-year-old American woman who had returned from Uganda had been hospitalized with a fever of unknown origin . At the time, serologic testing was negative for viral hemorrhagic fever . She was discharged on January 19, 2008. After the death of the Dutch patient and the discovery that the American woman had visited Python Cave, further testing confirmed the patient demonstrated MARV antibodies and RNA . In October 2017 an outbreak of Marburg virus disease was detected in Kween District , Eastern Uganda. All three initial cases (belonging to one family – two brothers and one sister) had died by 3 November. The fourth case – a health care worker – developed symptoms on 4 November and was admitted to a hospital. The first confirmed case traveled to Kenya before the death. A close contact of the second confirmed case traveled to Kampala . It is reported that several hundred people may have been exposed to infection. In August 2021, two months after the re-emergent Ebola epidemic in the Guéckédou prefecture was declared over, a case of the Marburg disease was confirmed by health authorities through laboratory analysis. Other potential case of the disease in a contact awaits official results. This was the first case of the Marburg hemorrhagic fever confirmed to happen in West Africa. The case of Marburg also has been identified in Guéckédou . During the outbreak, a total of one confirmed case, who died ( CFR =100%), and 173 contacts were identified, including 14 high-risk contacts based on exposure. Among them, 172 were followed for a period of 21 days, of which none developed symptoms. One high-risk contact was lost to follow up. Sequencing of an isolate from the Guinean patient showed that this outbreak was caused by the Angola-like Marburg virus. A colony of Egyptian rousettus bats ( reservoir host of Marburg virus ) was found in close proximity (4.5 km) to the village, where the Marburg virus disease outbreak emerged in 2021. Two sampled fruit bats from this colony were PCR-positive on the Marburg virus. In July 2022, preliminary analysis of samples taken from two patients – both deceased – in Ghana indicated the cases were positive for Marburg. However, per standard procedure, the samples were sent to the Pasteur Institute of Dakar for confirmation. On 17 July 2022 the two cases were confirmed by Ghana, which caused the country to declare a Marburg virus disease outbreak. An additional case was identified, bringing the total to three. A disease outbreak was first reported in Equatorial Guinea on 7 February 2023, and on 13 February 2023, it was identified as being Marburg virus disease. It was the first time the disease was detected in the country. Neighbouring Cameroon detected two suspected cases of Marburg virus disease on 13 February 2023, but they were later ruled out. On 25 February, a suspected case of Marburg was reported in the Spanish city of Valencia , however this case was subsequently discounted. As of 4 April 2023, there were 14 confirmed cases and 28 suspected cases, including ten confirmed deaths from the disease in Equatorial Guinea. On 8 June 2023, the World Health Organization declared the outbreak over. In total, 17 laboratory-confirmed cases and 12 deaths were recorded. All the 23 probable cases reportedly died. Four patients recovered from the virus and have been enrolled in a survivors programme to receive psychosocial and other post-recovery support. A Marburg virus disease outbreak in Tanzania was first reported on 21 March 2023 by the Ministry of Health of Tanzania. This was the first time that Tanzania had reported an outbreak of the disease. On 2 June 2023, Tanzania declared the outbreak over. There were 9 total infections, resulting in 6 total deaths. Experimentally, recombinant vesicular stomatitis Indiana virus (VSIV) expressing the glycoprotein of MARV has been used successfully in nonhuman primate models as post-exposure prophylaxis. A vaccine candidate has been effective in nonhuman primates. Experimental therapeutic regimens relying on antisense technology have shown promise, with phosphorodiamidate morpholino oligomers (PMOs) targeting the MARV genome New therapies from Sarepta and Tekmira have also been successfully used in humans as well as primates.

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Acute hemorrhagic fever syndrome

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Acute radiation syndrome

Acute radiation syndrome ( ARS ), also known as radiation sickness or radiation poisoning , is a collection of health effects that are caused by being exposed to high amounts of ionizing radiation in a short period of time. Symptoms can start within an hour of exposure, and can last for several months. Early symptoms are usually nausea, vomiting and loss of appetite. In the following hours or weeks, initial symptoms may appear to improve, before the development of additional symptoms, after which either recovery or death follow. ARS involves a total dose of greater than 0.7 Gy (70 rad ), that generally occurs from a source outside the body, delivered within a few minutes. Sources of such radiation can occur accidentally or intentionally. They may involve nuclear reactors , cyclotrons , certain devices used in cancer therapy , nuclear weapons , or radiological weapons . It is generally divided into three types: bone marrow, gastrointestinal, and neurovascular syndrome, with bone marrow syndrome occurring at 0.7 to 10 Gy, and neurovascular syndrome occurring at doses that exceed 50 Gy. The cells that are most affected are generally those that are rapidly dividing. At high doses, this causes DNA damage that may be irreparable. Diagnosis is based on a history of exposure and symptoms. Repeated complete blood counts (CBCs) can indicate the severity of exposure. Treatment of ARS is generally supportive care . This may include blood transfusions , antibiotics , colony-stimulating factors , or stem cell transplant . Radioactive material remaining on the skin or in the stomach should be removed. If radioiodine was inhaled or ingested, potassium iodide is recommended. Complications such as leukemia and other cancers among those who survive are managed as usual. Short term outcomes depend on the dose exposure. ARS is generally rare. A single event can affect a large number of people, as happened in the atomic bombings of Hiroshima and Nagasaki and the Chernobyl nuclear power plant disaster . ARS differs from chronic radiation syndrome , which occurs following prolonged exposures to relatively low doses of radiation. Classically, ARS is divided into three main presentations: hematopoietic , gastrointestinal , and neuro vascular . These syndromes may be preceded by a prodrome . The speed of symptom onset is related to radiation exposure, with greater doses resulting in a shorter delay in symptom onset. These presentations presume whole-body exposure, and many of them are markers that are invalid if the entire body has not been exposed. Each syndrome requires that the tissue showing the syndrome itself be exposed (e.g., gastrointestinal syndrome is not seen if the stomach and intestines are not exposed to radiation). Some areas affected are: Early symptoms of ARS typically include nausea , vomiting , headaches , fatigue, fever , and a short period of skin reddening . These symptoms may occur at radiation doses as low as 0.35 grays (35 rad) . These symptoms are common to many illnesses, and may not, by themselves, indicate acute radiation sickness. A similar table and description of symptoms (given in rems , where 100 rem = 1 Sv ), derived from data from the effects on humans subjected to the atomic bombings of Hiroshima and Nagasaki , the indigenous peoples of the Marshall Islands subjected to the Castle Bravo thermonuclear bomb, animal studies and lab experiment accidents, have been compiled by the U.S. Department of Defense . A person who was less than 1 mile (1.6 km) from the atomic bomb Little Boy ' s hypocenter at Hiroshima, Japan, was found to absorb about 9.46 grays (Gy) of ionizing radiation. The doses at the hypocenters of the Hiroshima and Nagasaki atomic bombings were 240 and 290 Gy, respectively. Cutaneous radiation syndrome (CRS) refers to the skin symptoms of radiation exposure. Within a few hours after irradiation, a transient and inconsistent redness (associated with itching ) can occur. Then, a latent phase may occur and last from a few days up to several weeks, when intense reddening, blistering , and ulceration of the irradiated site is visible. In most cases, healing occurs by regenerative means; however, very large skin doses can cause permanent hair loss, damaged sebaceous and sweat glands , atrophy , fibrosis (mostly keloids ), decreased or increased skin pigmentation, and ulceration or necrosis of the exposed tissue. As seen at Chernobyl , when skin is irradiated with high energy beta particles , moist desquamation (peeling of skin) and similar early effects can heal, only to be followed by the collapse of the dermal vascular system after two months, resulting in the loss of the full thickness of the exposed skin. Another example of skin loss caused by high-level exposure of radiation is during the 1999 Tokaimura nuclear accident , where technician Hisashi Ouchi had lost a majority of his skin due to the high amounts of radiation he absorbed during the irradiation. This effect had been demonstrated previously with pig skin using high energy beta sources at the Churchill Hospital Research Institute, in Oxford . A similar table and description of symptoms (given in rems , where 100 rem = 1 Sv ), derived from data from the effects on humans subjected to the atomic bombings of Hiroshima and Nagasaki , the indigenous peoples of the Marshall Islands subjected to the Castle Bravo thermonuclear bomb, animal studies and lab experiment accidents, have been compiled by the U.S. Department of Defense . A person who was less than 1 mile (1.6 km) from the atomic bomb Little Boy ' s hypocenter at Hiroshima, Japan, was found to absorb about 9.46 grays (Gy) of ionizing radiation. The doses at the hypocenters of the Hiroshima and Nagasaki atomic bombings were 240 and 290 Gy, respectively. Cutaneous radiation syndrome (CRS) refers to the skin symptoms of radiation exposure. Within a few hours after irradiation, a transient and inconsistent redness (associated with itching ) can occur. Then, a latent phase may occur and last from a few days up to several weeks, when intense reddening, blistering , and ulceration of the irradiated site is visible. In most cases, healing occurs by regenerative means; however, very large skin doses can cause permanent hair loss, damaged sebaceous and sweat glands , atrophy , fibrosis (mostly keloids ), decreased or increased skin pigmentation, and ulceration or necrosis of the exposed tissue. As seen at Chernobyl , when skin is irradiated with high energy beta particles , moist desquamation (peeling of skin) and similar early effects can heal, only to be followed by the collapse of the dermal vascular system after two months, resulting in the loss of the full thickness of the exposed skin. Another example of skin loss caused by high-level exposure of radiation is during the 1999 Tokaimura nuclear accident , where technician Hisashi Ouchi had lost a majority of his skin due to the high amounts of radiation he absorbed during the irradiation. This effect had been demonstrated previously with pig skin using high energy beta sources at the Churchill Hospital Research Institute, in Oxford . ARS is caused by exposure to a large dose of ionizing radiation (> ~0.1 Gy) over a short period of time (> ~0.1 Gy/h). Alpha and beta radiation have low penetrating power and are unlikely to affect vital internal organs from outside the body. Any type of ionizing radiation can cause burns, but alpha and beta radiation can only do so if radioactive contamination or nuclear fallout is deposited on the individual's skin or clothing. Gamma and neutron radiation can travel much greater distances and penetrate the body easily, so whole-body irradiation generally causes ARS before skin effects are evident. Local gamma irradiation can cause skin effects without any sickness. In the early twentieth century, radiographers would commonly calibrate their machines by irradiating their own hands and measuring the time to onset of erythema . Accidental exposure may be the result of a criticality or radiotherapy accident. There have been numerous criticality accidents dating back to atomic testing during World War II, while computer-controlled radiation therapy machines such as Therac-25 played a major part in radiotherapy accidents. The latter of the two is caused by the failure of equipment software used to monitor the radiational dose given. Human error has played a large part in accidental exposure incidents, including some of the criticality accidents, and larger scale events such as the Chernobyl disaster . Other events have to do with orphan sources , in which radioactive material is unknowingly kept, sold, or stolen. The Goiânia accident is an example, where a forgotten radioactive source was taken from a hospital, resulting in the deaths of 4 people from ARS. Theft and attempted theft of radioactive material by clueless thieves has also led to lethal exposure in at least one incident. Exposure may also come from routine spaceflight and solar flares that result in radiation effects on earth in the form of solar storms . During spaceflight, astronauts are exposed to both galactic cosmic radiation (GCR) and solar particle event (SPE) radiation. The exposure particularly occurs during flights beyond low Earth orbit (LEO). Evidence indicates past SPE radiation levels that would have been lethal for unprotected astronauts. GCR levels that might lead to acute radiation poisoning are less well understood. The latter cause is rarer, with an event possibly occurring during the solar storm of 1859 . Intentional exposure is controversial as it involves the use of nuclear weapons , human experiments , or is given to a victim in an act of murder. The intentional atomic bombings of Hiroshima and Nagasaki resulted in tens of thousands of casualties; the survivors of these bombings are known today as Hibakusha . Nuclear weapons emit large amounts of thermal radiation as visible, infrared, and ultraviolet light, to which the atmosphere is largely transparent. This event is also known as "Flash", where radiant heat and light are bombarded into any given victim's exposed skin, causing radiation burns. Death is highly likely, and radiation poisoning is almost certain if one is caught in the open with no terrain or building masking-effects within a radius of 0–3 km from a 1 megaton airburst. The 50% chance of death from the blast extends out to ~8 km from a 1 megaton atmospheric explosion. Scientific testing on humans within the United States occurred extensively throughout the atomic age. Experiments took place on a range of subjects including, but not limited to; the disabled, children, soldiers, and incarcerated persons, with the level of understanding and consent given by subjects varying from complete to none. Since 1997 there have been requirements for patients to give informed consent, and to be notified if experiments were classified. Across the world, the Soviet nuclear program involved human experiments on a large scale, which is still kept secret by the Russian government and the Rosatom agency. The human experiments that fall under intentional ARS exclude those that involved long term exposure . Criminal activity has involved murder and attempted murder carried out through abrupt victim contact with a radioactive substance such as polonium or plutonium .Accidental exposure may be the result of a criticality or radiotherapy accident. There have been numerous criticality accidents dating back to atomic testing during World War II, while computer-controlled radiation therapy machines such as Therac-25 played a major part in radiotherapy accidents. The latter of the two is caused by the failure of equipment software used to monitor the radiational dose given. Human error has played a large part in accidental exposure incidents, including some of the criticality accidents, and larger scale events such as the Chernobyl disaster . Other events have to do with orphan sources , in which radioactive material is unknowingly kept, sold, or stolen. The Goiânia accident is an example, where a forgotten radioactive source was taken from a hospital, resulting in the deaths of 4 people from ARS. Theft and attempted theft of radioactive material by clueless thieves has also led to lethal exposure in at least one incident. Exposure may also come from routine spaceflight and solar flares that result in radiation effects on earth in the form of solar storms . During spaceflight, astronauts are exposed to both galactic cosmic radiation (GCR) and solar particle event (SPE) radiation. The exposure particularly occurs during flights beyond low Earth orbit (LEO). Evidence indicates past SPE radiation levels that would have been lethal for unprotected astronauts. GCR levels that might lead to acute radiation poisoning are less well understood. The latter cause is rarer, with an event possibly occurring during the solar storm of 1859 .Intentional exposure is controversial as it involves the use of nuclear weapons , human experiments , or is given to a victim in an act of murder. The intentional atomic bombings of Hiroshima and Nagasaki resulted in tens of thousands of casualties; the survivors of these bombings are known today as Hibakusha . Nuclear weapons emit large amounts of thermal radiation as visible, infrared, and ultraviolet light, to which the atmosphere is largely transparent. This event is also known as "Flash", where radiant heat and light are bombarded into any given victim's exposed skin, causing radiation burns. Death is highly likely, and radiation poisoning is almost certain if one is caught in the open with no terrain or building masking-effects within a radius of 0–3 km from a 1 megaton airburst. The 50% chance of death from the blast extends out to ~8 km from a 1 megaton atmospheric explosion. Scientific testing on humans within the United States occurred extensively throughout the atomic age. Experiments took place on a range of subjects including, but not limited to; the disabled, children, soldiers, and incarcerated persons, with the level of understanding and consent given by subjects varying from complete to none. Since 1997 there have been requirements for patients to give informed consent, and to be notified if experiments were classified. Across the world, the Soviet nuclear program involved human experiments on a large scale, which is still kept secret by the Russian government and the Rosatom agency. The human experiments that fall under intentional ARS exclude those that involved long term exposure . Criminal activity has involved murder and attempted murder carried out through abrupt victim contact with a radioactive substance such as polonium or plutonium .The most commonly used predictor of ARS is the whole-body absorbed dose . Several related quantities, such as the equivalent dose , effective dose , and committed dose , are used to gauge long-term stochastic biological effects such as cancer incidence, but they are not designed to evaluate ARS. To help avoid confusion between these quantities, absorbed dose is measured in units of grays (in SI , unit symbol Gy ) or rads (in CGS ), while the others are measured in sieverts (in SI, unit symbol Sv ) or rems (in CGS). 1 rad = 0.01 Gy and 1 rem = 0.01 Sv. In most of the acute exposure scenarios that lead to radiation sickness, the bulk of the radiation is external whole-body gamma, in which case the absorbed, equivalent, and effective doses are all equal. There are exceptions, such as the Therac-25 accidents and the 1958 Cecil Kelley criticality accident , where the absorbed doses in Gy or rad are the only useful quantities, because of the targeted nature of the exposure to the body. Radiotherapy treatments are typically prescribed in terms of the local absorbed dose, which might be 60 Gy or higher. The dose is fractionated to about 2 Gy per day for "curative" treatment, which allows normal tissues to undergo repair , allowing them to tolerate a higher dose than would otherwise be expected. The dose to the targeted tissue mass must be averaged over the entire body mass, most of which receives negligible radiation, to arrive at a whole-body absorbed dose that can be compared to the table above. [ citation needed ] Exposure to high doses of radiation causes DNA damage, later creating serious and even lethal chromosomal aberrations if left unrepaired. Ionizing radiation can produce reactive oxygen species , and does directly damage cells by causing localized ionization events. The former is very damaging to DNA, while the latter events create clusters of DNA damage. This damage includes loss of nucleobases and breakage of the sugar-phosphate backbone that binds to the nucleobases. The DNA organization at the level of histones , nucleosomes, and chromatin also affects its susceptibility to radiation damage . Clustered damage, defined as at least two lesions within a helical turn, is especially harmful. While DNA damage happens frequently and naturally in the cell from endogenous sources, clustered damage is a unique effect of radiation exposure. Clustered damage takes longer to repair than isolated breakages, and is less likely to be repaired at all. Larger radiation doses are more prone to cause tighter clustering of damage, and closely localized damage is increasingly less likely to be repaired. Somatic mutations cannot be passed down from parent to offspring, but these mutations can propagate in cell lines within an organism. Radiation damage can also cause chromosome and chromatid aberrations, and their effects depend on in which stage of the mitotic cycle the cell is when the irradiation occurs. If the cell is in interphase, while it is still a single strand of chromatin, the damage will be replicated during the S1 phase of cell cycle , and there will be a break on both chromosome arms; the damage then will be apparent in both daughter cells. If the irradiation occurs after replication, only one arm will bear the damage; this damage will be apparent in only one daughter cell. A damaged chromosome may cyclize, binding to another chromosome, or to itself. Exposure to high doses of radiation causes DNA damage, later creating serious and even lethal chromosomal aberrations if left unrepaired. Ionizing radiation can produce reactive oxygen species , and does directly damage cells by causing localized ionization events. The former is very damaging to DNA, while the latter events create clusters of DNA damage. This damage includes loss of nucleobases and breakage of the sugar-phosphate backbone that binds to the nucleobases. The DNA organization at the level of histones , nucleosomes, and chromatin also affects its susceptibility to radiation damage . Clustered damage, defined as at least two lesions within a helical turn, is especially harmful. While DNA damage happens frequently and naturally in the cell from endogenous sources, clustered damage is a unique effect of radiation exposure. Clustered damage takes longer to repair than isolated breakages, and is less likely to be repaired at all. Larger radiation doses are more prone to cause tighter clustering of damage, and closely localized damage is increasingly less likely to be repaired. Somatic mutations cannot be passed down from parent to offspring, but these mutations can propagate in cell lines within an organism. Radiation damage can also cause chromosome and chromatid aberrations, and their effects depend on in which stage of the mitotic cycle the cell is when the irradiation occurs. If the cell is in interphase, while it is still a single strand of chromatin, the damage will be replicated during the S1 phase of cell cycle , and there will be a break on both chromosome arms; the damage then will be apparent in both daughter cells. If the irradiation occurs after replication, only one arm will bear the damage; this damage will be apparent in only one daughter cell. A damaged chromosome may cyclize, binding to another chromosome, or to itself. Diagnosis is typically made based on a history of significant radiation exposure and suitable clinical findings. An absolute lymphocyte count can give a rough estimate of radiation exposure. Time from exposure to vomiting can also give estimates of exposure levels if they are less than 10 Gray (1000 rad). A guiding principle of radiation safety is as low as reasonably achievable (ALARA). This means try to avoid exposure as much as possible and includes the three components of time, distance, and shielding. The longer that humans are subjected to radiation the larger the dose will be. The advice in the nuclear war manual entitled Nuclear War Survival Skills published by Cresson Kearny in the U.S. was that if one needed to leave the shelter then this should be done as rapidly as possible to minimize exposure. In chapter 12, he states that "[q]uickly putting or dumping wastes outside is not hazardous once fallout is no longer being deposited. For example, assume the shelter is in an area of heavy fallout and the dose rate outside is 400 roentgen (R) per hour, enough to give a potentially fatal dose in about an hour to a person exposed in the open. If a person needs to be exposed for only 10 seconds to dump a bucket, in this 1/360 of an hour he will receive a dose of only about 1 R. Under war conditions, an additional 1-R dose is of little concern." In peacetime, radiation workers are taught to work as quickly as possible when performing a task that exposes them to radiation. For instance, the recovery of a radioactive source should be done as quickly as possible. [ citation needed ] Matter attenuates radiation in most cases, so placing any mass (e.g., lead, dirt, sandbags, vehicles, water, even air) between humans and the source will reduce the radiation dose. This is not always the case, however; care should be taken when constructing shielding for a specific purpose. For example, although high atomic number materials are very effective in shielding photons , using them to shield beta particles may cause higher radiation exposure due to the production of bremsstrahlung x-rays, and hence low atomic number materials are recommended. Also, using material with a high neutron activation cross section to shield neutrons will result in the shielding material itself becoming radioactive and hence more dangerous than if it were not present. [ citation needed ] There are many types of shielding strategies that can be used to reduce the effects of radiation exposure. Internal contamination protective equipment such as respirators are used to prevent internal deposition as a result of inhalation and ingestion of radioactive material. Dermal protective equipment, which protects against external contamination, provides shielding to prevent radioactive material from being deposited on external structures. While these protective measures do provide a barrier from radioactive material deposition, they do not shield from externally penetrating gamma radiation. This leaves anyone exposed to penetrating gamma rays at high risk of ARS. Naturally, shielding the entire body from high energy gamma radiation is optimal, but the required mass to provide adequate attenuation makes functional movement nearly impossible. In the event of a radiation catastrophe, medical and security personnel need mobile protection equipment in order to safely assist in containment, evacuation, and many other necessary public safety objectives. Research has been done exploring the feasibility of partial body shielding, a radiation protection strategy that provides adequate attenuation to only the most radio-sensitive organs and tissues inside the body. Irreversible stem cell damage in the bone marrow is the first life-threatening effect of intense radiation exposure and therefore one of the most important bodily elements to protect. Due to the regenerative property of hematopoietic stem cells , it is only necessary to protect enough bone marrow to repopulate the exposed areas of the body with the shielded supply. This concept allows for the development of lightweight mobile radiation protection equipment , which provides adequate protection, deferring the onset of ARS to much higher exposure doses. One example of such equipment is the 360 gamma , a radiation protection belt that applies selective shielding to protect the bone marrow stored in the pelvic area as well as other radio sensitive organs in the abdominal region without hindering functional mobility. More information on bone marrow shielding can be found in the "Health Physics Radiation Safety Journal" . article Waterman, Gideon; Kase, Kenneth; Orion, Itzhak; Broisman, Andrey; Milstein, Oren (September 2017). "Selective Shielding of Bone Marrow: An Approach to Protecting Humans from External Gamma Radiation". Health Physics . 113 (3): 195–208. doi : 10.1097/HP.0000000000000688 . PMID 28749810 . S2CID 3300412 . , or in the Organisation for Economic Co-operation and Development (OECD) and the Nuclear Energy Agency (NEA) 's 2015 report: "Occupational Radiation Protection in Severe Accident Management" (PDF) . Where radioactive contamination is present, an elastomeric respirator , dust mask , or good hygiene practices may offer protection, depending on the nature of the contaminant. Potassium iodide (KI) tablets can reduce the risk of cancer in some situations due to slower uptake of ambient radioiodine. Although this does not protect any organ other than the thyroid gland, their effectiveness is still highly dependent on the time of ingestion, which would protect the gland for the duration of a twenty-four-hour period. They do not prevent ARS as they provide no shielding from other environmental radionuclides. If an intentional dose is broken up into a number of smaller doses, with time allowed for recovery between irradiations, the same total dose causes less cell death . Even without interruptions, a reduction in dose rate below 0.1 Gy/h also tends to reduce cell death. This technique is routinely used in radiotherapy. [ citation needed ] The human body contains many types of cells and a human can be killed by the loss of a single type of cells in a vital organ. For many short term radiation deaths (3–30 days), the loss of two important types of cells that are constantly being regenerated causes death. The loss of cells forming blood cells ( bone marrow ) and the cells in the digestive system ( microvilli , which form part of the wall of the intestines ) is fatal. [ citation needed ]The longer that humans are subjected to radiation the larger the dose will be. The advice in the nuclear war manual entitled Nuclear War Survival Skills published by Cresson Kearny in the U.S. was that if one needed to leave the shelter then this should be done as rapidly as possible to minimize exposure. In chapter 12, he states that "[q]uickly putting or dumping wastes outside is not hazardous once fallout is no longer being deposited. For example, assume the shelter is in an area of heavy fallout and the dose rate outside is 400 roentgen (R) per hour, enough to give a potentially fatal dose in about an hour to a person exposed in the open. If a person needs to be exposed for only 10 seconds to dump a bucket, in this 1/360 of an hour he will receive a dose of only about 1 R. Under war conditions, an additional 1-R dose is of little concern." In peacetime, radiation workers are taught to work as quickly as possible when performing a task that exposes them to radiation. For instance, the recovery of a radioactive source should be done as quickly as possible. [ citation needed ]Matter attenuates radiation in most cases, so placing any mass (e.g., lead, dirt, sandbags, vehicles, water, even air) between humans and the source will reduce the radiation dose. This is not always the case, however; care should be taken when constructing shielding for a specific purpose. For example, although high atomic number materials are very effective in shielding photons , using them to shield beta particles may cause higher radiation exposure due to the production of bremsstrahlung x-rays, and hence low atomic number materials are recommended. Also, using material with a high neutron activation cross section to shield neutrons will result in the shielding material itself becoming radioactive and hence more dangerous than if it were not present. [ citation needed ] There are many types of shielding strategies that can be used to reduce the effects of radiation exposure. Internal contamination protective equipment such as respirators are used to prevent internal deposition as a result of inhalation and ingestion of radioactive material. Dermal protective equipment, which protects against external contamination, provides shielding to prevent radioactive material from being deposited on external structures. While these protective measures do provide a barrier from radioactive material deposition, they do not shield from externally penetrating gamma radiation. This leaves anyone exposed to penetrating gamma rays at high risk of ARS. Naturally, shielding the entire body from high energy gamma radiation is optimal, but the required mass to provide adequate attenuation makes functional movement nearly impossible. In the event of a radiation catastrophe, medical and security personnel need mobile protection equipment in order to safely assist in containment, evacuation, and many other necessary public safety objectives. Research has been done exploring the feasibility of partial body shielding, a radiation protection strategy that provides adequate attenuation to only the most radio-sensitive organs and tissues inside the body. Irreversible stem cell damage in the bone marrow is the first life-threatening effect of intense radiation exposure and therefore one of the most important bodily elements to protect. Due to the regenerative property of hematopoietic stem cells , it is only necessary to protect enough bone marrow to repopulate the exposed areas of the body with the shielded supply. This concept allows for the development of lightweight mobile radiation protection equipment , which provides adequate protection, deferring the onset of ARS to much higher exposure doses. One example of such equipment is the 360 gamma , a radiation protection belt that applies selective shielding to protect the bone marrow stored in the pelvic area as well as other radio sensitive organs in the abdominal region without hindering functional mobility. More information on bone marrow shielding can be found in the "Health Physics Radiation Safety Journal" . article Waterman, Gideon; Kase, Kenneth; Orion, Itzhak; Broisman, Andrey; Milstein, Oren (September 2017). "Selective Shielding of Bone Marrow: An Approach to Protecting Humans from External Gamma Radiation". Health Physics . 113 (3): 195–208. doi : 10.1097/HP.0000000000000688 . PMID 28749810 . S2CID 3300412 . , or in the Organisation for Economic Co-operation and Development (OECD) and the Nuclear Energy Agency (NEA) 's 2015 report: "Occupational Radiation Protection in Severe Accident Management" (PDF) .Where radioactive contamination is present, an elastomeric respirator , dust mask , or good hygiene practices may offer protection, depending on the nature of the contaminant. Potassium iodide (KI) tablets can reduce the risk of cancer in some situations due to slower uptake of ambient radioiodine. Although this does not protect any organ other than the thyroid gland, their effectiveness is still highly dependent on the time of ingestion, which would protect the gland for the duration of a twenty-four-hour period. They do not prevent ARS as they provide no shielding from other environmental radionuclides. If an intentional dose is broken up into a number of smaller doses, with time allowed for recovery between irradiations, the same total dose causes less cell death . Even without interruptions, a reduction in dose rate below 0.1 Gy/h also tends to reduce cell death. This technique is routinely used in radiotherapy. [ citation needed ] The human body contains many types of cells and a human can be killed by the loss of a single type of cells in a vital organ. For many short term radiation deaths (3–30 days), the loss of two important types of cells that are constantly being regenerated causes death. The loss of cells forming blood cells ( bone marrow ) and the cells in the digestive system ( microvilli , which form part of the wall of the intestines ) is fatal. [ citation needed ]Treatment usually involves supportive care with possible symptomatic measures employed. The former involves the possible use of antibiotics , blood products , colony stimulating factors , and stem cell transplant . There is a direct relationship between the degree of the neutropenia that emerges after exposure to radiation and the increased risk of developing infection. Since there are no controlled studies of therapeutic intervention in humans, most of the current recommendations are based on animal research. [ citation needed ] The treatment of established or suspected infection following exposure to radiation (characterized by neutropenia and fever) is similar to the one used for other febrile neutropenic patients. However, important differences between the two conditions exist. Individuals that develop neutropenia after exposure to radiation are also susceptible to irradiation damage in other tissues, such as the gastrointestinal tract, lungs and central nervous system. These patients may require therapeutic interventions not needed in other types of neutropenic patients. The response of irradiated animals to antimicrobial therapy can be unpredictable, as was evident in experimental studies where metronidazole and pefloxacin therapies were detrimental. Antimicrobials that reduce the number of the strict anaerobic component of the gut flora (i.e., metronidazole ) generally should not be given because they may enhance systemic infection by aerobic or facultative bacteria, thus facilitating mortality after irradiation. An empirical regimen of antimicrobials should be chosen based on the pattern of bacterial susceptibility and nosocomial infections in the affected area and medical center and the degree of neutropenia . Broad-spectrum empirical therapy (see below for choices) with high doses of one or more antibiotics should be initiated at the onset of fever. These antimicrobials should be directed at the eradication of Gram-negative aerobic bacilli (i.e., Enterobacteriace, Pseudomonas) that account for more than three quarters of the isolates causing sepsis. Because aerobic and facultative Gram-positive bacteria (mostly alpha-hemolytic streptococci) cause sepsis in about a quarter of the victims, coverage for these organisms may also be needed. A standardized management plan for people with neutropenia and fever should be devised. Empirical regimens contain antibiotics broadly active against Gram-negative aerobic bacteria ( quinolones : i.e., ciprofloxacin , levofloxacin , a third- or fourth-generation cephalosporin with pseudomonal coverage: e.g., cefepime , ceftazidime , or an aminoglycoside: i.e. gentamicin , amikacin ). There is a direct relationship between the degree of the neutropenia that emerges after exposure to radiation and the increased risk of developing infection. Since there are no controlled studies of therapeutic intervention in humans, most of the current recommendations are based on animal research. [ citation needed ] The treatment of established or suspected infection following exposure to radiation (characterized by neutropenia and fever) is similar to the one used for other febrile neutropenic patients. However, important differences between the two conditions exist. Individuals that develop neutropenia after exposure to radiation are also susceptible to irradiation damage in other tissues, such as the gastrointestinal tract, lungs and central nervous system. These patients may require therapeutic interventions not needed in other types of neutropenic patients. The response of irradiated animals to antimicrobial therapy can be unpredictable, as was evident in experimental studies where metronidazole and pefloxacin therapies were detrimental. Antimicrobials that reduce the number of the strict anaerobic component of the gut flora (i.e., metronidazole ) generally should not be given because they may enhance systemic infection by aerobic or facultative bacteria, thus facilitating mortality after irradiation. An empirical regimen of antimicrobials should be chosen based on the pattern of bacterial susceptibility and nosocomial infections in the affected area and medical center and the degree of neutropenia . Broad-spectrum empirical therapy (see below for choices) with high doses of one or more antibiotics should be initiated at the onset of fever. These antimicrobials should be directed at the eradication of Gram-negative aerobic bacilli (i.e., Enterobacteriace, Pseudomonas) that account for more than three quarters of the isolates causing sepsis. Because aerobic and facultative Gram-positive bacteria (mostly alpha-hemolytic streptococci) cause sepsis in about a quarter of the victims, coverage for these organisms may also be needed. A standardized management plan for people with neutropenia and fever should be devised. Empirical regimens contain antibiotics broadly active against Gram-negative aerobic bacteria ( quinolones : i.e., ciprofloxacin , levofloxacin , a third- or fourth-generation cephalosporin with pseudomonal coverage: e.g., cefepime , ceftazidime , or an aminoglycoside: i.e. gentamicin , amikacin ). The prognosis for ARS is dependent on the exposure dose, with anything above 8 Gy being almost always lethal, even with medical care. Radiation burns from lower-level exposures usually manifest after 2 months, while reactions from the burns occur months to years after radiation treatment. Complications from ARS include an increased risk of developing radiation-induced cancer later in life. According to the controversial but commonly applied linear no-threshold model , any exposure to ionizing radiation, even at doses too low to produce any symptoms of radiation sickness, can induce cancer due to cellular and genetic damage. The probability of developing cancer is a linear function with respect to the effective radiation dose . Radiation cancer may occur after ionizing radiation exposure following a latent period averaging 20 to 40 years. Acute effects of ionizing radiation were first observed when Wilhelm Röntgen intentionally subjected his fingers to X-rays in 1895. He published his observations concerning the burns that developed that eventually healed, and misattributed them to ozone. Röntgen believed the free radical produced in air by X-rays from the ozone was the cause, but other free radicals produced within the body are now understood to be more important. David Walsh first established the symptoms of radiation sickness in 1897. Ingestion of radioactive materials caused many radiation-induced cancers in the 1930s, but no one was exposed to high enough doses at high enough rates to bring on ARS. The atomic bombings of Hiroshima and Nagasaki resulted in high acute doses of radiation to a large number of Japanese people, allowing for greater insight into its symptoms and dangers. Red Cross Hospital Surgeon Terufumi Sasaki led intensive research into the syndrome in the weeks and months following the Hiroshima and Nagasaki bombings. Sasaki and his team were able to monitor the effects of radiation in patients of varying proximities to the blast itself, leading to the establishment of three recorded stages of the syndrome. Within 25–30 days of the explosion, Sasaki noticed a sharp drop in white blood cell count and established this drop, along with symptoms of fever, as prognostic standards for ARS. Actress Midori Naka , who was present during the atomic bombing of Hiroshima, was the first incident of radiation poisoning to be extensively studied. Her death on 24 August 1945 was the first death ever to be officially certified as a result of ARS (or "Atomic bomb disease"). There are two major databases that track radiation accidents: The American ORISE REAC/TS and the European IRSN ACCIRAD. REAC/TS shows 417 accidents occurring between 1944 and 2000, causing about 3000 cases of ARS, of which 127 were fatal. ACCIRAD lists 580 accidents with 180 ARS fatalities for an almost identical period. The two deliberate bombings are not included in either database, nor are any possible radiation-induced cancers from low doses. The detailed accounting is difficult because of confounding factors. ARS may be accompanied by conventional injuries such as steam burns, or may occur in someone with a pre-existing condition undergoing radiotherapy. There may be multiple causes for death, and the contribution from radiation may be unclear. Some documents may incorrectly refer to radiation-induced cancers as radiation poisoning, or may count all overexposed individuals as survivors without mentioning if they had any symptoms of ARS. The following table includes only those known for their attempted survival with ARS. These cases exclude chronic radiation syndrome such as Albert Stevens , in which radiation is exposed to a given subject over a long duration. The table also necessarily excludes cases where the individual was exposed to so much radiation that death occurred before medical assistance or dose estimations could be made, such as an attempted cobalt-60 thief who reportedly died 30 minutes after exposure. The "result" column represents the time of exposure to the time of death attributed to the short and long term effects attributed to initial exposure. As ARS is measured by a whole-body absorbed dose , the "exposure" column only includes units of Gray (Gy).The following table includes only those known for their attempted survival with ARS. These cases exclude chronic radiation syndrome such as Albert Stevens , in which radiation is exposed to a given subject over a long duration. The table also necessarily excludes cases where the individual was exposed to so much radiation that death occurred before medical assistance or dose estimations could be made, such as an attempted cobalt-60 thief who reportedly died 30 minutes after exposure. The "result" column represents the time of exposure to the time of death attributed to the short and long term effects attributed to initial exposure. As ARS is measured by a whole-body absorbed dose , the "exposure" column only includes units of Gray (Gy).Thousands of scientific experiments have been performed to study ARS in animals. [ citation needed ] There is a simple guide for predicting survival and death in mammals, including humans, following the acute effects of inhaling radioactive particles.

Wiki

Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/Acute_disseminated_encephalomyelitis/html

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis ( ADEM ), or acute demyelinating encephalomyelitis , is a rare autoimmune disease marked by a sudden, widespread attack of inflammation in the brain and spinal cord . As well as causing the brain and spinal cord to become inflamed, ADEM also attacks the nerves of the central nervous system and damages their myelin insulation, which, as a result, destroys the white matter . The cause is often a trigger such as from viral infection or vaccinations . ADEM's symptoms resemble the symptoms of multiple sclerosis (MS), so the disease itself is sorted into the classification of the multiple sclerosis borderline diseases. However, ADEM has several features that distinguish it from MS. Unlike MS, ADEM occurs usually in children and is marked with rapid fever, although adolescents and adults can get the disease too. ADEM consists of a single flare-up whereas MS is marked with several flare-ups (or relapses), over a long period of time. Relapses following ADEM are reported in up to a quarter of patients, but the majority of these 'multiphasic' presentations following ADEM likely represent MS. ADEM is also distinguished by a loss of consciousness, coma and death, which is very rare in MS, except in severe cases. It affects about 8 per 1,000,000 people per year. Although it occurs in all ages, most reported cases are in children and adolescents , with the average age around 5 to 8 years old. The disease affects males and females almost equally. ADEM shows seasonal variation with higher incidence in winter and spring months which may coincide with higher viral infections during these months. The mortality rate may be as high as 5%; however, full recovery is seen in 50 to 75% of cases with increase in survival rates up to 70 to 90% with figures including minor residual disability as well. The average time to recover from ADEM flare-ups is one to six months. ADEM produces multiple inflammatory lesions in the brain and spinal cord , particularly in the white matter . Usually these are found in the subcortical and central white matter and cortical gray-white junction of both cerebral hemispheres , cerebellum , brainstem , and spinal cord, but periventricular white matter and gray matter of the cortex , thalami and basal ganglia may also be involved. When a person has more than one demyelinating episode of ADEM, the disease is then called recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis ( MDEM ). Also, a fulminant course in adults has been described. ADEM has an abrupt onset and a monophasic course. Symptoms usually begin 1–3 weeks after infection. Major symptoms include fever , headache , nausea and vomiting , confusion , vision impairment , drowsiness, seizures and coma . Although initially the symptoms are usually mild, they worsen rapidly over the course of hours to days, with the average time to maximum severity being about four and a half days. Additional symptoms include hemiparesis, paraparesis, and cranial nerve palsies. Neurological symptoms were the main presentation of COVID-19, which did not correlate with the severity of respiratory symptoms. The high incidence of ADEM with hemorrhage is striking. Brain inflammation is likely caused by an immune response to the disease rather than neurotropism. CSF analysis was not indicative of an infectious process, neurological impairment was not present in the acute phase of the infection, and neuroimaging findings were not typical of classical toxic and metabolic disorders. The finding of bilateral periventricular relatively asymmetrical lesions allied with deep white matter involvement, that may also be present in cortical gray-white matter junction, thalami, basal ganglia, cerebellum, and brainstem suggests an acute demyelination process. Additionally, hemorrhagic white matter lesions, clusters of macrophages related to axonal injury and ADEM-like appearance were also found in subcortical white matter. Neurological symptoms were the main presentation of COVID-19, which did not correlate with the severity of respiratory symptoms. The high incidence of ADEM with hemorrhage is striking. Brain inflammation is likely caused by an immune response to the disease rather than neurotropism. CSF analysis was not indicative of an infectious process, neurological impairment was not present in the acute phase of the infection, and neuroimaging findings were not typical of classical toxic and metabolic disorders. The finding of bilateral periventricular relatively asymmetrical lesions allied with deep white matter involvement, that may also be present in cortical gray-white matter junction, thalami, basal ganglia, cerebellum, and brainstem suggests an acute demyelination process. Additionally, hemorrhagic white matter lesions, clusters of macrophages related to axonal injury and ADEM-like appearance were also found in subcortical white matter. Since the discovery of the anti- MOG specificity against multiple sclerosis diagnosis it is considered that ADEM is one of the possible clinical causes of anti-MOG associated encephalomyelitis . About how the anti-MOG antibodies appear in the patients serum there are several theories:The term ADEM has been inconsistently used at different times. Currently, the commonly accepted international standard for the clinical case definition is the one published by the International Pediatric MS Study Group , revision 2007. Given that the definition is clinical, it is currently unknown if all the cases of ADEM are positive for anti- MOG autoantibody; in any case, it appears to be strongly related to ADEM diagnosis. While ADEM and MS both involve autoimmune demyelination, they differ in many clinical, genetic, imaging, and histopathological aspects. Some authors consider MS and its borderline forms to constitute a spectrum, differing only in chronicity, severity, and clinical course, while others consider them discretely different diseases. Typically, ADEM appears in children following an antigenic challenge and remains monophasic. Nevertheless, ADEM does occur in adults, and can also be clinically multiphasic. Problems for differential diagnosis increase due to the lack of agreement for a definition of multiple sclerosis. If MS were defined only by the separation in time and space of the demyelinating lesions as McDonald did, it would not be enough to make a difference, as some cases of ADEM satisfy these conditions. Therefore, some authors propose to establish the dividing line as the shape of the lesions around the veins, being therefore "perivenous vs. confluent demyelination". The pathology of ADEM is very similar to that of MS with some differences. The pathological hallmark of ADEM is perivenous inflammation with limited "sleeves of demyelination". Nevertheless, MS-like plaques (confluent demyelination) can appear Plaques in the white matter in MS are sharply delineated, while the glial scar in ADEM is smooth. Axons are better preserved in ADEM lesions. Inflammation in ADEM is widely disseminated and ill-defined, and finally, lesions are strictly perivenous, while in MS they are disposed around veins, but not so sharply. Nevertheless, the co-occurrence of perivenous and confluent demyelination in some individuals suggests pathogenic overlap between acute disseminated encephalomyelitis and multiple sclerosis and misclassification even with biopsy or even postmortem ADEM in adults can progress to MS When the person has more than one demyelinating episode of ADEM, the disease is then called recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis (MDEM). It has been found that anti- MOG auto-antibodies are related to this kind of ADEM Another variant of ADEM in adults has been described, also related to anti-MOG auto-antibodies, has been named fulminant disseminated encephalomyelitis, and it has been reported to be clinically ADEM, but showing MS-like lesions on autopsy. It has been classified inside the anti-MOG associated inflammatory demyelinating diseases . Acute hemorrhagic leukoencephalitis (AHL, or AHLE), acute hemorrhagic encephalomyelitis (AHEM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE), Weston-Hurst syndrome, or Hurst's disease, is a hyperacute and frequently fatal form of ADEM. AHL is relatively rare (less than 100 cases have been reported in the medical literature as of 2006 [ update ] ), it is seen in about 2% of ADEM cases, and is characterized by necrotizing vasculitis of venules and hemorrhage, and edema. Death is common in the first week and overall mortality is about 70%, but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange. About 70% of survivors show residual neurological deficits, but some survivors have shown surprisingly little deficit considering the extent of the white matter affected. This disease has been occasionally associated with ulcerative colitis and Crohn's disease , malaria , sepsis associated with immune complex deposition, methanol poisoning, and other underlying conditions. Also anecdotal association with MS has been reported Laboratory studies that support diagnosis of AHL are: peripheral leukocytosis, cerebrospinal fluid (CSF) pleocytosis associated with normal glucose and increased protein. On magnetic resonance imaging (MRI), lesions of AHL typically show extensive T2-weighted and fluid-attenuated inversion recovery (FLAIR) white matter hyperintensities with areas of hemorrhages, significant edema, and mass effect. While ADEM and MS both involve autoimmune demyelination, they differ in many clinical, genetic, imaging, and histopathological aspects. Some authors consider MS and its borderline forms to constitute a spectrum, differing only in chronicity, severity, and clinical course, while others consider them discretely different diseases. Typically, ADEM appears in children following an antigenic challenge and remains monophasic. Nevertheless, ADEM does occur in adults, and can also be clinically multiphasic. Problems for differential diagnosis increase due to the lack of agreement for a definition of multiple sclerosis. If MS were defined only by the separation in time and space of the demyelinating lesions as McDonald did, it would not be enough to make a difference, as some cases of ADEM satisfy these conditions. Therefore, some authors propose to establish the dividing line as the shape of the lesions around the veins, being therefore "perivenous vs. confluent demyelination". The pathology of ADEM is very similar to that of MS with some differences. The pathological hallmark of ADEM is perivenous inflammation with limited "sleeves of demyelination". Nevertheless, MS-like plaques (confluent demyelination) can appear Plaques in the white matter in MS are sharply delineated, while the glial scar in ADEM is smooth. Axons are better preserved in ADEM lesions. Inflammation in ADEM is widely disseminated and ill-defined, and finally, lesions are strictly perivenous, while in MS they are disposed around veins, but not so sharply. Nevertheless, the co-occurrence of perivenous and confluent demyelination in some individuals suggests pathogenic overlap between acute disseminated encephalomyelitis and multiple sclerosis and misclassification even with biopsy or even postmortem ADEM in adults can progress to MS When the person has more than one demyelinating episode of ADEM, the disease is then called recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis (MDEM). It has been found that anti- MOG auto-antibodies are related to this kind of ADEM Another variant of ADEM in adults has been described, also related to anti-MOG auto-antibodies, has been named fulminant disseminated encephalomyelitis, and it has been reported to be clinically ADEM, but showing MS-like lesions on autopsy. It has been classified inside the anti-MOG associated inflammatory demyelinating diseases . Acute hemorrhagic leukoencephalitis (AHL, or AHLE), acute hemorrhagic encephalomyelitis (AHEM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE), Weston-Hurst syndrome, or Hurst's disease, is a hyperacute and frequently fatal form of ADEM. AHL is relatively rare (less than 100 cases have been reported in the medical literature as of 2006 [ update ] ), it is seen in about 2% of ADEM cases, and is characterized by necrotizing vasculitis of venules and hemorrhage, and edema. Death is common in the first week and overall mortality is about 70%, but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange. About 70% of survivors show residual neurological deficits, but some survivors have shown surprisingly little deficit considering the extent of the white matter affected. This disease has been occasionally associated with ulcerative colitis and Crohn's disease , malaria , sepsis associated with immune complex deposition, methanol poisoning, and other underlying conditions. Also anecdotal association with MS has been reported Laboratory studies that support diagnosis of AHL are: peripheral leukocytosis, cerebrospinal fluid (CSF) pleocytosis associated with normal glucose and increased protein. On magnetic resonance imaging (MRI), lesions of AHL typically show extensive T2-weighted and fluid-attenuated inversion recovery (FLAIR) white matter hyperintensities with areas of hemorrhages, significant edema, and mass effect. While ADEM and MS both involve autoimmune demyelination, they differ in many clinical, genetic, imaging, and histopathological aspects. Some authors consider MS and its borderline forms to constitute a spectrum, differing only in chronicity, severity, and clinical course, while others consider them discretely different diseases. Typically, ADEM appears in children following an antigenic challenge and remains monophasic. Nevertheless, ADEM does occur in adults, and can also be clinically multiphasic. Problems for differential diagnosis increase due to the lack of agreement for a definition of multiple sclerosis. If MS were defined only by the separation in time and space of the demyelinating lesions as McDonald did, it would not be enough to make a difference, as some cases of ADEM satisfy these conditions. Therefore, some authors propose to establish the dividing line as the shape of the lesions around the veins, being therefore "perivenous vs. confluent demyelination". The pathology of ADEM is very similar to that of MS with some differences. The pathological hallmark of ADEM is perivenous inflammation with limited "sleeves of demyelination". Nevertheless, MS-like plaques (confluent demyelination) can appear Plaques in the white matter in MS are sharply delineated, while the glial scar in ADEM is smooth. Axons are better preserved in ADEM lesions. Inflammation in ADEM is widely disseminated and ill-defined, and finally, lesions are strictly perivenous, while in MS they are disposed around veins, but not so sharply. Nevertheless, the co-occurrence of perivenous and confluent demyelination in some individuals suggests pathogenic overlap between acute disseminated encephalomyelitis and multiple sclerosis and misclassification even with biopsy or even postmortem ADEM in adults can progress to MS When the person has more than one demyelinating episode of ADEM, the disease is then called recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis (MDEM). It has been found that anti- MOG auto-antibodies are related to this kind of ADEM Another variant of ADEM in adults has been described, also related to anti-MOG auto-antibodies, has been named fulminant disseminated encephalomyelitis, and it has been reported to be clinically ADEM, but showing MS-like lesions on autopsy. It has been classified inside the anti-MOG associated inflammatory demyelinating diseases . Acute hemorrhagic leukoencephalitis (AHL, or AHLE), acute hemorrhagic encephalomyelitis (AHEM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE), Weston-Hurst syndrome, or Hurst's disease, is a hyperacute and frequently fatal form of ADEM. AHL is relatively rare (less than 100 cases have been reported in the medical literature as of 2006 [ update ] ), it is seen in about 2% of ADEM cases, and is characterized by necrotizing vasculitis of venules and hemorrhage, and edema. Death is common in the first week and overall mortality is about 70%, but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange. About 70% of survivors show residual neurological deficits, but some survivors have shown surprisingly little deficit considering the extent of the white matter affected. This disease has been occasionally associated with ulcerative colitis and Crohn's disease , malaria , sepsis associated with immune complex deposition, methanol poisoning, and other underlying conditions. Also anecdotal association with MS has been reported Laboratory studies that support diagnosis of AHL are: peripheral leukocytosis, cerebrospinal fluid (CSF) pleocytosis associated with normal glucose and increased protein. On magnetic resonance imaging (MRI), lesions of AHL typically show extensive T2-weighted and fluid-attenuated inversion recovery (FLAIR) white matter hyperintensities with areas of hemorrhages, significant edema, and mass effect. No controlled clinical trials have been conducted on ADEM treatment, but aggressive treatment aimed at rapidly reducing inflammation of the CNS is standard. The widely accepted first-line treatment is high doses of intravenous corticosteroids , such as methylprednisolone or dexamethasone , followed by 3–6 weeks of gradually lower oral doses of prednisolone . Patients treated with methylprednisolone have shown better outcomes than those treated with dexamethasone. Oral tapers of less than three weeks duration show a higher chance of relapsing, and tend to show poorer outcomes. [ citation needed ] Other anti-inflammatory and immunosuppressive therapies have been reported to show beneficial effect, such as plasmapheresis , high doses of intravenous immunoglobulin (IVIg), mitoxantrone and cyclophosphamide . These are considered alternative therapies, used when corticosteroids cannot be used or fail to show an effect. [ citation needed ] There is some evidence to suggest that patients may respond to a combination of methylprednisolone and immunoglobulins if they fail to respond to either separately In a study of 16 children with ADEM, 10 recovered completely after high-dose methylprednisolone, one severe case that failed to respond to steroids recovered completely after IV Ig; the five most severe cases – with ADAM and severe peripheral neuropathy – were treated with combined high-dose methylprednisolone and immunoglobulin, two remained paraplegic, one had motor and cognitive handicaps, and two recovered. A recent review of IVIg treatment of ADEM (of which the previous study formed the bulk of the cases) found that 70% of children showed complete recovery after treatment with IVIg, or IVIg plus corticosteroids. A study of IVIg treatment in adults with ADEM showed that IVIg seems more effective in treating sensory and motor disturbances, while steroids seem more effective in treating impairments of cognition, consciousness and rigor. This same study found one subject, a 71-year-old man who had not responded to steroids, that responded to an IVIg treatment 58 days after disease onset. [ citation needed ]Full recovery is seen in 50 to 70% of cases, ranging to 70 to 90% recovery with some minor residual disability (typically assessed using measures such as mRS or EDSS ), average time to recover is one to six months. The mortality rate may be as high as 5–10%. Poorer outcomes are associated with unresponsiveness to steroid therapy, unusually severe neurological symptoms, or sudden onset. Children tend to have more favorable outcomes than adults, and cases presenting without fevers tend to have poorer outcomes. The latter effect may be due to either protective effects of fever, or that diagnosis and treatment is sought more rapidly when fever is present. ADEM can progress to MS. It will be considered MS if some lesions appear in different times and brain areas Residual motor deficits are estimated to remain in about 8 to 30% of cases, the range in severity from mild clumsiness to ataxia and hemiparesis . Patients with demyelinating illnesses, such as MS, have shown cognitive deficits even when there is minimal physical disability. Research suggests that similar effects are seen after ADEM, but that the deficits are less severe than those seen in MS. A study of six children with ADEM (mean age at presentation 7.7 years) were tested for a range of neurocognitive tests after an average of 3.5 years of recovery. All six children performed in the normal range on most tests, including verbal IQ and performance IQ , but performed at least one standard deviation below age norms in at least one cognitive domain, such as complex attention (one child), short-term memory (one child) and internalizing behaviour/ affect (two children). Group means for each cognitive domain were all within one standard deviation of age norms, demonstrating that, as a group, they were normal. These deficits were less severe than those seen in similar aged children with a diagnosis of MS. Another study compared nineteen children with a history of ADEM, of which 10 were five years of age or younger at the time (average age 3.8 years old, tested an average of 3.9 years later) and nine were older (mean age 7.7y at time of ADEM, tested an average of 2.2 years later) to nineteen matched controls. Scores on IQ tests and educational achievement were lower for the young onset ADEM group (average IQ 90) compared to the late onset (average IQ 100) and control groups (average IQ 106), while the late onset ADEM children scored lower on verbal processing speed. Again, all groups means were within one standard deviation of the controls, meaning that while effects were statistically reliable, the children were as a whole, still within the normal range. There were also more behavioural problems in the early onset group, although there is some suggestion that this may be due, at least in part, to the stress of hospitalization at a young age. Residual motor deficits are estimated to remain in about 8 to 30% of cases, the range in severity from mild clumsiness to ataxia and hemiparesis . Patients with demyelinating illnesses, such as MS, have shown cognitive deficits even when there is minimal physical disability. Research suggests that similar effects are seen after ADEM, but that the deficits are less severe than those seen in MS. A study of six children with ADEM (mean age at presentation 7.7 years) were tested for a range of neurocognitive tests after an average of 3.5 years of recovery. All six children performed in the normal range on most tests, including verbal IQ and performance IQ , but performed at least one standard deviation below age norms in at least one cognitive domain, such as complex attention (one child), short-term memory (one child) and internalizing behaviour/ affect (two children). Group means for each cognitive domain were all within one standard deviation of age norms, demonstrating that, as a group, they were normal. These deficits were less severe than those seen in similar aged children with a diagnosis of MS. Another study compared nineteen children with a history of ADEM, of which 10 were five years of age or younger at the time (average age 3.8 years old, tested an average of 3.9 years later) and nine were older (mean age 7.7y at time of ADEM, tested an average of 2.2 years later) to nineteen matched controls. Scores on IQ tests and educational achievement were lower for the young onset ADEM group (average IQ 90) compared to the late onset (average IQ 100) and control groups (average IQ 106), while the late onset ADEM children scored lower on verbal processing speed. Again, all groups means were within one standard deviation of the controls, meaning that while effects were statistically reliable, the children were as a whole, still within the normal range. There were also more behavioural problems in the early onset group, although there is some suggestion that this may be due, at least in part, to the stress of hospitalization at a young age. The relationship between ADEM and anti-MOG associated encephalomyelitis is currently under research. A new entity called MOGDEM has been proposed. About animal models, the main animal model for MS, experimental autoimmune encephalomyelitis (EAE) is also an animal model for ADEM. Being an acute monophasic illness, EAE is far more similar to ADEM than MS.

Wiki

Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/Waterhouse–Friderichsen_syndrome/html

Waterhouse–Friderichsen syndrome

Waterhouse–Friderichsen syndrome ( WFS ) is defined as adrenal gland failure due to bleeding into the adrenal glands, commonly caused by severe bacterial infection. Typically, it is caused by Neisseria meningitidis . The bacterial infection leads to massive bleeding into one or (usually) both adrenal glands. It is characterized by overwhelming bacterial infection meningococcemia leading to massive blood invasion, organ failure , coma , low blood pressure and shock , disseminated intravascular coagulation (DIC) with widespread purpura , rapidly developing adrenocortical insufficiency and death.Waterhouse–Friderichsen syndrome can be caused by a number of different organisms (see below). When caused by Neisseria meningitidis , WFS is considered the most severe form of meningococcal sepsis . The onset of the illness is nonspecific with fever, rigors, vomiting, and headache. Soon a rash appears; first macular, not much different from the rose spots of typhoid , and rapidly becoming petechial and purpuric with a dusky gray color. Low blood pressure ( hypotension ) develops and rapidly leads to septic shock . The cyanosis of extremities can be extreme and the patient is very prostrated or comatose. In this form of meningococcal disease, meningitis generally does not occur. Low levels of blood glucose and sodium , high levels of potassium in the blood , and the ACTH stimulation test demonstrate the acute adrenal failure. Leukocytosis need not be extreme and in fact leukopenia may be seen and it is a very poor prognostic sign. C-reactive protein levels can be elevated or almost normal. Thrombocytopenia is sometimes extreme, with alteration in prothrombin time (PT) and partial thromboplastin time (PTT) suggestive of disseminated intravascular coagulation (DIC). Acidosis and acute kidney failure can be seen as in any severe sepsis. Meningococci can be readily cultured from blood or cerebrospinal fluid , and can sometimes be seen in smears of cutaneous lesions. Difficulty swallowing, atrophy of the tongue, and cracks at the corners of the mouth are also characteristic features. [ citation needed ]Multiple species of bacteria can be associated with the condition: Viruses may also be implicated in adrenal problems:Diagnostic criteria are based on clinical features of adrenal insufficiency as well as identifying the causal agent. If the causal agent is suspected to be meningitis a lumbar puncture is performed. If the causal agent is suspected to be bacterial a blood culture and complete blood count is performed. An adrenocorticotropic hormone stimulation test can be performed to assess adrenal function.Routine vaccination against meningococcus is recommended by the Centers for Disease Control and Prevention for all 11- to 18-year-olds and people who have poor splenic function (who, for example, have had their spleen removed or who have sickle-cell disease which damages the spleen), or who have certain immune disorders, such as a complement deficiency. Fulminant infection from meningococcal bacteria in the bloodstream is a medical emergency and requires emergent treatment with vasopressors, fluid resuscitation, and appropriate antibiotics. Benzylpenicillin was once the drug of choice with chloramphenicol as a good alternative in allergic patients. Ceftriaxone is an antibiotic commonly employed today. Hydrocortisone can sometimes reverse the adrenal insufficiency. Amputations, reconstructive surgery, and tissue grafting are sometimes needed as a result of tissue necrosis (typically of the extremities) caused by the infection. [ citation needed ]The prognosis of Waterhouse–Friderichsen syndrome varies by severity of the illness. Around 15% of patients with significant acute bilateral adrenal bleeding experience a fatal outcome. In cases where diagnosis and appropriate treatment are delayed, the case fatality rate approaches 50%. Recovery is possible with appropriate, timely management of the illness. Mineralocorticoid and glucocorticoid treatments may be necessary depending on the recovering patient's electrolyte status and response to treatment. Research shows that people with adrenal hemorrhage can regain adrenal function to some degree. Waterhouse–Friderichsen syndrome is named after Rupert Waterhouse (1873–1958), an English physician , and Carl Friderichsen (1886–1979), a Danish pediatrician , who wrote papers on the syndrome, which had been previously described.

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Acute hemorrhagic fever syndrome

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Acute respiratory distress syndrome

Acute respiratory distress syndrome ( ARDS ) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs . Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin coloration (cyanosis). For those who survive, a decreased quality of life is common. Causes may include sepsis , pancreatitis , trauma , pneumonia , and aspiration . The underlying mechanism involves diffuse injury to cells which form the barrier of the microscopic air sacs of the lungs , surfactant dysfunction, activation of the immune system , and dysfunction of the body's regulation of blood clotting . In effect, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide . Adult diagnosis is based on a PaO 2 /FiO 2 ratio (ratio of partial pressure arterial oxygen and fraction of inspired oxygen) of less than 300 mm Hg despite a positive end-expiratory pressure (PEEP) of more than 5 cm H 2 O. Cardiogenic pulmonary edema , as the cause, must be excluded. The primary treatment involves mechanical ventilation together with treatments directed at the underlying cause. Ventilation strategies include using low volumes and low pressures. If oxygenation remains insufficient, lung recruitment maneuvers and neuromuscular blockers may be used. If these are insufficient, extracorporeal membrane oxygenation (ECMO) may be an option. The syndrome is associated with a death rate between 35 and 50%. Globally, ARDS affects more than 3 million people a year. The condition was first described in 1967. Although the terminology of "adult respiratory distress syndrome" has at times been used to differentiate ARDS from " infant respiratory distress syndrome " in newborns, the international consensus is that "acute respiratory distress syndrome" is the best term because ARDS can affect people of all ages. There are separate diagnostic criteria for children and those in areas of the world with fewer resources. The signs and symptoms of ARDS often begin within two hours of an inciting event, but have been known to take as long as 1–3 days; diagnostic criteria require a known insult to have happened within 7 days of the syndrome. Signs and symptoms may include shortness of breath , fast breathing , and a low oxygen level in the blood due to abnormal ventilation. Other common symptoms include muscle fatigue and general weakness, low blood pressure, a dry, hacking cough, and fever. Complications may include the following: Other complications that are typically associated with ARDS include: Complications may include the following: Other complications that are typically associated with ARDS include: There are direct and indirect causes of ARDS depending whether the lungs are initially affected. Direct causes include pneumonia (including bacterial and viral), aspiration, inhalational lung injury, lung contusion, chest trauma, and near-drowning. Indirect causes include sepsis , shock , pancreatitis , trauma (e.g. fat embolism), cardiopulmonary bypass , TRALI , burns, increased intracranial pressure . Fewer cases of ARDS are linked to large volumes of fluid used during post-trauma resuscitation. ARDS is a form of fluid accumulation in the lungs not explained by heart failure (noncardiogenic pulmonary edema). It is typically provoked by an acute injury to the lungs that results in flooding of the lungs' microscopic air sacs responsible for the exchange of gases such as oxygen and carbon dioxide with capillaries in the lungs. Additional common findings in ARDS include partial collapse of the alveoli( atelectasis ) and low levels of oxygen in the blood ( hypoxemia ). The clinical syndrome is associated with pathological findings including pneumonia, eosinophilic pneumonia , cryptogenic organizing pneumonia , acute fibrinous organizing pneumonia, and diffuse alveolar damage (DAD) . Of these, the pathology most commonly associated with ARDS is DAD, which is characterized by a diffuse inflammation of lung tissue. The triggering insult to the tissue usually results in an initial release of chemical signals and other inflammatory mediators secreted by local epithelial and endothelial cells. [ citation needed ] Neutrophils and some T- lymphocytes quickly migrate into the inflamed lung tissue and contribute in the amplification of the phenomenon. The typical histological presentation involves diffuse alveolar damage and hyaline membrane formation in alveolar walls. Although the triggering mechanisms are not completely understood, recent research has examined the role of inflammation and mechanical stress. [ citation needed ] One research group has reported that broncho-alveolar lavage fluid in later-stage ARDS often contains trichomonads , in an amoeboid form (i.e. lacking their characteristic flagellum) which makes them difficult to identify under the microscope. Diagnostic criteria for ARDS have changed over time as understanding of the pathophysiology has evolved. The international consensus criteria for ARDS were most recently updated in 2012 and are known as the "Berlin definition". In addition to generally broadening the diagnostic thresholds, other notable changes from the prior 1994 consensus criteria include discouraging the term "acute lung injury", and defining grades of ARDS severity according to degree of decrease in the oxygen content of the blood . [ citation needed ] According to the 2012 Berlin definition, adult ARDS is characterized by the following: [ citation needed ] mild ARDS : 201 – 300 mmHg (≤ 39.9 kPa) moderate ARDS : 101 – 200 mmHg (≤ 26.6 kPa) severe ARDS : ≤ 100 mmHg (≤ 13.3 kPa) The Berlin definition requires a minimum positive end expiratory pressure (PEEP) of 5 cm H 2 O for consideration of the Pa O 2 /Fi O 2 ratio. This degree of PEEP may be delivered noninvasively with CPAP to diagnose mild ARDS. The 2012 "Berlin criteria" are a modification of the prior 1994 consensus conference definitions (see history ). Radiologic imaging has long been a criterion for diagnosis of ARDS. Original definitions of ARDS specified that correlative chest X-ray findings were required for diagnosis, the diagnostic criteria have been expanded over time to accept CT and ultrasound findings as equally contributory. Generally, radiographic findings of fluid accumulation (pulmonary edema) affecting both lungs and unrelated to increased cardiopulmonary vascular pressure (such as in heart failure) may be suggestive of ARDS. Ultrasound findings suggestive of ARDS include the following: Anterior subpleural consolidations Absence or reduction of lung sliding "Spared areas" of normal parenchyma Pleural line abnormalities (irregular thickened fragmented pleural line) Nonhomogeneous distribution of B-lines (a characteristic ultrasound finding suggestive of fluid accumulation in the lungs) Diagnostic criteria for ARDS have changed over time as understanding of the pathophysiology has evolved. The international consensus criteria for ARDS were most recently updated in 2012 and are known as the "Berlin definition". In addition to generally broadening the diagnostic thresholds, other notable changes from the prior 1994 consensus criteria include discouraging the term "acute lung injury", and defining grades of ARDS severity according to degree of decrease in the oxygen content of the blood . [ citation needed ] According to the 2012 Berlin definition, adult ARDS is characterized by the following: [ citation needed ] mild ARDS : 201 – 300 mmHg (≤ 39.9 kPa) moderate ARDS : 101 – 200 mmHg (≤ 26.6 kPa) severe ARDS : ≤ 100 mmHg (≤ 13.3 kPa) The Berlin definition requires a minimum positive end expiratory pressure (PEEP) of 5 cm H 2 O for consideration of the Pa O 2 /Fi O 2 ratio. This degree of PEEP may be delivered noninvasively with CPAP to diagnose mild ARDS. The 2012 "Berlin criteria" are a modification of the prior 1994 consensus conference definitions (see history ). Radiologic imaging has long been a criterion for diagnosis of ARDS. Original definitions of ARDS specified that correlative chest X-ray findings were required for diagnosis, the diagnostic criteria have been expanded over time to accept CT and ultrasound findings as equally contributory. Generally, radiographic findings of fluid accumulation (pulmonary edema) affecting both lungs and unrelated to increased cardiopulmonary vascular pressure (such as in heart failure) may be suggestive of ARDS. Ultrasound findings suggestive of ARDS include the following: Anterior subpleural consolidations Absence or reduction of lung sliding "Spared areas" of normal parenchyma Pleural line abnormalities (irregular thickened fragmented pleural line) Nonhomogeneous distribution of B-lines (a characteristic ultrasound finding suggestive of fluid accumulation in the lungs) Acute respiratory distress syndrome is usually treated with mechanical ventilation in the intensive care unit (ICU) . Mechanical ventilation is usually delivered through a rigid tube which enters the oral cavity and is secured in the airway (endotracheal intubation), or by tracheostomy when prolonged ventilation (≥2 weeks) is necessary. The role of non-invasive ventilation is limited to the very early period of the disease or to prevent worsening respiratory distress in individuals with atypical pneumonias , lung bruising , or major surgery patients, who are at risk of developing ARDS. Treatment of the underlying cause is crucial. Appropriate antibiotic therapy is started as soon as culture results are available, or if infection is suspected (whichever is earlier). Empirical therapy may be appropriate if local microbiological surveillance is efficient. Where possible the origin of the infection is removed. When sepsis is diagnosed, appropriate local protocols are followed. [ citation needed ] The overall goal of mechanical ventilation is to maintain acceptable gas exchange to meet the body's metabolic demands and to minimize adverse effects in its application. The parameters PEEP (positive end-expiratory pressure, to keep alveoli open), mean airway pressure (to promote recruitment (opening) of easily collapsible alveoli and predictor of hemodynamic effects), and plateau pressure (best predictor of alveolar overdistention) are used. Previously, mechanical ventilation aimed to achieve tidal volumes ( V t ) of 12–15 ml/kg (where the weight is ideal body weight rather than actual weight). Recent studies have shown that high tidal volumes can overstretch alveoli resulting in volutrauma (secondary lung injury). The ARDS Clinical Network, or ARDSNet, completed a clinical trial that showed improved mortality when people with ARDS were ventilated with a tidal volume of 6 ml/kg compared to the traditional 12 ml/kg. Low tidal volumes ( V t ) may cause a permitted rise in blood carbon dioxide levels and collapse of alveoli because of their inherent tendency to increase shunting within the lung. Physiologic dead space cannot change as it is ventilation without perfusion. A shunt is a perfusion without ventilation within a lung region. [ citation needed ] Low tidal volume ventilation was the primary independent variable associated with reduced mortality in the NIH-sponsored ARDSNet trial of tidal volume in ARDS. Plateau pressure less than 30 cm H 2 O was a secondary goal, and subsequent analyses of the data from the ARDSNet trial and other experimental data demonstrate that there appears to be no safe upper limit to plateau pressure; regardless of plateau pressure, individuals with ARDS fare better with low tidal volumes. No particular ventilator mode is known to improve mortality in acute respiratory distress syndrome (ARDS). Some practitioners favor airway pressure release ventilation when treating ARDS. Well documented advantages to APRV ventilation include decreased airway pressures, decreased minute ventilation , decreased dead-space ventilation, promotion of spontaneous breathing, almost 24-hour-a-day alveolar recruitment, decreased use of sedation, near elimination of neuromuscular blockade, optimized arterial blood gas results, mechanical restoration of FRC (functional residual capacity), a positive effect on cardiac output (due to the negative inflection from the elevated baseline with each spontaneous breath), increased organ and tissue perfusion and potential for increased urine output secondary to increased kidney perfusion. [ citation needed ] A patient with ARDS, on average, spends between 8 and 11 days on a mechanical ventilator; APRV may reduce this time significantly and thus may conserve valuable resources. Positive end-expiratory pressure (PEEP) is used in mechanically ventilated people with ARDS to improve oxygenation. In ARDS, three populations of alveoli can be distinguished. There are normal alveoli that are always inflated and engaging in gas exchange, flooded alveoli which can never, under any ventilatory regime, be used for gas exchange, and atelectatic or partially flooded alveoli that can be "recruited" to participate in gas exchange under certain ventilatory regimens. The recruitable alveoli represent a continuous population, some of which can be recruited with minimal PEEP, and others can only be recruited with high levels of PEEP. An additional complication is that some alveoli can only be opened with higher airway pressures than are needed to keep them open, hence the justification for maneuvers where PEEP is increased to very high levels for seconds to minutes before dropping the PEEP to a lower level. PEEP can be harmful; high PEEP necessarily increases mean airway pressure and alveolar pressure, which can damage normal alveoli by overdistension resulting in DAD. A compromise between the beneficial and adverse effects of PEEP is inevitable. [ citation needed ] The 'best PEEP' used to be defined as 'some' cm H 2 O above the lower inflection point (LIP) in the sigmoidal pressure-volume relationship curve of the lung. Recent research has shown that the LIP-point pressure is no better than any pressure above it, as recruitment of collapsed alveoli — and, more importantly, the overdistension of aerated units — occur throughout the whole inflation. Despite the awkwardness of most procedures used to trace the pressure-volume curve, it is still used by some [ who? ] to define the minimum PEEP to be applied to their patients. Some new ventilators can automatically plot a pressure-volume curve. [ citation needed ] PEEP may also be set empirically. Some authors [ who? ] suggest performing a 'recruiting maneuver' — a short time at a very high continuous positive airway pressure, such as 50 cm H 2 O (4.9 kPa) — to recruit or open collapsed units with a high distending pressure before restoring previous ventilation. The final PEEP level should be the one just before the drop in Pa O 2 or peripheral blood oxygen saturation during a step-down trial. A large randomized controlled trial of patients with ARDS found that lung recruitment maneuvers and PEEP titration was associated with high rates of barotrauma and pneumothorax and increased mortality. Intrinsic PEEP (iPEEP) or auto-PEEP — first described by John Marini of St. Paul Regions Hospital — is a potentially unrecognized contributor to PEEP in intubated individuals. When ventilating at high frequencies, its contribution can be substantial, particularly in people with obstructive lung disease such as asthma or chronic obstructive pulmonary disease (COPD). iPEEP has been measured in very few formal studies on ventilation in ARDS, and its contribution is largely unknown. Its measurement is recommended in the treatment of people who have ARDS, especially when using high-frequency (oscillatory/jet) ventilation . [ citation needed ] The position of lung infiltrates in acute respiratory distress syndrome is non-uniform. Repositioning into the prone position (face down) might improve oxygenation by relieving atelectasis and improving perfusion. If this is done early in the treatment of severe ARDS, it confers a mortality benefit of 26% compared to supine ventilation. However, attention should be paid to avoid the SIDS in the management of the respiratory distressed infants by continuous careful monitoring of their cardiovascular system. Several studies have shown that pulmonary function and outcome are better in people with ARDS who lost weight or whose pulmonary wedge pressure was lowered by diuresis or fluid restriction. As of 2019, it is uncertain whether or not treatment with corticosteroids improves overall survival. Corticosteroids may increase the number of ventilator-free days during the first 28 days of hospitalization. One study found that dexamethasone may help. The combination of hydrocortisone, ascorbic acid, and thiamine also requires further study as of 2018. Inhaled nitric oxide (NO) selectively widens the lung's arteries which allows for more blood flow to open alveoli for gas exchange . Despite evidence of increased oxygenation status, there is no evidence that inhaled nitric oxide decreases morbidity and mortality in people with ARDS. Furthermore, nitric oxide may cause kidney damage and is not recommended as therapy for ARDS regardless of severity. Alvelestat (AZD 9668) had been quoted according to one review article. Extracorporeal membrane oxygenation (ECMO) is mechanically applied prolonged cardiopulmonary support. There are two types of ECMO: Venovenous which provides respiratory support and venoarterial which provides respiratory and hemodynamic support. People with ARDS who do not require cardiac support typically undergo venovenous ECMO. Multiple studies have shown the effectiveness of ECMO in acute respiratory failure. Specifically, the CESAR (Conventional ventilatory support versus Extracorporeal membrane oxygenation for Severe Acute Respiratory failure) trial demonstrated that a group referred to an ECMO center demonstrated significantly increased survival compared to conventional management (63% to 47%). As of 2019, there is no evidence showing that treatments with exogenous surfactants , statins , beta-blockers or n-acetylcysteine decreases early mortality, late all-cause mortality, duration of mechanical ventilation, or number of ventilator-free days. The overall goal of mechanical ventilation is to maintain acceptable gas exchange to meet the body's metabolic demands and to minimize adverse effects in its application. The parameters PEEP (positive end-expiratory pressure, to keep alveoli open), mean airway pressure (to promote recruitment (opening) of easily collapsible alveoli and predictor of hemodynamic effects), and plateau pressure (best predictor of alveolar overdistention) are used. Previously, mechanical ventilation aimed to achieve tidal volumes ( V t ) of 12–15 ml/kg (where the weight is ideal body weight rather than actual weight). Recent studies have shown that high tidal volumes can overstretch alveoli resulting in volutrauma (secondary lung injury). The ARDS Clinical Network, or ARDSNet, completed a clinical trial that showed improved mortality when people with ARDS were ventilated with a tidal volume of 6 ml/kg compared to the traditional 12 ml/kg. Low tidal volumes ( V t ) may cause a permitted rise in blood carbon dioxide levels and collapse of alveoli because of their inherent tendency to increase shunting within the lung. Physiologic dead space cannot change as it is ventilation without perfusion. A shunt is a perfusion without ventilation within a lung region. [ citation needed ] Low tidal volume ventilation was the primary independent variable associated with reduced mortality in the NIH-sponsored ARDSNet trial of tidal volume in ARDS. Plateau pressure less than 30 cm H 2 O was a secondary goal, and subsequent analyses of the data from the ARDSNet trial and other experimental data demonstrate that there appears to be no safe upper limit to plateau pressure; regardless of plateau pressure, individuals with ARDS fare better with low tidal volumes. No particular ventilator mode is known to improve mortality in acute respiratory distress syndrome (ARDS). Some practitioners favor airway pressure release ventilation when treating ARDS. Well documented advantages to APRV ventilation include decreased airway pressures, decreased minute ventilation , decreased dead-space ventilation, promotion of spontaneous breathing, almost 24-hour-a-day alveolar recruitment, decreased use of sedation, near elimination of neuromuscular blockade, optimized arterial blood gas results, mechanical restoration of FRC (functional residual capacity), a positive effect on cardiac output (due to the negative inflection from the elevated baseline with each spontaneous breath), increased organ and tissue perfusion and potential for increased urine output secondary to increased kidney perfusion. [ citation needed ] A patient with ARDS, on average, spends between 8 and 11 days on a mechanical ventilator; APRV may reduce this time significantly and thus may conserve valuable resources. Positive end-expiratory pressure (PEEP) is used in mechanically ventilated people with ARDS to improve oxygenation. In ARDS, three populations of alveoli can be distinguished. There are normal alveoli that are always inflated and engaging in gas exchange, flooded alveoli which can never, under any ventilatory regime, be used for gas exchange, and atelectatic or partially flooded alveoli that can be "recruited" to participate in gas exchange under certain ventilatory regimens. The recruitable alveoli represent a continuous population, some of which can be recruited with minimal PEEP, and others can only be recruited with high levels of PEEP. An additional complication is that some alveoli can only be opened with higher airway pressures than are needed to keep them open, hence the justification for maneuvers where PEEP is increased to very high levels for seconds to minutes before dropping the PEEP to a lower level. PEEP can be harmful; high PEEP necessarily increases mean airway pressure and alveolar pressure, which can damage normal alveoli by overdistension resulting in DAD. A compromise between the beneficial and adverse effects of PEEP is inevitable. [ citation needed ] The 'best PEEP' used to be defined as 'some' cm H 2 O above the lower inflection point (LIP) in the sigmoidal pressure-volume relationship curve of the lung. Recent research has shown that the LIP-point pressure is no better than any pressure above it, as recruitment of collapsed alveoli — and, more importantly, the overdistension of aerated units — occur throughout the whole inflation. Despite the awkwardness of most procedures used to trace the pressure-volume curve, it is still used by some [ who? ] to define the minimum PEEP to be applied to their patients. Some new ventilators can automatically plot a pressure-volume curve. [ citation needed ] PEEP may also be set empirically. Some authors [ who? ] suggest performing a 'recruiting maneuver' — a short time at a very high continuous positive airway pressure, such as 50 cm H 2 O (4.9 kPa) — to recruit or open collapsed units with a high distending pressure before restoring previous ventilation. The final PEEP level should be the one just before the drop in Pa O 2 or peripheral blood oxygen saturation during a step-down trial. A large randomized controlled trial of patients with ARDS found that lung recruitment maneuvers and PEEP titration was associated with high rates of barotrauma and pneumothorax and increased mortality. Intrinsic PEEP (iPEEP) or auto-PEEP — first described by John Marini of St. Paul Regions Hospital — is a potentially unrecognized contributor to PEEP in intubated individuals. When ventilating at high frequencies, its contribution can be substantial, particularly in people with obstructive lung disease such as asthma or chronic obstructive pulmonary disease (COPD). iPEEP has been measured in very few formal studies on ventilation in ARDS, and its contribution is largely unknown. Its measurement is recommended in the treatment of people who have ARDS, especially when using high-frequency (oscillatory/jet) ventilation . [ citation needed ]No particular ventilator mode is known to improve mortality in acute respiratory distress syndrome (ARDS). Some practitioners favor airway pressure release ventilation when treating ARDS. Well documented advantages to APRV ventilation include decreased airway pressures, decreased minute ventilation , decreased dead-space ventilation, promotion of spontaneous breathing, almost 24-hour-a-day alveolar recruitment, decreased use of sedation, near elimination of neuromuscular blockade, optimized arterial blood gas results, mechanical restoration of FRC (functional residual capacity), a positive effect on cardiac output (due to the negative inflection from the elevated baseline with each spontaneous breath), increased organ and tissue perfusion and potential for increased urine output secondary to increased kidney perfusion. [ citation needed ] A patient with ARDS, on average, spends between 8 and 11 days on a mechanical ventilator; APRV may reduce this time significantly and thus may conserve valuable resources. Positive end-expiratory pressure (PEEP) is used in mechanically ventilated people with ARDS to improve oxygenation. In ARDS, three populations of alveoli can be distinguished. There are normal alveoli that are always inflated and engaging in gas exchange, flooded alveoli which can never, under any ventilatory regime, be used for gas exchange, and atelectatic or partially flooded alveoli that can be "recruited" to participate in gas exchange under certain ventilatory regimens. The recruitable alveoli represent a continuous population, some of which can be recruited with minimal PEEP, and others can only be recruited with high levels of PEEP. An additional complication is that some alveoli can only be opened with higher airway pressures than are needed to keep them open, hence the justification for maneuvers where PEEP is increased to very high levels for seconds to minutes before dropping the PEEP to a lower level. PEEP can be harmful; high PEEP necessarily increases mean airway pressure and alveolar pressure, which can damage normal alveoli by overdistension resulting in DAD. A compromise between the beneficial and adverse effects of PEEP is inevitable. [ citation needed ] The 'best PEEP' used to be defined as 'some' cm H 2 O above the lower inflection point (LIP) in the sigmoidal pressure-volume relationship curve of the lung. Recent research has shown that the LIP-point pressure is no better than any pressure above it, as recruitment of collapsed alveoli — and, more importantly, the overdistension of aerated units — occur throughout the whole inflation. Despite the awkwardness of most procedures used to trace the pressure-volume curve, it is still used by some [ who? ] to define the minimum PEEP to be applied to their patients. Some new ventilators can automatically plot a pressure-volume curve. [ citation needed ] PEEP may also be set empirically. Some authors [ who? ] suggest performing a 'recruiting maneuver' — a short time at a very high continuous positive airway pressure, such as 50 cm H 2 O (4.9 kPa) — to recruit or open collapsed units with a high distending pressure before restoring previous ventilation. The final PEEP level should be the one just before the drop in Pa O 2 or peripheral blood oxygen saturation during a step-down trial. A large randomized controlled trial of patients with ARDS found that lung recruitment maneuvers and PEEP titration was associated with high rates of barotrauma and pneumothorax and increased mortality. Intrinsic PEEP (iPEEP) or auto-PEEP — first described by John Marini of St. Paul Regions Hospital — is a potentially unrecognized contributor to PEEP in intubated individuals. When ventilating at high frequencies, its contribution can be substantial, particularly in people with obstructive lung disease such as asthma or chronic obstructive pulmonary disease (COPD). iPEEP has been measured in very few formal studies on ventilation in ARDS, and its contribution is largely unknown. Its measurement is recommended in the treatment of people who have ARDS, especially when using high-frequency (oscillatory/jet) ventilation . [ citation needed ]The position of lung infiltrates in acute respiratory distress syndrome is non-uniform. Repositioning into the prone position (face down) might improve oxygenation by relieving atelectasis and improving perfusion. If this is done early in the treatment of severe ARDS, it confers a mortality benefit of 26% compared to supine ventilation. However, attention should be paid to avoid the SIDS in the management of the respiratory distressed infants by continuous careful monitoring of their cardiovascular system. Several studies have shown that pulmonary function and outcome are better in people with ARDS who lost weight or whose pulmonary wedge pressure was lowered by diuresis or fluid restriction. As of 2019, it is uncertain whether or not treatment with corticosteroids improves overall survival. Corticosteroids may increase the number of ventilator-free days during the first 28 days of hospitalization. One study found that dexamethasone may help. The combination of hydrocortisone, ascorbic acid, and thiamine also requires further study as of 2018. Inhaled nitric oxide (NO) selectively widens the lung's arteries which allows for more blood flow to open alveoli for gas exchange . Despite evidence of increased oxygenation status, there is no evidence that inhaled nitric oxide decreases morbidity and mortality in people with ARDS. Furthermore, nitric oxide may cause kidney damage and is not recommended as therapy for ARDS regardless of severity. Alvelestat (AZD 9668) had been quoted according to one review article. Extracorporeal membrane oxygenation (ECMO) is mechanically applied prolonged cardiopulmonary support. There are two types of ECMO: Venovenous which provides respiratory support and venoarterial which provides respiratory and hemodynamic support. People with ARDS who do not require cardiac support typically undergo venovenous ECMO. Multiple studies have shown the effectiveness of ECMO in acute respiratory failure. Specifically, the CESAR (Conventional ventilatory support versus Extracorporeal membrane oxygenation for Severe Acute Respiratory failure) trial demonstrated that a group referred to an ECMO center demonstrated significantly increased survival compared to conventional management (63% to 47%). As of 2019, there is no evidence showing that treatments with exogenous surfactants , statins , beta-blockers or n-acetylcysteine decreases early mortality, late all-cause mortality, duration of mechanical ventilation, or number of ventilator-free days. The overall prognosis of ARDS is poor, with mortality rates of approximately 40%. Exercise limitation, physical and psychological sequelae, decreased physical quality of life, and increased costs and use of health care services are important sequelae of ARDS. [ citation needed ]The annual rate of ARDS is generally 13–23 people per 100,000 in the general population. It is more common in people who are mechanically ventilated with acute lung injury (ALI) occurring in 16% of ventilated people. Rates increased in 2020 due to COVID-19 , with some cases also appearing similar to HAPE . Worldwide, severe sepsis is the most common trigger causing ARDS. Other triggers include mechanical ventilation, sepsis, pneumonia, Gilchrist's disease, drowning, circulatory shock, aspiration , trauma — especially pulmonary contusion — major surgery, massive blood transfusions , smoke inhalation , drug reaction or overdose, fat emboli and reperfusion pulmonary edema after lung transplantation or pulmonary embolectomy. However, the majority of patients with all these conditions mentioned do not develop ARDS. It is unclear why some people with the mentioned factors above do not develop ARDS and others do. [ citation needed ] Pneumonia and sepsis are the most common triggers, and pneumonia is present in up to 60% of patients and may be either causes or complications of ARDS. Alcohol excess appears to increase the risk of ARDS. Diabetes was originally thought to decrease the risk of ARDS, but this has shown to be due to an increase in the risk of pulmonary edema. Elevated abdominal pressure of any cause is also probably a risk factor for the development of ARDS, particularly during mechanical ventilation. [ citation needed ]Acute respiratory distress syndrome was first described in 1967 by Ashbaugh et al. Initially there was no clearly established definition, which resulted in controversy regarding the incidence and death of ARDS. In 1988, an expanded definition was proposed, which quantified physiologic respiratory impairment. In 1994, a new definition was recommended by the American-European Consensus Conference Committee which recognized the variability in severity of pulmonary injury. The definition required the following criteria to be met: acute onset, persistent dyspnea bilateral infiltrates on chest radiograph consistent with pulmonary edema hypoxemia, defined as Pa O 2 :Fi O 2 < 200 mmHg (26.7 kPa) absence of left atrial (LA) hypertension pulmonary artery wedge pressure < 18 mmHg (obtained by pulmonary artery catheterization ) if no measured LA pressure available, there must be no other clinical evidence to suggest elevated left heart pressure. If Pa O 2 :Fi O 2 < 300 mmHg (40 kPa), then the definitions recommended a classification as "acute lung injury" (ALI). Note that according to these criteria, arterial blood gas analysis and chest X-ray were required for formal diagnosis. Limitations of these definitions include lack of precise definition of acuity, nonspecific imaging criteria, lack of precise definition of hypoxemia with regards to PEEP (affects arterial oxygen partial pressure), arbitrary Pa O 2 thresholds without systematic data. In 2012, the Berlin Definition of ARDS was devised by the European Society of Intensive Care Medicine, and was endorsed by the American Thoracic Society and the Society of Critical Care Medicine . These recommendations were an effort to both update classification criteria in order to improve clinical usefulness and to clarify terminology. Notably, the Berlin guidelines discourage the use of the term "acute lung injury" or ALI, as the term was commonly being misused to characterize a less severe degree of lung injury. Instead, the committee proposes a classification of ARDS severity as mild, moderate, or severe according to arterial oxygen saturation. The Berlin definitions represent the current international consensus guidelines for both clinical and research classification of ARDS. [ citation needed ]In 1994, a new definition was recommended by the American-European Consensus Conference Committee which recognized the variability in severity of pulmonary injury. The definition required the following criteria to be met: acute onset, persistent dyspnea bilateral infiltrates on chest radiograph consistent with pulmonary edema hypoxemia, defined as Pa O 2 :Fi O 2 < 200 mmHg (26.7 kPa) absence of left atrial (LA) hypertension pulmonary artery wedge pressure < 18 mmHg (obtained by pulmonary artery catheterization ) if no measured LA pressure available, there must be no other clinical evidence to suggest elevated left heart pressure. If Pa O 2 :Fi O 2 < 300 mmHg (40 kPa), then the definitions recommended a classification as "acute lung injury" (ALI). Note that according to these criteria, arterial blood gas analysis and chest X-ray were required for formal diagnosis. Limitations of these definitions include lack of precise definition of acuity, nonspecific imaging criteria, lack of precise definition of hypoxemia with regards to PEEP (affects arterial oxygen partial pressure), arbitrary Pa O 2 thresholds without systematic data. In 2012, the Berlin Definition of ARDS was devised by the European Society of Intensive Care Medicine, and was endorsed by the American Thoracic Society and the Society of Critical Care Medicine . These recommendations were an effort to both update classification criteria in order to improve clinical usefulness and to clarify terminology. Notably, the Berlin guidelines discourage the use of the term "acute lung injury" or ALI, as the term was commonly being misused to characterize a less severe degree of lung injury. Instead, the committee proposes a classification of ARDS severity as mild, moderate, or severe according to arterial oxygen saturation. The Berlin definitions represent the current international consensus guidelines for both clinical and research classification of ARDS. [ citation needed ]ARDS is the severe form of acute lung injury (ALI), and of transfusion-related acute lung injury (TRALI), though there are other causes. The Berlin definition included ALI as a mild form of ARDS. However, the criteria for the diagnosis of ARDS in the Berlin definition excludes many children, and a new definition for children was termed pediatric acute respiratory distress syndrome (PARDS); this is known as the PALICC definition (2015). There is ongoing research on the treatment of ARDS by interferon (IFN) beta-1a to aid in preventing leakage of vascular beds. Traumakine (FP-1201-lyo) is a recombinant human IFN beta-1a drug, developed by the Finnish company Faron Pharmaceuticals , which is undergoing international phase-III clinical trials after an open-label, early-phase trial showed an 81% reduction-in-odds of 28-day mortality in ICU patients with ARDS. The drug is known to function by enhancing lung CD73 expression and increasing production of anti-inflammatory adenosine, such that vascular leaking and escalation of inflammation are reduced. Aspirin has been studied in those who are at high risk and was not found to be useful. An intravenous ascorbic acid treatment was tested in the 2019 RCT , in people with ARDS due to sepsis and there was no change in primary endpoints.

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Acute hemorrhagic fever syndrome

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Dengue fever

Dengue fever is a mosquito-borne tropical disease caused by dengue virus . It is frequently asymptomatic ; if symptoms appear they typically begin 3 to 14 days after infection. These may include a high fever , headache , vomiting , muscle and joint pains , and a characteristic skin itching and skin rash . Recovery generally takes two to seven days. In a small proportion of cases, the disease develops into severe dengue (previously known as dengue hemorrhagic fever or dengue shock syndrome) with bleeding , low levels of blood platelets , blood plasma leakage, and dangerously low blood pressure . Dengue virus has four confirmed serotypes ; infection with one type usually gives lifelong immunity to that type, but only short-term immunity to the others. Subsequent infection with a different type increases the risk of severe complications. The symptoms of dengue resemble many other diseases including malaria , influenza , and Zika . Blood tests are available to confirm the diagnosis including detecting viral RNA , or antibodies to the virus. There is no specific treatment for dengue fever. In mild cases, treatment is focused on treating pain symptoms. Severe cases of dengue require hospitalisation; treatment of acute dengue is supportive and includes giving fluid either by mouth or intravenously . Dengue is spread by several species of female mosquitoes of the Aedes genus , principally Aedes aegypti . Infection can be prevented by mosquito elimination and the prevention of bites. Two types of dengue vaccine have been approved and are commercially available. Dengvaxia became available in 2016 but it is only recommended to prevent re-infection in individuals who have been previously infected. The second vaccine, Qdenga, became available in 2022 and is suitable for adults, adolescents and children from four years of age. The earliest descriptions of a dengue outbreak date from 1779; its viral cause and spread were understood by the early 20th century. Already endemic in more than one hundred countries, dengue is spreading from tropical and subtropical regions to the Iberian Peninsula and the southern states of the US, partly attributed to climate change. It is classified as a neglected tropical disease . During 2023, more than 5 million infections were reported, with more than 5,000 dengue-related deaths. As most cases are asymptomatic or mild, the actual numbers of dengue cases and deaths are under-reported. Typically, people infected with dengue virus are asymptomatic (80%) or have only mild symptoms such as an uncomplicated fever. Others have more severe illness (5%), and in a small proportion it is life-threatening. The incubation period (time between exposure and onset of symptoms) ranges from 3 to 14 days, but most often it is 4 to 7 days. The characteristic symptoms of mild dengue are sudden-onset fever, headache (typically located behind the eyes), muscle and joint pains, nausea, vomiting, swollen glands and a rash. If this progresses to severe dengue the symptoms are severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums or nose, fatigue, restlessness, blood in vomit or stool, extreme thirst, pale and cold skin, and feelings of weakness. The course of infection is divided into three phases: febrile, critical, and recovery. The febrile phase involves high fever (40 °C/104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days. There may also be nausea, vomiting, a rash, and pains in the muscle and joints. Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This is called severe dengue , (formerly called dengue hemorrhagic fever or dengue shock syndrome ). Severe dengue can lead to shock, internal bleeding, organ failure and even death. Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools. During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets . This may result in fluid accumulation in the chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs . The recovery phase usually lasts two to three days. The improvement is often striking, and can be accompanied with severe itching and a slow heart rate . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . The course of infection is divided into three phases: febrile, critical, and recovery. The febrile phase involves high fever (40 °C/104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days. There may also be nausea, vomiting, a rash, and pains in the muscle and joints. Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This is called severe dengue , (formerly called dengue hemorrhagic fever or dengue shock syndrome ). Severe dengue can lead to shock, internal bleeding, organ failure and even death. Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools. During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets . This may result in fluid accumulation in the chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs . The recovery phase usually lasts two to three days. The improvement is often striking, and can be accompanied with severe itching and a slow heart rate . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . Dengue virus (DENV) is an RNA virus of the family Flaviviridae ; genus Flavivirus . Other members of the same genus include yellow fever virus , West Nile virus , and Zika virus . Dengue virus genome (genetic material) contains about 11,000 nucleotide bases , which code for the three structural protein molecules (C, prM and E) that form the virus particle and seven other protein molecules that are required for replication of the virus. There are four confirmed strains of the virus, called serotypes , referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity . Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti . They prefer to feed at dusk and dawn, but they may bite and thus spread infection at any time of day. Other Aedes species that may transmit the disease include A. albopictus , A. polynesiensis and A. scutellaris . Humans are the primary host of the virus, but it also circulates in nonhuman primates , and can infect other mammals. An infection can be acquired via a single bite. For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the viremic period). A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut. Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Dengue can also be transmitted via infected blood products and through organ donation . Vertical transmission (from mother to child) during pregnancy or at birth has been reported. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent ( DEET being the most effective). Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease. Other risk factors for severe disease include female sex, and high body mass index , Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. Subsequent re-infection with a different serotype increases the risk of severe complications due to phenomenon known as antibody-dependent enhancement (ADE). The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes , as well as specialized immune cell located in the skin, called a Langerhans cells . The Langerhans cells migrate to the lymph nodes , where the infection spreads to white blood cells , and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing several signaling proteins, such as cytokines and interferons , which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow ) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability . As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective); it's also advisable to treat clothing, nets and tents with 0.5% permethrin . Protection of the home can be achieved with door and window screens, by using air conditioning, and by regularly emptying and cleaning all receptacles both indoors and outdoors which may accumulate water (such as buckets, planters, pools or trashcans). The primary method of controlling A. aegypti is by eliminating its habitats . This is done by eliminating open sources of water, or if this is not possible, by adding insecticides or biological control agents to these areas. Generalized spraying with organophosphate or pyrethroid insecticides, while sometimes done, is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents. Ideally, mosquito control would be a community activity, e.g. when all members of a community clear blocked gutters and street drains and keep their yards free of containers with standing water. If residences have direct water connections this eliminates the need for wells or street pumps and water-carrying containers. As of March 2024, there are two vaccines to protect against dengue infection; Dengvaxia and Qdenga . Dengvaxia (formerly CYD-TDV) became available in 2015, and is approved for use in the US, EU and in some Asian and Latin American countries. It is an attenuated virus, is suitable for individuals aged 6–45 years and protects against all four serotypes of dengue. Due to safety concerns about antibody-dependent enhancement (ADE), it should only be given to individuals who have previously been infected with dengue, in order to protect them from reinfection. It is given subcutaneously as three doses at six month intervals. Qdenga (formerly TAK-003) completed clinical trials in 2022 and was approved for use in the European Union in December 2022; it has been approved by a number of other countries including Indonesia and Brazil, and has been recommended by the SAGE committee of the World Health Organization. It is indicated for the prevention of dengue disease in individuals four years of age and older, and can be administered to people who have not been previously infected with dengue. It is a live attenuated vaccine containing the four serotypes of dengue virus, administered subcutaneously as two doses three months apart. Dengue virus (DENV) is an RNA virus of the family Flaviviridae ; genus Flavivirus . Other members of the same genus include yellow fever virus , West Nile virus , and Zika virus . Dengue virus genome (genetic material) contains about 11,000 nucleotide bases , which code for the three structural protein molecules (C, prM and E) that form the virus particle and seven other protein molecules that are required for replication of the virus. There are four confirmed strains of the virus, called serotypes , referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity . Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti . They prefer to feed at dusk and dawn, but they may bite and thus spread infection at any time of day. Other Aedes species that may transmit the disease include A. albopictus , A. polynesiensis and A. scutellaris . Humans are the primary host of the virus, but it also circulates in nonhuman primates , and can infect other mammals. An infection can be acquired via a single bite. For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the viremic period). A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut. Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Dengue can also be transmitted via infected blood products and through organ donation . Vertical transmission (from mother to child) during pregnancy or at birth has been reported. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent ( DEET being the most effective). Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease. Other risk factors for severe disease include female sex, and high body mass index , Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. Subsequent re-infection with a different serotype increases the risk of severe complications due to phenomenon known as antibody-dependent enhancement (ADE). The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes , as well as specialized immune cell located in the skin, called a Langerhans cells . The Langerhans cells migrate to the lymph nodes , where the infection spreads to white blood cells , and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing several signaling proteins, such as cytokines and interferons , which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow ) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability . As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective); it's also advisable to treat clothing, nets and tents with 0.5% permethrin . Protection of the home can be achieved with door and window screens, by using air conditioning, and by regularly emptying and cleaning all receptacles both indoors and outdoors which may accumulate water (such as buckets, planters, pools or trashcans). The primary method of controlling A. aegypti is by eliminating its habitats . This is done by eliminating open sources of water, or if this is not possible, by adding insecticides or biological control agents to these areas. Generalized spraying with organophosphate or pyrethroid insecticides, while sometimes done, is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents. Ideally, mosquito control would be a community activity, e.g. when all members of a community clear blocked gutters and street drains and keep their yards free of containers with standing water. If residences have direct water connections this eliminates the need for wells or street pumps and water-carrying containers. As of March 2024, there are two vaccines to protect against dengue infection; Dengvaxia and Qdenga . Dengvaxia (formerly CYD-TDV) became available in 2015, and is approved for use in the US, EU and in some Asian and Latin American countries. It is an attenuated virus, is suitable for individuals aged 6–45 years and protects against all four serotypes of dengue. Due to safety concerns about antibody-dependent enhancement (ADE), it should only be given to individuals who have previously been infected with dengue, in order to protect them from reinfection. It is given subcutaneously as three doses at six month intervals. Qdenga (formerly TAK-003) completed clinical trials in 2022 and was approved for use in the European Union in December 2022; it has been approved by a number of other countries including Indonesia and Brazil, and has been recommended by the SAGE committee of the World Health Organization. It is indicated for the prevention of dengue disease in individuals four years of age and older, and can be administered to people who have not been previously infected with dengue. It is a live attenuated vaccine containing the four serotypes of dengue virus, administered subcutaneously as two doses three months apart. The World Health Organization 's International Classification of Diseases divides dengue fever into two classes: uncomplicated and severe. Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage. Severe dengue can develop suddenly, sometimes after a few days as the fever subsides. Leakage of plasma from the capillaries results in extreme low blood pressure and hypovolemic shock ; Patients with severe plasma leakage may have fluid accumulation in the lungs or abdomen , insufficient protein in the blood , or thickening of the blood . Severe dengue is a medical emergency which can cause damage to organs, leading to multiple organ failure and death. Mild cases of dengue fever can easily be confused with several common diseases including Influenza , measles , chikungunya , and zika . Dengue, chikungunya and zika share the same mode of transmission ( Aedes mosquitoes) and are often endemic in the same regions, so that it is possible to be infected simultaneously by more than one disease. For travellers, dengue fever diagnosis should be considered in anyone who develops a fever within two weeks of being in the tropics or subtropics . Warning symptoms of severe dengue include abdominal pain, persistent vomiting, odema, bleeding, lethargy, and liver enlargement. Once again, these symptoms can be confused with other diseases such as malaria, gastroenteritis, leptospirosis, and typhus. Blood tests can be used to confirm a diagnosis of dengue. During the first few days of infection, enzyme-linked immunosorbent assay ( ELISA ) can be used to detect the NS1 antigen ; however this antigen is produced by all flaviviruses. Four or five days into the infection, it is possible to reliably detect anti-dengue IgM antibodies, but this does not determine the serotype. Nucleic acid amplification tests provide the most reliable method of diagnosis. As of March 2024, there is no specific antiviral treatment available for dengue fever. Most cases of dengue fever have mild symptoms, and recovery takes place in a few days. No treatment is required for these cases. Acetaminophen (Paracetamol, Tylenol ) may be used to relieve mild fever or pain. Other common pain relievers, including aspirin , ibuprofen (Advil, Motrin IB, others) and naproxen sodium (Aleve) should be avoided as they can increase the risk of bleeding complications. For moderate illness, those who can drink, are passing urine, have no warning signs and are otherwise reasonably healthy can be monitored carefully at home. Supportive care with analgesics, fluid replacement, and bed rest are recommended. Severe dengue is a life-threatening emergency, requiring hospitalization and potentially intensive care. Warning signs include dehydration , decreasing platelets and increasing hematocrit . Treatment modes include intravenous fluids, and transfusion with platelets or plasma. Most people with dengue recover without any ongoing problems. The risk of death among those with severe dengue is 0.8% to 2.5%, and with adequate treatment this is less than 1%. However, those who develop significantly low blood pressure may have a fatality rate of up to 26%. The risk of death among children less than five years old is four times greater than among those over the age of 10. Elderly people are also at higher risk of a poor outcome. As of March 2023, dengue is endemic in more than 100 countries with cases reported in every continent with the exception of Antarctica. The Americas, Southeast Asia and the Western Pacific regions are the most seriously affected. It is difficult to estimate the full extent of the disease, as many cases are mild and not correctly diagnosed. WHO currently estimates that 3.9 billion people are at risk of dengue infection. In 2013, it was estimated that 390 million dengue infections occur every year, with 500,000 of these developing severe symptoms and 25,000 deaths. Generally, areas where dengue is endemic have only one serotype of the virus in circulation. The disease is said to be hyperendemic in areas where more than one serotype is circulating; this increases the risk of severe disease on a second or subsequent infection. Infections are most commonly acquired in urban environments where the virus is primarily transmitted by the mosquito species Aedes aegypti . This species has adapted to the urban environment, is generally found close to human habitation, prefers humans as its host, and takes advantage of small bodies of standing water (such as tanks and buckets) in which to breed. In rural settings the virus is transmitted to humans by A. aegypti and other related mosquitoes such as Aedes albopictus . Both these species have expanding ranges. Dengue has increased in incidence in recent decades, with WHO recording a ten fold increase between 2010 and 2019 (from 500,000 to 5 million recorded cases). This increase is tied closely to the increasing range of Aedes mosquitoes, which is attributed to a combination of urbanization , population growth, and an increasingly warm climate . In endemic areas, dengue infections peak when rainfall is optimal for mosquito breeding. The disease infects all races, sexes, and ages equally. In endemic areas, the infection is most commonly seen in children who then acquire a lifelong partial immunity. The first historical record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin Dynasty (266–420) which referred to a "water poison" associated with flying insects. The principal mosquito vector of dengue, Aedes aegypti , spread out of Africa in the 15th to 19th centuries due to the slave trade and consequent expansion of international trading. There have been descriptions of epidemics of dengue-like illness in the 17th century, and it is likely that epidemics in Jakarta , Cairo , and Philadelphia during the 18th century were caused by dengue. It is assumed that dengue was constantly present in many tropical urban centres throughout the 19th and early 20th centuries, even though significant outbreaks were infrequent. The marked spread of dengue during and after the Second World War has been attributed partly to disruption caused by the war, and partly to subsequent urbanisation in south-east Asia. As novel serotypes were introduced to regions already endemic with dengue, outbreaks of severe disease followed. The severe hemorrhagic form of the disease was first reported in the Philippines in 1953; by the 1970s, it had become recognised as a major cause of child mortality in Southeast Asia. In Central and South America, the Aedes mosquito had been eradicated in the 1950s; however the eradication program was discontinued in the 1970s and the diesase re-established itself in the region during the 1980s, becoming hyperendemic and causing significant epidemics. Dengue has continued to increase in prevalence during the 21st century, as the mosquito vector continues to expand its range. This is attributed partly to continuing urbanisation, and partly to the impact of a warmer climate. The name came into English in the early 19th century from West Indian Spanish, which borrowed it from the Kiswahili term dinga (in full kidingapopo , "disease caused by an evil spirit"). The borrowed term changed to dengue in Spanish due to this word existing in Spanish with the meaning "fastidiousness" and this folk etymology referring to the dislike of movement by affected patients. Slaves in the West Indies having contracted dengue were said to have the posture and gait of a dandy , and the disease was known as "dandy fever". The term break-bone fever was applied by physician and United States Founding Father Benjamin Rush , in a 1789 report of the 1780 epidemic in Philadelphia , due to the associated muscle and joint pains. In the report title he uses the more formal term "bilious remitting fever". The term dengue fever came into general use only after 1828. Other historical terms include "breakheart fever" and "la dengue". Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever". The name came into English in the early 19th century from West Indian Spanish, which borrowed it from the Kiswahili term dinga (in full kidingapopo , "disease caused by an evil spirit"). The borrowed term changed to dengue in Spanish due to this word existing in Spanish with the meaning "fastidiousness" and this folk etymology referring to the dislike of movement by affected patients. Slaves in the West Indies having contracted dengue were said to have the posture and gait of a dandy , and the disease was known as "dandy fever". The term break-bone fever was applied by physician and United States Founding Father Benjamin Rush , in a 1789 report of the 1780 epidemic in Philadelphia , due to the associated muscle and joint pains. In the report title he uses the more formal term "bilious remitting fever". The term dengue fever came into general use only after 1828. Other historical terms include "breakheart fever" and "la dengue". Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever". Research directions include dengue pathogenesis (the process by which the disease develops in humans), as well as the biology, ecology and behaviour of the mosquito vector. Improved diagnostics would enable faster and more appropriate treatment. Attempts are ongoing to develop an antiviral medicine targeting the NS3 or NS5 proteins. In addition to the two vaccines which are already available, several vaccine candidates are in development. Outbreaks of dengue fever increase the need for blood products while decreasing the number of potential blood donors due to potential infection with the virus. Someone who has a dengue infection is typically not allowed to donate blood for at least the next six months. International Anti-Dengue Day is observed every year on 15 June in a number of countries. The idea was first agreed upon in 2010 with the first event held in Jakarta , Indonesia, in 2011. Further events were held in 2012 in Yangon , Myanmar, and in 2013 in Vietnam . Goals are to increase public awareness about dengue, mobilize resources for its prevention and control and, to demonstrate the Southeast Asian region's commitment in tackling the disease. Efforts are ongoing as of 2019 to make it a global event. The Philippines has an awareness month in June since 1998. A National Dengue Day is held in India annually on 16 May. A study estimate that the global burden of dengue in 2013 amounted to US$8·9 billion. Outbreaks of dengue fever increase the need for blood products while decreasing the number of potential blood donors due to potential infection with the virus. Someone who has a dengue infection is typically not allowed to donate blood for at least the next six months. International Anti-Dengue Day is observed every year on 15 June in a number of countries. The idea was first agreed upon in 2010 with the first event held in Jakarta , Indonesia, in 2011. Further events were held in 2012 in Yangon , Myanmar, and in 2013 in Vietnam . Goals are to increase public awareness about dengue, mobilize resources for its prevention and control and, to demonstrate the Southeast Asian region's commitment in tackling the disease. Efforts are ongoing as of 2019 to make it a global event. The Philippines has an awareness month in June since 1998. A National Dengue Day is held in India annually on 16 May. A study estimate that the global burden of dengue in 2013 amounted to US$8·9 billion.

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Acute hemorrhagic fever syndrome

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Acute pancreatitis

Acute pancreatitis (AP) is a sudden inflammation of the pancreas . Causes, in order of frequency, include: a gallstone impacted in the common bile duct beyond the point where the pancreatic duct joins it; heavy alcohol use ; systemic disease ; trauma ; and, in children, mumps . Acute pancreatitis may be a single event; it may be recurrent ; or it may progress to chronic pancreatitis . Mild cases are usually successfully treated with conservative measures: hospitalization, pain control, nothing by mouth , intravenous nutritional support, and intravenous fluid rehydration. Severe cases often require admission to an intensive care unit to monitor and manage complications of the disease. Complications are associated with a high mortality, even with optimal management. For people with this condition, the pancreas will begin to secrete active enzymes such as Trypsin, chymotrypsin and carboxypeptidase instead of their inactive forms. Damage to the pancreatic ducts can occur as a result of this.Although these are common symptoms, frequently they are not all present; and epigastric pain may be the only symptom. The following are associated with severe disease: Locoregional complications include pancreatic pseudocyst (most common, occurring in up to 25% of all cases, typically after 4–6 weeks) and phlegmon/abscess formation, splenic artery pseudoaneurysms, hemorrhage from erosions into splenic artery and vein, thrombosis of the splenic vein, superior mesenteric vein and portal veins (in descending order of frequency), duodenal obstruction, common bile duct obstruction, progression to chronic pancreatitis, pancreatic ascites, pleural effusion, sterile/infected pancreatic necrosis. Systemic complications include acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome , disseminated intravascular coagulation (DIC), hypocalcemia (from fat saponification), hyperglycemia and insulin dependent diabetes mellitus (from pancreatic insulin-producing beta cell damage), malabsorption due to exocrine failure Renal artery or vein thrombosis Kidney failure Gastrointestinal hemorrhage from stress ulceration Gastric varices (secondary to splenic vein thrombosis) Gastrointestinal obstruction Subcutaneous fat necrosis ArthalgiaAlthough these are common symptoms, frequently they are not all present; and epigastric pain may be the only symptom. The following are associated with severe disease:Locoregional complications include pancreatic pseudocyst (most common, occurring in up to 25% of all cases, typically after 4–6 weeks) and phlegmon/abscess formation, splenic artery pseudoaneurysms, hemorrhage from erosions into splenic artery and vein, thrombosis of the splenic vein, superior mesenteric vein and portal veins (in descending order of frequency), duodenal obstruction, common bile duct obstruction, progression to chronic pancreatitis, pancreatic ascites, pleural effusion, sterile/infected pancreatic necrosis. Systemic complications include acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome , disseminated intravascular coagulation (DIC), hypocalcemia (from fat saponification), hyperglycemia and insulin dependent diabetes mellitus (from pancreatic insulin-producing beta cell damage), malabsorption due to exocrine failure Renal artery or vein thrombosis Kidney failure Gastrointestinal hemorrhage from stress ulceration Gastric varices (secondary to splenic vein thrombosis) Gastrointestinal obstruction Subcutaneous fat necrosis ArthalgiaAcute pancreatitis occurs when there is abnormal activation of digestive enzymes within the pancreas. This occurs through inappropriate activation of inactive enzyme precursors called zymogens (or proenzymes) inside the pancreas, most notably trypsinogen . Normally, trypsinogen is converted to its active form ( trypsin ) in the first part of the small intestine ( duodenum ), where the enzyme assists in the digestion of proteins. During an episode of acute pancreatitis, trypsinogen comes into contact with lysosomal enzymes (specifically cathepsin ), which activate trypsinogen to trypsin. The active form trypsin then leads to further activation of other molecules of trypsinogen. The activation of these digestive enzymes lead to inflammation, edema, vascular injury, and even cellular death. The death of pancreatic cells occurs via two main mechanisms: necrosis, which is less organized and more damaging, or apoptosis, which is more controlled. The balance between these two mechanisms of cellular death is mediated by caspases which regulate apoptosis and have important anti-necrosis functions during pancreatitis: preventing trypsinogen activation, preventing ATP depletion through inhibiting polyADP-ribose polymerase, and by inhibiting the inhibitors of apoptosis (IAPs). If, however, the caspases are depleted due to either chronic ethanol exposure or through a severe insult then necrosis can predominate. The two types of acute pancreatitis are mild and severe, which are defined based on whether the predominant response to cell injury is inflammation (mild) or necrosis (severe). In mild pancreatitis, there is inflammation and edema of the pancreas. In severe pancreatitis, there is necrosis of the pancreas, and nearby organs may become injured. As part of the initial injury there is an extensive inflammatory response due to pancreatic cells synthesizing and secreting inflammatory mediators: primarily TNF-alpha and IL-1 . A hallmark of acute pancreatitis is a manifestation of the inflammatory response, namely the recruitment of neutrophils to the pancreas. The inflammatory response leads to the secondary manifestations of pancreatitis: hypovolemia from capillary permeability, acute respiratory distress syndrome, disseminated intravascular coagulations, renal failure, cardiovascular failure, and gastrointestinal hemorrhage. The acute pancreatitis (acute hemorrhagic pancreatic necrosis) is characterized by acute inflammation and necrosis of pancreas parenchyma , focal enzymic necrosis of pancreatic fat and vessel necrosis ( hemorrhage ). These are produced by intrapancreatic activation of pancreatic enzymes. Lipase activation produces the necrosis of fat tissue in pancreatic interstitium and peripancreatic spaces as well as vessel damage. Necrotic fat cells appear as shadows, contours of cells, lacking the nucleus, pink, finely granular cytoplasm. It is possible to find calcium precipitates ( hematoxylinophilic ). Digestion of vascular walls results in thrombosis and hemorrhage. Inflammatory infiltrate is rich in neutrophils . Due to the pancreas lacking a capsule, the inflammation and necrosis can extend to include fascial layers in the immediate vicinity of the pancreas.Acute pancreatitis occurs when there is abnormal activation of digestive enzymes within the pancreas. This occurs through inappropriate activation of inactive enzyme precursors called zymogens (or proenzymes) inside the pancreas, most notably trypsinogen . Normally, trypsinogen is converted to its active form ( trypsin ) in the first part of the small intestine ( duodenum ), where the enzyme assists in the digestion of proteins. During an episode of acute pancreatitis, trypsinogen comes into contact with lysosomal enzymes (specifically cathepsin ), which activate trypsinogen to trypsin. The active form trypsin then leads to further activation of other molecules of trypsinogen. The activation of these digestive enzymes lead to inflammation, edema, vascular injury, and even cellular death. The death of pancreatic cells occurs via two main mechanisms: necrosis, which is less organized and more damaging, or apoptosis, which is more controlled. The balance between these two mechanisms of cellular death is mediated by caspases which regulate apoptosis and have important anti-necrosis functions during pancreatitis: preventing trypsinogen activation, preventing ATP depletion through inhibiting polyADP-ribose polymerase, and by inhibiting the inhibitors of apoptosis (IAPs). If, however, the caspases are depleted due to either chronic ethanol exposure or through a severe insult then necrosis can predominate.The two types of acute pancreatitis are mild and severe, which are defined based on whether the predominant response to cell injury is inflammation (mild) or necrosis (severe). In mild pancreatitis, there is inflammation and edema of the pancreas. In severe pancreatitis, there is necrosis of the pancreas, and nearby organs may become injured. As part of the initial injury there is an extensive inflammatory response due to pancreatic cells synthesizing and secreting inflammatory mediators: primarily TNF-alpha and IL-1 . A hallmark of acute pancreatitis is a manifestation of the inflammatory response, namely the recruitment of neutrophils to the pancreas. The inflammatory response leads to the secondary manifestations of pancreatitis: hypovolemia from capillary permeability, acute respiratory distress syndrome, disseminated intravascular coagulations, renal failure, cardiovascular failure, and gastrointestinal hemorrhage.The acute pancreatitis (acute hemorrhagic pancreatic necrosis) is characterized by acute inflammation and necrosis of pancreas parenchyma , focal enzymic necrosis of pancreatic fat and vessel necrosis ( hemorrhage ). These are produced by intrapancreatic activation of pancreatic enzymes. Lipase activation produces the necrosis of fat tissue in pancreatic interstitium and peripancreatic spaces as well as vessel damage. Necrotic fat cells appear as shadows, contours of cells, lacking the nucleus, pink, finely granular cytoplasm. It is possible to find calcium precipitates ( hematoxylinophilic ). Digestion of vascular walls results in thrombosis and hemorrhage. Inflammatory infiltrate is rich in neutrophils . Due to the pancreas lacking a capsule, the inflammation and necrosis can extend to include fascial layers in the immediate vicinity of the pancreas.Acute pancreatitis is diagnosed using clinical history and physical examination , based on the presence of at least 2 of 3 criteria: abdominal pain, elevated serum lipase or amylase, and abdominal imaging findings consistent with acute pancreatitis. Additional blood studies are used to identify organ failure, offer prognostic information, and determine if fluid resuscitation is adequate and whether endoscopic retrograde cholangiopancreatography is necessary. The differential diagnosis includes: Elevated serum amylase and lipase levels, in combination with severe abdominal pain, often trigger the initial diagnosis of acute pancreatitis. However, they have no role in assessing disease severity. Serum lipase rises 4 to 8 hours from the onset of symptoms and normalizes within 7 to 14 days after treatment. Serum amylase may be normal (in 10% of cases) for cases of acute or chronic pancreatitis (depleted acinar cell mass) and hypertriglyceridemia. Reasons for false positive elevated serum amylase include salivary gland disease (elevated salivary amylase), bowel obstruction, infarction, cholecystitis, and a perforated ulcer. If the lipase level is about 2.5 to 3 times that of amylase, it is an indication of pancreatitis due to alcohol. Decreased serum calcium Glycosuria Decreased serum calcium Glycosuria Regarding selection on these tests, two practice guidelines state: Most, but not all individual studies support the superiority of the lipase. In one large study, there were no patients with pancreatitis who had an elevated amylase with a normal lipase. Another study found that the amylase could add diagnostic value to the lipase, but only if the results of the two tests were combined with a discriminant function equation. While often quoted lipase levels of 3 or more times the upper-limit of normal is diagnostic of pancreatitis, there are also other differential diagnosis to be considered relating to this rise. Regarding the need for computed tomography , practice guidelines state: CT is an important common initial assessment tool for acute pancreatitis. Imaging is indicated during the initial presentation if: the diagnosis of acute pancreatitis is uncertain there is abdominal distension and tenderness, fever >102 F (38,9 C), or leukocytosis there is a Ranson score > 3 or APACHE score > 8 there is no improvement after 72 hours of conservative medical therapy there has been an acute change in status: fever, pain, or shock CT is recommended as a delayed assessment tool in the following situations: acute change in status to determine therapeutic response after surgery or interventional radiologic procedure before discharge in patients with severe acute pancreatitis Abdominal CT should not be performed before the first 12 hours of onset of symptoms as early CT (102 F (38,9 C), or leukocytosis there is a Ranson score > 3 or APACHE score > 8 there is no improvement after 72 hours of conservative medical therapy there has been an acute change in status: fever, pain, or shock CT is recommended as a delayed assessment tool in the following situations: acute change in status to determine therapeutic response after surgery or interventional radiologic procedure before discharge in patients with severe acute pancreatitis Abdominal CT should not be performed before the first 12 hours of onset of symptoms as early CT ( 55 years white blood cell count > 16000 cells/mm3 blood glucose > 11.1 mmol/L (> 200 mg/dL) serum AST > 250 IU/L serum LDH > 350 IU/L Calcium (serum calcium 10% Oxygen (hypoxemia PO2 4 mEq/L Sequestration of fluids > 6 L The criteria for point assignment is that a certain breakpoint be met at any time during that 48 hour period, so that in some situations it can be calculated shortly after admission. It is applicable to both gallstone and alcoholic pancreatitis. Alternatively, pancreatitis can be diagnosed by meeting any of the following: Ranson's score of ≥ 8 Organ failure Substantial pancreatic necrosis (at least 30% glandular necrosis according to contrast-enhanced CT) Interpretation If the score ≥ 3, severe pancreatitis likely. If the score < 3, severe pancreatitis is unlikely Or Score 0 to 2 : 2% mortality Score 3 to 4 : 15% mortality Score 5 to 6 : 40% mortality Score 7 to 8 : 100% mortality "Acute Physiology And Chronic Health Evaluation" ( APACHE II ) score > 8 points predicts 11% to 18% mortality Developed in the early 1990s by Emil J. Balthazar et al. , the Computed Tomography Severity Index (CTSI) is a grading system used to determine the severity of acute pancreatitis. The numerical CTSI has a maximum of ten points, and is the sum of the Balthazar grade points and pancreatic necrosis grade points: Balthazar grade Necrosis score CTSI's staging of acute pancreatitis severity has been shown by a number of studies to provide more accurate assessment than APACHE II, Ranson, and C-reactive protein (CRP) level. However, a few studies indicate that CTSI is not significantly associated with the prognosis of hospitalization in patients with pancreatic necrosis, nor is it an accurate predictor of AP severity. The Glasgow score is valid for both gallstone and alcohol induced pancreatitis, whereas the Ranson score is only for alcohol induced pancreatitis [ citation needed ] . If a patient scores 3 or more it indicates severe pancreatitis and the patient should be considered for transfer to ITU. It is scored through the mnemonic, PANCREAS: P – PaO2 55-years-old N – Neutrophilia: WCC >15x10(9)/L C – Calcium 16 mmol/L E – Enzymes: LDH >600iu/L; AST >200iu/L A – Albumin 10 mmol/L Predicts mortality risk in pancreatitis with fewer variables than Ranson's criteria. Data should be taken from the first 24 hours of the patient's evaluation. BUN >25 mg/dL (8.9 mmol/L) Abnormal mental status with a Glasgow coma score 60 years old Imaging study reveals pleural effusion Patients with a score of zero had a mortality of less than one percent, whereas patients with a score of five had a mortality rate of 22 percent. In the validation cohort, the BISAP score had similar test performance characteristics for predicting mortality as the APACHE II score. As is a problem with many of the other scoring systems, the BISAP has not been validated for predicting outcomes such as length of hospital stay, need for ICU care, or need for intervention.The Ranson score is used to predict the severity of acute pancreatitis. They were introduced in 1974. age in years > 55 years white blood cell count > 16000 cells/mm3 blood glucose > 11.1 mmol/L (> 200 mg/dL) serum AST > 250 IU/L serum LDH > 350 IU/L Calcium (serum calcium 10% Oxygen (hypoxemia PO2 4 mEq/L Sequestration of fluids > 6 L The criteria for point assignment is that a certain breakpoint be met at any time during that 48 hour period, so that in some situations it can be calculated shortly after admission. It is applicable to both gallstone and alcoholic pancreatitis. Alternatively, pancreatitis can be diagnosed by meeting any of the following:age in years > 55 years white blood cell count > 16000 cells/mm3 blood glucose > 11.1 mmol/L (> 200 mg/dL) serum AST > 250 IU/L serum LDH > 350 IU/LCalcium (serum calcium 10% Oxygen (hypoxemia PO2 4 mEq/L Sequestration of fluids > 6 L The criteria for point assignment is that a certain breakpoint be met at any time during that 48 hour period, so that in some situations it can be calculated shortly after admission. It is applicable to both gallstone and alcoholic pancreatitis. Alternatively, pancreatitis can be diagnosed by meeting any of the following:Ranson's score of ≥ 8 Organ failure Substantial pancreatic necrosis (at least 30% glandular necrosis according to contrast-enhanced CT) Interpretation If the score ≥ 3, severe pancreatitis likely. If the score < 3, severe pancreatitis is unlikely Or Score 0 to 2 : 2% mortality Score 3 to 4 : 15% mortality Score 5 to 6 : 40% mortality Score 7 to 8 : 100% mortality"Acute Physiology And Chronic Health Evaluation" ( APACHE II ) score > 8 points predicts 11% to 18% mortality Developed in the early 1990s by Emil J. Balthazar et al. , the Computed Tomography Severity Index (CTSI) is a grading system used to determine the severity of acute pancreatitis. The numerical CTSI has a maximum of ten points, and is the sum of the Balthazar grade points and pancreatic necrosis grade points: Balthazar grade Necrosis score CTSI's staging of acute pancreatitis severity has been shown by a number of studies to provide more accurate assessment than APACHE II, Ranson, and C-reactive protein (CRP) level. However, a few studies indicate that CTSI is not significantly associated with the prognosis of hospitalization in patients with pancreatic necrosis, nor is it an accurate predictor of AP severity. The Glasgow score is valid for both gallstone and alcohol induced pancreatitis, whereas the Ranson score is only for alcohol induced pancreatitis [ citation needed ] . If a patient scores 3 or more it indicates severe pancreatitis and the patient should be considered for transfer to ITU. It is scored through the mnemonic, PANCREAS: P – PaO2 55-years-old N – Neutrophilia: WCC >15x10(9)/L C – Calcium 16 mmol/L E – Enzymes: LDH >600iu/L; AST >200iu/L A – Albumin 10 mmol/LPredicts mortality risk in pancreatitis with fewer variables than Ranson's criteria. Data should be taken from the first 24 hours of the patient's evaluation. BUN >25 mg/dL (8.9 mmol/L) Abnormal mental status with a Glasgow coma score 60 years old Imaging study reveals pleural effusion Patients with a score of zero had a mortality of less than one percent, whereas patients with a score of five had a mortality rate of 22 percent. In the validation cohort, the BISAP score had similar test performance characteristics for predicting mortality as the APACHE II score. As is a problem with many of the other scoring systems, the BISAP has not been validated for predicting outcomes such as length of hospital stay, need for ICU care, or need for intervention.In the United States, the annual incidence is 18 cases of acute pancreatitis per 100,000 population, and it accounts for 220,000 hospitalizations in the US. In a European cross-sectional study, incidence of acute pancreatitis increased from 12.4 to 15.9 per 100,000 annually from 1985 to 1995; however, mortality remained stable as a result of better outcomes. Another study showed a lower incidence of 9.8 per 100,000 but a similar worsening trend (increasing from 4.9 in 1963–74) over time. In Western countries, the most common cause is alcohol, accounting for 65 percent of acute pancreatitis cases in the US, 20 percent of cases in Sweden, and 5 percent of those in the United Kingdom. [ citation needed ] In Eastern countries, gallstones are the most common cause of acute pancreatitis. The causes of acute pancreatitis also varies across age groups, with trauma and systemic disease (such as infection) being more common in children. Mumps is a more common cause in adolescents and young adults than in other age groups.

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Acute hemorrhagic fever syndrome

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Lassa fever

Lassa fever , also known as Lassa hemorrhagic fever , is a type of viral hemorrhagic fever caused by the Lassa virus . Many of those infected by the virus do not develop symptoms . When symptoms occur they typically include fever , weakness, headaches, vomiting , and muscle pains . Less commonly there may be bleeding from the mouth or gastrointestinal tract . The risk of death once infected is about one percent and frequently occurs within two weeks of the onset of symptoms. Of those who survive, about a quarter have hearing loss , which improves within three months in about half of these cases. The disease is usually initially spread to people via contact with the urine or feces of an infected multimammate mouse . Spread can then occur via direct contact between people. Diagnosis based on symptoms is difficult. Confirmation is by laboratory testing to detect the virus's RNA , antibodies for the virus, or the virus itself in cell culture . Other conditions that may present similarly include Ebola , malaria , typhoid fever , and yellow fever . The Lassa virus is a member of the Arenaviridae family of viruses . There is no vaccine . Prevention requires isolating those who are infected and decreasing contact with the mice. Other efforts to control the spread of disease include having a cat to hunt vermin , and storing food in sealed containers. Treatment is directed at addressing dehydration and improving symptoms. The antiviral medication ribavirin has been recommended, but evidence to support its use is weak. Descriptions of the disease date from the 1950s. The virus was first described in 1969 from a case in the town of Lassa, in Borno State , Nigeria . Lassa fever is relatively common in West Africa including the countries of Nigeria , Liberia , Sierra Leone , Guinea , and Ghana . There are about 300,000 to 500,000 cases which result in 5,000 deaths a year. Onset of symptoms is typically 7 to 21 days after exposure. In 80% of those who are infected few or no symptoms occur. These mild symptoms may include fever, tiredness, weakness, and headache. In 20% of people more severe symptoms such as bleeding gums, breathing problems, vomiting, chest pain, or dangerously low blood pressure may occur. Long term complications may include hearing loss . In those who are pregnant , miscarriage may occur in 95% of child-bearing females . Lassa fever can be difficult to distinguish clinically from other viral hemorrhagic fevers, such as Ebola virus disease . A combination of pharyngitis , pain behind the sternum , presence of excess protein in the urine and fever can indicate Lassa fever with higher specificity. In cases in which death occurs, this typically occurs within 14 days of onset. About 1% of all Lassa virus infections result in death. Approximately 15%-20% of those who have required hospitalization for Lassa fever die. The risk of death is greater in those who are pregnant. A "Swollen baby syndrome" may occur in newborns, infants and toddlers with pitting edema , abdominal distension and bleeding. Lassa virus is a member of the Arenaviridae , a family of negative-sense, single-stranded RNA viruses . Specifically it is an old world arenavirus, which is enveloped, single-stranded, and bi-segmented RNA. Lassa virus contains both a large and a small genome section, with seven lineages identified to date: Lineages I, II, and III from Nigeria ; Lineage IV from Sierra Leone , Guinea , and Liberia ; Lineage V from Cote D'Ivoire and Mali Lineage VI from Togo ; and Lineage VII from Benin . Lassa virus commonly spreads to humans from other animals, specifically the Natal multimammate mouse or African rat, also called the Natal multimammate rat ( Mastomys natalensis ). This is probably the most common mouse in equatorial Africa, common in human households and eaten as a delicacy in some areas. The multimammate mouse can quickly produce a large number of offspring, tends to colonize human settlements, increasing the risk of rodent-human contact, and is found throughout the west, central and eastern parts of the African continent. Once the mouse has become a carrier, it will excrete the virus throughout the rest of its lifetime through feces and urine creating ample opportunity for exposure. The virus is probably transmitted by contact with the feces or urine of animals accessing grain stores in residences. No study has proven presence in breast milk, but the high level of viremia suggests it may be possible. Individuals who are at a higher risk of contracting the infection are those who live in rural areas where Mastomys are discovered, and where sanitation is not prevalent. Infection typically occurs by direct or indirect exposure to animal excrement through the respiratory or gastrointestinal tracts. Inhalation of tiny particles of infectious material (aerosol) is believed to be the most significant means of exposure. It is possible to acquire the infection through broken skin or mucous membranes that are directly exposed to infectious material. Transmission from person to person has been established, presenting a disease risk for healthcare workers. The virus is present in urine for between three and nine weeks after infection, and it can be transmitted in semen for up to three months after becoming infected. Lassa virus is a member of the Arenaviridae , a family of negative-sense, single-stranded RNA viruses . Specifically it is an old world arenavirus, which is enveloped, single-stranded, and bi-segmented RNA. Lassa virus contains both a large and a small genome section, with seven lineages identified to date: Lineages I, II, and III from Nigeria ; Lineage IV from Sierra Leone , Guinea , and Liberia ; Lineage V from Cote D'Ivoire and Mali Lineage VI from Togo ; and Lineage VII from Benin . Lassa virus commonly spreads to humans from other animals, specifically the Natal multimammate mouse or African rat, also called the Natal multimammate rat ( Mastomys natalensis ). This is probably the most common mouse in equatorial Africa, common in human households and eaten as a delicacy in some areas. The multimammate mouse can quickly produce a large number of offspring, tends to colonize human settlements, increasing the risk of rodent-human contact, and is found throughout the west, central and eastern parts of the African continent. Once the mouse has become a carrier, it will excrete the virus throughout the rest of its lifetime through feces and urine creating ample opportunity for exposure. The virus is probably transmitted by contact with the feces or urine of animals accessing grain stores in residences. No study has proven presence in breast milk, but the high level of viremia suggests it may be possible. Individuals who are at a higher risk of contracting the infection are those who live in rural areas where Mastomys are discovered, and where sanitation is not prevalent. Infection typically occurs by direct or indirect exposure to animal excrement through the respiratory or gastrointestinal tracts. Inhalation of tiny particles of infectious material (aerosol) is believed to be the most significant means of exposure. It is possible to acquire the infection through broken skin or mucous membranes that are directly exposed to infectious material. Transmission from person to person has been established, presenting a disease risk for healthcare workers. The virus is present in urine for between three and nine weeks after infection, and it can be transmitted in semen for up to three months after becoming infected. A range of laboratory investigations are performed, where possible, to diagnose the disease and assess its course and complications. The confidence of a diagnosis can be compromised if laboratory tests are not available. One comprising factor is the number of febrile illnesses present in Africa, such as malaria or typhoid fever that could potentially exhibit similar symptoms, particularly for non-specific manifestations of Lassa fever. In cases with abdominal pain , in countries where Lassa is common, Lassa fever is often misdiagnosed as appendicitis and intussusception which delays treatment with the antiviral ribavirin . In West Africa, where Lassa is most common, it is difficult to diagnose due to the absence of proper equipment to perform testing. The FDA has yet to approve a widely validated laboratory test for Lassa, but there are tests that have been able to provide definitive proof of the presence of the LASV virus. These tests include cell cultures, PCR, ELISA antigen assays, plaque neutralization assays, and immunofluorescence essays. However, immunofluorescence essays provide less definitive proof of Lassa infection. An ELISA test for antigen and Immunoglobulin M antibodies give 88% sensitivity and 90% specificity for the presence of the infection. Other laboratory findings in Lassa fever include lymphocytopenia (low white blood cell count), thrombocytopenia (low platelets), and elevated aspartate transaminase levels in the blood. Lassa fever virus can also be found in cerebrospinal fluid . Control of the Mastomys rodent population is impractical, so measures focus on keeping rodents out of homes and food supplies, encouraging effective personal hygiene, storing grain and other foodstuffs in rodent-proof containers, and disposing of garbage far from the home to help sustain clean households. Gloves, masks, laboratory coats, and goggles are advised while in contact with an infected person, to avoid contact with blood and body fluids. These issues in many countries are monitored by a department of public health . In less developed countries, these types of organizations may not have the necessary means to effectively control outbreaks. There is no vaccine for humans as of 2023. Researchers at the United States Army Medical Research Institute of Infectious Diseases facility had a promising vaccine candidate in 2002. They have developed a replication -competent vaccine against Lassa virus based on recombinant vesicular stomatitis virus vectors expressing the Lassa virus glycoprotein. After a single intramuscular injection , test primates have survived lethal challenge, while showing no clinical symptoms. There is no vaccine for humans as of 2023. Researchers at the United States Army Medical Research Institute of Infectious Diseases facility had a promising vaccine candidate in 2002. They have developed a replication -competent vaccine against Lassa virus based on recombinant vesicular stomatitis virus vectors expressing the Lassa virus glycoprotein. After a single intramuscular injection , test primates have survived lethal challenge, while showing no clinical symptoms. Treatment is directed at addressing dehydration and improving symptoms. All persons suspected of Lassa fever infection should be admitted to isolation facilities and their body fluids and excreta properly disposed of. [ citation needed ] The antiviral medication ribavirin has been recommended, but evidence to support its use is weak. Some evidence has found that it may worsen outcomes in certain cases. Fluid replacement, blood transfusions, and medication for low blood pressure may be required. Intravenous interferon therapy has also been used. When Lassa fever infects pregnant women late in their third trimester, inducing delivery is necessary for the mother to have a good chance of survival. This is because the virus has an affinity for the placenta and other highly vascular tissues. The fetus has only a one in ten chance of survival no matter what course of action is taken; hence, the focus is always on saving the life of the mother. Following delivery, women should receive the same treatment as other people with Lassa fever. [ citation needed ]The antiviral medication ribavirin has been recommended, but evidence to support its use is weak. Some evidence has found that it may worsen outcomes in certain cases. Fluid replacement, blood transfusions, and medication for low blood pressure may be required. Intravenous interferon therapy has also been used. When Lassa fever infects pregnant women late in their third trimester, inducing delivery is necessary for the mother to have a good chance of survival. This is because the virus has an affinity for the placenta and other highly vascular tissues. The fetus has only a one in ten chance of survival no matter what course of action is taken; hence, the focus is always on saving the life of the mother. Following delivery, women should receive the same treatment as other people with Lassa fever. [ citation needed ]About 15–20% of hospitalized people with Lassa fever will die from the illness. The overall case fatality rate is estimated to be 1%, but during epidemics , mortality can climb as high as 50%. The mortality rate is greater than 80% when it occurs in pregnant women during their third trimester; fetal death also occurs in nearly all those cases. Abortion decreases the risk of death to the mother. Some survivors experience lasting effects of the disease, and can include partial or complete deafness. Because of treatment with ribavirin , fatality rates have declined. There are about 300,000 to 500,000 cases which result in 5,000 deaths a year. One estimate places the number as high as 3 million cases per year. Estimates of Lassa fever are complicated by the lack of easy-available diagnosis, limited public health surveillance infrastructure, and high clustering of incidence near high intensity sampling. The infection affects females 1.2 times more than males. The age group predominantly infected is 21–30 years. Lassa high risk areas are near the western and eastern extremes of West Africa. As of 2018, the Lassa belt includes Guinea, Nigeria, Sierra Leone and Liberia. As of 2003, 10-16% of people in Sierra Leone and Liberia admitted to hospital had the virus. The case fatality rate for those who are hospitalized for the disease is about 15-20%. Research showed a twofold increase risk of infection for those living in close proximity to someone with infection symptoms within the last year. [ citation needed ] The high risk areas cannot be well defined by any known biogeographical or environmental breaks except for the multimammate rat, particularly Guinea ( Kindia , Faranah and Nzérékoré regions), Liberia (mostly in Lofa , Bong , and Nimba counties), Nigeria (in about 10 of 36 states) and Sierra Leone (typically from Kenema and Kailahun districts). It is less common in the Central African Republic, Mali, Senegal and other nearby countries, and less common yet in Ghana and the Democratic Republic of the Congo. Benin had its first confirmed cases in 2014, and Togo had its first confirmed cases in 2016. As of 2013, the spread of Lassa outside of West Africa had been very limited. Twenty to thirty cases had been described in Europe, as being caused by importation through infected individuals. These cases found outside of West Africa were found to have a high fatality risk because of the delay of diagnosis and treatment due to being unaware of the risk associated with the symptoms. Imported cases have not manifested in larger epidemics outside of Africa due to a lack of human to human transmission in hospital settings. An exception had occurred in 2003 when a healthcare worker became infected before the person showed clear symptoms. An outbreak of Lassa fever occurred in Nigeria during 2018 and spread to 18 of the country's states; it was the largest outbreak of Lassa recorded. On 25 February 2018, there were 1081 suspected cases and 90 reported deaths; 317 of the cases and 72 deaths were confirmed as Lassa which increased to a total of 431 reported cases in 2018. The total cases in Nigeria in 2019 was 810 with 167 deaths, the largest case fatality rate (23.3%) until then. The epidemic started from the second week of the January. By the tenth week the total number of cases has risen to 855 and deaths to 144, the case fatality rate of 16.8%. On the 8th of December 2021, the Nigeria Centre for Disease Control (NCDC) was notified of the death of two persons from Lassa fever. The epidemic took a new form, from 3 to 30 January 2022, 211 laboratory confirmed Lassa fever cases including 40 deaths (case fatality ratio: 19%) have been cumulatively reported in 14 of the 36 Nigerian states and the Federal Capital Territory across the country. In total from January until March, 132 deaths have been reported with a case fatality rate (CFR) of 19.1% which is lower than the CFR for the same period in 2021 (21.0%). Lassa high risk areas are near the western and eastern extremes of West Africa. As of 2018, the Lassa belt includes Guinea, Nigeria, Sierra Leone and Liberia. As of 2003, 10-16% of people in Sierra Leone and Liberia admitted to hospital had the virus. The case fatality rate for those who are hospitalized for the disease is about 15-20%. Research showed a twofold increase risk of infection for those living in close proximity to someone with infection symptoms within the last year. [ citation needed ] The high risk areas cannot be well defined by any known biogeographical or environmental breaks except for the multimammate rat, particularly Guinea ( Kindia , Faranah and Nzérékoré regions), Liberia (mostly in Lofa , Bong , and Nimba counties), Nigeria (in about 10 of 36 states) and Sierra Leone (typically from Kenema and Kailahun districts). It is less common in the Central African Republic, Mali, Senegal and other nearby countries, and less common yet in Ghana and the Democratic Republic of the Congo. Benin had its first confirmed cases in 2014, and Togo had its first confirmed cases in 2016. As of 2013, the spread of Lassa outside of West Africa had been very limited. Twenty to thirty cases had been described in Europe, as being caused by importation through infected individuals. These cases found outside of West Africa were found to have a high fatality risk because of the delay of diagnosis and treatment due to being unaware of the risk associated with the symptoms. Imported cases have not manifested in larger epidemics outside of Africa due to a lack of human to human transmission in hospital settings. An exception had occurred in 2003 when a healthcare worker became infected before the person showed clear symptoms. An outbreak of Lassa fever occurred in Nigeria during 2018 and spread to 18 of the country's states; it was the largest outbreak of Lassa recorded. On 25 February 2018, there were 1081 suspected cases and 90 reported deaths; 317 of the cases and 72 deaths were confirmed as Lassa which increased to a total of 431 reported cases in 2018. The total cases in Nigeria in 2019 was 810 with 167 deaths, the largest case fatality rate (23.3%) until then. The epidemic started from the second week of the January. By the tenth week the total number of cases has risen to 855 and deaths to 144, the case fatality rate of 16.8%. On the 8th of December 2021, the Nigeria Centre for Disease Control (NCDC) was notified of the death of two persons from Lassa fever. The epidemic took a new form, from 3 to 30 January 2022, 211 laboratory confirmed Lassa fever cases including 40 deaths (case fatality ratio: 19%) have been cumulatively reported in 14 of the 36 Nigerian states and the Federal Capital Territory across the country. In total from January until March, 132 deaths have been reported with a case fatality rate (CFR) of 19.1% which is lower than the CFR for the same period in 2021 (21.0%). An outbreak of Lassa fever occurred in Nigeria during 2018 and spread to 18 of the country's states; it was the largest outbreak of Lassa recorded. On 25 February 2018, there were 1081 suspected cases and 90 reported deaths; 317 of the cases and 72 deaths were confirmed as Lassa which increased to a total of 431 reported cases in 2018. The total cases in Nigeria in 2019 was 810 with 167 deaths, the largest case fatality rate (23.3%) until then. The epidemic started from the second week of the January. By the tenth week the total number of cases has risen to 855 and deaths to 144, the case fatality rate of 16.8%. On the 8th of December 2021, the Nigeria Centre for Disease Control (NCDC) was notified of the death of two persons from Lassa fever. The epidemic took a new form, from 3 to 30 January 2022, 211 laboratory confirmed Lassa fever cases including 40 deaths (case fatality ratio: 19%) have been cumulatively reported in 14 of the 36 Nigerian states and the Federal Capital Territory across the country. In total from January until March, 132 deaths have been reported with a case fatality rate (CFR) of 19.1% which is lower than the CFR for the same period in 2021 (21.0%). Lassa fever is endemic in Liberia. From 1 January 2017 through 23 January 2018, 91 suspected cases were reported from six counties: Bong, Grand Bassa, Grand Kru, Lofa, Margibi, and Nimba. Thirty-three of these cases were laboratory confirmed, including 15 deaths (case fatality rate for confirmed cases = 45.4%). In February 2020, a total of 24 confirmed cases with nine associated deaths has been reported from nine health districts in six counties. Grand Bossa and Bong counties account for 20 of the confirmed cases. The disease was identified in Nigeria in 1969. It is named after the town of Lassa, where it was discovered. A prominent expert in the disease, Aniru Conteh , died from the disease. The Lassa virus is one of several viruses identified by WHO as a likely cause of a future epidemic. They therefore list it for urgent research and development to develop new diagnostic tests, vaccines, and medicines. In 2007, SIGA Technologies , studied a medication in guinea pig with Lassa fever. Work on a vaccine is continuing, with multiple approaches showing positive results in animal trials.

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Acute hemorrhagic fever syndrome

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Kawasaki disease

Kawasaki disease (also known as mucocutaneous lymph node syndrome ) is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis , where medium-sized blood vessels become inflamed throughout the body. The fever typically lasts for more than five days and is not affected by usual medications . Other common symptoms include large lymph nodes in the neck, a rash in the genital area, lips, palms , or soles of the feet, and red eyes . Within three weeks of the onset, the skin from the hands and feet may peel, after which recovery typically occurs. The disease is the leading cause of acquired heart disease in children in developed countries, which include the formation of coronary artery aneurysms and myocarditis . While the specific cause is unknown, it is thought to result from an excessive immune response to particular infections in children who are genetically predisposed to those infections. It is not an infectious disease , that is, it does not spread between people. Diagnosis is usually based on a person's signs and symptoms. Other tests such as an ultrasound of the heart and blood tests may support the diagnosis. Diagnosis must take into account many other conditions that may present similar features, including scarlet fever and juvenile rheumatoid arthritis . An emerging 'Kawasaki-like' disease temporally associated with COVID-19 appears to be a distinct syndrome. Typically, initial treatment of Kawasaki disease consists of high doses of aspirin and immunoglobulin . Usually, with treatment, fever resolves within 24 hours and full recovery occurs. If the coronary arteries are involved, ongoing treatment or surgery may occasionally be required. Without treatment, coronary artery aneurysms occur in up to 25% and about 1% die. With treatment, the risk of death is reduced to 0.17%. People who have had coronary artery aneurysms after Kawasaki disease require lifelong cardiological monitoring by specialized teams. Kawasaki disease is rare. It affects between 8 and 67 per 100,000 people under the age of five except in Japan, where it affects 124 per 100,000. Boys are more commonly affected than girls. The disorder is named after Japanese pediatrician Tomisaku Kawasaki , who first described it in 1967. Kawasaki disease often begins with a high and persistent fever that is not very responsive to normal treatment with paracetamol (acetaminophen) or ibuprofen . This is the most prominent symptom of Kawasaki disease, and is a characteristic sign that the disease is in its acute phase; the fever normally presents as a high (above 39–40 °C) and remittent , and is followed by extreme irritability . Recently, it is reported to be present in patients with atypical or incomplete Kawasaki disease; nevertheless, it is not present in 100% of cases. The first day of fever is considered the first day of the illness, and its duration is typically one to two weeks; in the absence of treatment, it may extend for three to four weeks. Prolonged fever is associated with a higher incidence of cardiac involvement. It responds partially to antipyretic drugs and does not cease with the introduction of antibiotics . However, when appropriate therapy is started – intravenous immunoglobulin and aspirin – the fever subsides after two days. Bilateral conjunctival inflammation has been reported to be the most common symptom after fever. It typically involves the bulbar conjunctivae, is not accompanied by suppuration, and is not painful. This usually begins shortly after the onset of fever during the acute stage of the disease. Anterior uveitis may be present under slit-lamp examination . Iritis can occur, too. Keratic precipitates are another eye manifestation (detectable by a slit lamp, but are usually too small to be seen by the unaided eye). Kawasaki disease also presents with a set of mouth symptoms, the most characteristic of which are a red tongue, swollen lips with vertical cracking, and bleeding. The mucosa of the mouth and throat may be bright red, and the tongue may have a typical " strawberry tongue " appearance (marked redness with prominent gustative papillae ). These mouth symptoms are caused by necrotizing microvasculitis with fibrinoid necrosis . Cervical lymphadenopathy is seen in 50% to 75% of children, whereas the other features are estimated to occur in 90%, but sometimes it can be the dominant presenting symptom. According to the diagnostic criteria, at least one impaired lymph node ≥ 15 mm in diameter should be involved. Affected lymph nodes are painless or minimally painful, nonfluctuant, and nonsuppurative; erythema of the neighboring skin may occur. Children with fever and neck adenitis who do not respond to antibiotics should have Kawasaki disease considered as part of the differential diagnoses . In the acute phase of the disease, changes in the peripheral extremities can include erythema of the palms and soles , which is often striking with sharp demarcation and often accompanied by painful, brawny edema of the dorsa of the hands or feet, so affected children frequently refuse to hold objects in their hands or to bear weight on their feet. Later, during the convalescent or the subacute phase, desquamation of the fingers and toes usually begins in the periungual region within two to three weeks after the onset of fever and may extend to include the palms and soles. Around 11% of children affected by the disease may continue skin-peeling for many years. One to two months after the onset of fever, deep transverse grooves across the nails may develop ( Beau's lines ), and occasionally nails are shed. The most common skin manifestation is a diffuse macular - papular erythematous rash, which is quite nonspecific. The rash varies over time and is characteristically located on the trunk; it may further spread to involve the face, extremities, and perineum. Many other forms of cutaneous lesions have been reported; they may include scarlatiniform, papular, urticariform , multiform-like erythema , and purpuric lesions; even micropustules were reported. It can be polymorphic, not itchy , and normally observed up to the fifth day of fever. However, it is never bullous or vesicular . In the acute stage of Kawasaki disease, systemic inflammatory changes are evident in many organs. Joint pain ( arthralgia ) and swelling, frequently symmetrical, and arthritis can also occur. Myocarditis , diarrhea , pericarditis , valvulitis , aseptic meningitis , pneumonitis , lymphadenitis , and hepatitis may be present and are manifested by the presence of inflammatory cells in the affected tissues. If left untreated, some symptoms will eventually relent, but coronary artery aneurysms will not improve, resulting in a significant risk of death or disability due to myocardial infarction . If treated quickly, this risk can be mostly avoided and the course of illness cut short. Other reported nonspecific symptoms include cough , rhinorrhea , sputum , vomiting , headache , and seizure . The course of the disease can be divided into three clinical phases. Adult onset of Kawasaki disease is rare. The presentation differs between adults and children: in particular, it seems that adults more often have cervical lymphadenopathy, hepatitis , and arthralgia . Some children, especially young infants , have atypical presentations without the classic set of symptoms. Such presentations are associated with a higher risk of cardiac artery aneurysms. Heart complications are the most important aspect of Kawasaki disease, which is the leading cause of heart disease acquired in childhood in the United States and Japan. In developed nations, it appears to have replaced acute rheumatic fever as the most common cause of acquired heart disease in children. Coronary artery aneurysms occur as a sequela of the vasculitis in 20–25% of untreated children. It is first detected at a mean of 10 days of illness and the peak frequency of coronary artery dilation or aneurysms occurs within four weeks of onset. Aneurysms are classified into small (internal diameter of vessel wall 8 mm). Saccular and fusiform aneurysms usually develop between 18 and 25 days after the onset of illness. Even when treated with high-dose IVIG regimens within the first 10 days of illness, 5% of children with Kawasaki disease develop at the least transient coronary artery dilation and 1% develop giant aneurysms. Death can occur either due to myocardial infarction secondary to blood clot formation in a coronary artery aneurysm or to rupture of a large coronary artery aneurysm. Death is most common two to 12 weeks after the onset of illness. Many risk factors predicting coronary artery aneurysms have been identified, including persistent fever after IVIG therapy, low hemoglobin concentrations, low albumin concentrations, high white-blood-cell count, high band count , high CRP concentrations, male sex, and age less than one year. Coronary artery lesions resulting from Kawasaki disease change dynamically with time. Resolution one to two years after the onset of the disease has been observed in half of vessels with coronary aneurysms. Narrowing of the coronary artery, which occurs as a result of the healing process of the vessel wall, often leads to significant obstruction of the blood vessel and the heart not receiving enough blood and oxygen . This can eventually lead to heart muscle tissue death, i.e., myocardial infarction (MI). MI caused by thrombotic occlusion in an aneurysmal, stenotic, or both aneurysmal and stenotic coronary artery is the main cause of death from Kawasaki disease. The highest risk of MI occurs in the first year after the onset of the disease. MI in children presents with different symptoms from those in adults. The main symptoms were shock , unrest , vomiting , and abdominal pain ; chest pain was most common in older children. Most of these children had the attack occurring during sleep or at rest, and around one-third of attacks were asymptomatic. Valvular insufficiencies , particularly of mitral or tricuspid valves , are often observed in the acute phase of Kawasaki disease due to inflammation of the heart valve or inflammation of the heart muscle -induced myocardial dysfunction, regardless of coronary involvement. These lesions mostly disappear with the resolution of acute illness, but a very small group of the lesions persist and progress. There is also late-onset aortic or mitral insufficiency caused by thickening or deformation of fibrosed valves , with the timing ranging from several months to years after the onset of Kawasaki disease. Some of these lesions require valve replacement . Other Kawasaki disease complications have been described, such as aneurysm of other arteries: aortic aneurysm, with a higher number of reported cases involving the abdominal aorta , axillary artery aneurysm, brachiocephalic artery aneurysm, aneurysm of iliac and femoral arteries , and renal artery aneurysm. Other vascular complications can occur such as increased wall thickness and decreased distensibility of carotid arteries , aorta , and brachioradial artery . This change in the vascular tone is secondary to endothelial dysfunction. In addition, children with Kawasaki disease, with or without coronary artery complications, may have a more adverse cardiovascular risk profile, such as high blood pressure , obesity , and abnormal serum lipid profile. Gastrointestinal complications in Kawasaki disease are similar to those observed in Henoch–Schönlein purpura , such as: intestinal obstruction , colon swelling, intestinal ischemia , intestinal pseudo-obstruction , and acute abdomen . Eye changes associated with the disease have been described since the 1980s, being found as uveitis , iridocyclitis , conjunctival hemorrhage , optic neuritis , amaurosis , and ocular artery obstruction . It can also be found as necrotizing vasculitis, progressing into peripheral gangrene . The neurological complications per central nervous system lesions are increasingly reported. The neurological complications found are meningoencephalitis , subdural effusion , cerebral hypoperfusion , cerebral ischemia and infarct , cerebellar infarction , manifesting with seizures , chorea , hemiplegia , mental confusion , lethargy and coma , or even a cerebral infarction with no neurological manifestations. Other neurological complications from cranial nerve involvement are reported as ataxia , facial palsy , and sensorineural hearing loss . Behavioral changes are thought to be caused by localised cerebral hypoperfusion , can include attention deficits, learning deficits, emotional disorders ( emotional lability , fear of night, and night terrors ), and internalization problems ( anxious , depressive or aggressive behavior ). Heart complications are the most important aspect of Kawasaki disease, which is the leading cause of heart disease acquired in childhood in the United States and Japan. In developed nations, it appears to have replaced acute rheumatic fever as the most common cause of acquired heart disease in children. Coronary artery aneurysms occur as a sequela of the vasculitis in 20–25% of untreated children. It is first detected at a mean of 10 days of illness and the peak frequency of coronary artery dilation or aneurysms occurs within four weeks of onset. Aneurysms are classified into small (internal diameter of vessel wall 8 mm). Saccular and fusiform aneurysms usually develop between 18 and 25 days after the onset of illness. Even when treated with high-dose IVIG regimens within the first 10 days of illness, 5% of children with Kawasaki disease develop at the least transient coronary artery dilation and 1% develop giant aneurysms. Death can occur either due to myocardial infarction secondary to blood clot formation in a coronary artery aneurysm or to rupture of a large coronary artery aneurysm. Death is most common two to 12 weeks after the onset of illness. Many risk factors predicting coronary artery aneurysms have been identified, including persistent fever after IVIG therapy, low hemoglobin concentrations, low albumin concentrations, high white-blood-cell count, high band count , high CRP concentrations, male sex, and age less than one year. Coronary artery lesions resulting from Kawasaki disease change dynamically with time. Resolution one to two years after the onset of the disease has been observed in half of vessels with coronary aneurysms. Narrowing of the coronary artery, which occurs as a result of the healing process of the vessel wall, often leads to significant obstruction of the blood vessel and the heart not receiving enough blood and oxygen . This can eventually lead to heart muscle tissue death, i.e., myocardial infarction (MI). MI caused by thrombotic occlusion in an aneurysmal, stenotic, or both aneurysmal and stenotic coronary artery is the main cause of death from Kawasaki disease. The highest risk of MI occurs in the first year after the onset of the disease. MI in children presents with different symptoms from those in adults. The main symptoms were shock , unrest , vomiting , and abdominal pain ; chest pain was most common in older children. Most of these children had the attack occurring during sleep or at rest, and around one-third of attacks were asymptomatic. Valvular insufficiencies , particularly of mitral or tricuspid valves , are often observed in the acute phase of Kawasaki disease due to inflammation of the heart valve or inflammation of the heart muscle -induced myocardial dysfunction, regardless of coronary involvement. These lesions mostly disappear with the resolution of acute illness, but a very small group of the lesions persist and progress. There is also late-onset aortic or mitral insufficiency caused by thickening or deformation of fibrosed valves , with the timing ranging from several months to years after the onset of Kawasaki disease. Some of these lesions require valve replacement . Other Kawasaki disease complications have been described, such as aneurysm of other arteries: aortic aneurysm, with a higher number of reported cases involving the abdominal aorta , axillary artery aneurysm, brachiocephalic artery aneurysm, aneurysm of iliac and femoral arteries , and renal artery aneurysm. Other vascular complications can occur such as increased wall thickness and decreased distensibility of carotid arteries , aorta , and brachioradial artery . This change in the vascular tone is secondary to endothelial dysfunction. In addition, children with Kawasaki disease, with or without coronary artery complications, may have a more adverse cardiovascular risk profile, such as high blood pressure , obesity , and abnormal serum lipid profile. Gastrointestinal complications in Kawasaki disease are similar to those observed in Henoch–Schönlein purpura , such as: intestinal obstruction , colon swelling, intestinal ischemia , intestinal pseudo-obstruction , and acute abdomen . Eye changes associated with the disease have been described since the 1980s, being found as uveitis , iridocyclitis , conjunctival hemorrhage , optic neuritis , amaurosis , and ocular artery obstruction . It can also be found as necrotizing vasculitis, progressing into peripheral gangrene . The neurological complications per central nervous system lesions are increasingly reported. The neurological complications found are meningoencephalitis , subdural effusion , cerebral hypoperfusion , cerebral ischemia and infarct , cerebellar infarction , manifesting with seizures , chorea , hemiplegia , mental confusion , lethargy and coma , or even a cerebral infarction with no neurological manifestations. Other neurological complications from cranial nerve involvement are reported as ataxia , facial palsy , and sensorineural hearing loss . Behavioral changes are thought to be caused by localised cerebral hypoperfusion , can include attention deficits, learning deficits, emotional disorders ( emotional lability , fear of night, and night terrors ), and internalization problems ( anxious , depressive or aggressive behavior ). The specific cause of Kawasaki disease is unknown. A plausible explanation is that it may be caused by an infection that triggers an inappropriate immunologic cascade in a small number of genetically predisposed children. The pathogenesis is complex and incompletely understood. Various explanations exist. (See #Classification ) Circumstantial evidence points to an infectious cause. Since recurrences are unusual in Kawasaki disease, it is thought that the trigger is more likely to be represented by a single pathogen , rather than a range of viral or bacterial agents. Various candidates have been implicated, including upper respiratory tract infection by some novel RNA virus . Despite intensive search, no single pathogen has been identified. There has been debate as to whether the infectious agent might be a superantigen (i.e. one commonly associated with excessive immune system activation). Current consensus favors an excessive immunologic response to a conventional antigen which usually provides future protection. Research points to an unidentified ubiquitous virus, possibly one that enters through the respiratory tract. Seasonal trends in the appearance of new cases of Kawasaki disease have been linked to tropospheric wind patterns, which suggests wind-borne transport of something capable of triggering an immunologic cascade when inhaled by genetically susceptible children. Winds blowing from central Asia correlate with numbers of new cases of Kawasaki disease in Japan, Hawaii, and San Diego. These associations are themselves modulated by seasonal and interannual events in the El Niño–Southern Oscillation in winds and sea surface temperatures over the tropical eastern Pacific Ocean. Efforts have been made to identify a possible pathogen in air-filters flown at altitude above Japan. One source has been suggested in northeastern China. Genetic susceptibility is suggested by increased incidence among children of Japanese descent around the world, and also among close and extended family members of affected people. Genetic factors are also thought to influence development of coronary artery aneurysms and response to treatment. The exact genetic contribution remains unknown. Genome-wide association studies and studies of individual candidate genes have together helped identify specific single nucleotide polymorphisms (SNPs), mostly found in genes with immune regulatory functions. The associated genes and their levels of expression appear to vary among different ethnic groups, both with Asian and non-Asian backgrounds. SNPs in FCGR2A , CASP3 , BLK , ITPKC , CD40 and ORAI1 have all been linked to susceptibility, prognosis, and risk of developing coronary artery aneurysms. Various other possible susceptibility genes have been proposed, including polymorphisms in the HLA region, but their significance is disputed. Genetic susceptibility to Kawasaki disease appears complex. Gene–gene interactions also seem to affect susceptibility and prognosis. At an epigenetic level, altered DNA methylation has been proposed as an early mechanistic factor during the acute phase of the disease. Genetic susceptibility is suggested by increased incidence among children of Japanese descent around the world, and also among close and extended family members of affected people. Genetic factors are also thought to influence development of coronary artery aneurysms and response to treatment. The exact genetic contribution remains unknown. Genome-wide association studies and studies of individual candidate genes have together helped identify specific single nucleotide polymorphisms (SNPs), mostly found in genes with immune regulatory functions. The associated genes and their levels of expression appear to vary among different ethnic groups, both with Asian and non-Asian backgrounds. SNPs in FCGR2A , CASP3 , BLK , ITPKC , CD40 and ORAI1 have all been linked to susceptibility, prognosis, and risk of developing coronary artery aneurysms. Various other possible susceptibility genes have been proposed, including polymorphisms in the HLA region, but their significance is disputed. Genetic susceptibility to Kawasaki disease appears complex. Gene–gene interactions also seem to affect susceptibility and prognosis. At an epigenetic level, altered DNA methylation has been proposed as an early mechanistic factor during the acute phase of the disease. Since no specific laboratory test exists for Kawasaki disease, diagnosis must be based on clinical signs and symptoms , together with laboratory findings. Timely diagnosis requires careful history-taking and thorough physical examination . Establishing the diagnosis is difficult, especially early in the course of the illness, and frequently children are not diagnosed until they have seen several health-care providers. Many other serious illnesses can cause similar symptoms, and must be considered in the differential diagnosis, including scarlet fever , toxic shock syndrome, juvenile idiopathic arthritis , and childhood mercury poisoning ( infantile acrodynia ). Classically, five days of fever plus four of five diagnostic criteria must be met to establish the diagnosis. The criteria are: erythema of the lips or oral cavity or cracking of the lips rash on the trunk swelling or erythema of the hands or feet red eyes (conjunctival injection) swollen lymph node in the neck of at least 15 mm Many children, especially infants, eventually diagnosed with Kawasaki disease, do not exhibit all of the above criteria. In fact, many experts now recommend treating for Kawasaki disease even if only three days of fever have passed and at least three diagnostic criteria are present, especially if other tests reveal abnormalities consistent with Kawasaki disease. In addition, the diagnosis can be made purely by the detection of coronary artery aneurysms in the proper clinical setting. [ citation needed ] A physical examination will demonstrate many of the features listed above. Blood tests Other optional tests include: Biopsy is rarely performed, as it is not necessary for diagnosis. Based on clinical findings, a diagnostic distinction may be made between the 'classic' / 'typical' presentation of Kawasaki disease and 'incomplete' / 'atypical' presentation of a "suspected" form of the disease. Regarding 'incomplete' / 'atypical' presentation, American Heart Association guidelines state that Kawasaki disease "should be considered in the differential diagnosis of prolonged unexplained fever in childhood associated with any of the principal clinical features of the disease, and the diagnosis can be considered confirmed when coronary artery aneurysms are identified in such patients by echocardiography." A further distinction between 'incomplete' and 'atypical' subtypes may also be made in the presence of non-typical symptoms. For study purposes, including vaccine safety monitoring, an international case definition has been proposed to categorize 'definite' (i.e. complete/incomplete), 'probable' and 'possible' cases of Kawasaki disease. The broadness of the differential diagnosis is a challenge to timely diagnosis of Kawasaki disease. Infectious and noninfectious conditions requiring consideration include: measles and other viral infections (e.g. adenovirus , enterovirus ); staphylococcal and streptococcal toxin-mediated diseases such as scarlet fever and toxic shock syndrome; drug hypersensitivity reactions (including Stevens Johnson syndrome ); systemic onset juvenile idiopathic arthritis; Rocky Mountain spotted fever or other rickettsial infections; and leptospirosis . Infectious conditions that can mimic Kawasaki disease include periorbital cellulitis , peritonsillar abscess , retropharyngeal abscess , cervical lymphadenitis , parvovirus B19 , mononucleosis , rheumatic fever , meningitis , staphylococcal scalded skin syndrome , toxic epidermal necrolysis , and Lyme disease . In 2020, reports of a Kawasaki-like disease following exposure to SARS-CoV-2 , the virus responsible for COVID-19 , emerged in the US and Europe. The World Health Organization is examining possible links with COVID-19. This emerging condition was named 'paediatric multisystem inflammatory syndrome' by the Royal College of Paediatrics and Child Health , and 'multisystem inflammatory syndrome in children' by the Centers for Disease Control and Prevention . Guidance for diagnosis and reporting of cases has been issued by these organizations. Several reported cases suggest that this Kawasaki-like multisystem inflammatory syndrome is not limited to children; there is the possibility of an analogous disease in adults, which has been termed MIS-A. Some suspected patients have presented with positive test results for SARS-CoV-2 and reports suggest intravenous immunoglobulin, anticoagulation, tocilizumab, plasmapheresis and steroids are potential treatments. Debate has occurred about whether Kawasaki disease should be viewed as a characteristic immune response to some infectious pathogen , as an autoimmune process, or as an autoinflammatory disease (i.e. involving innate rather than adaptive immune pathways). Overall, immunological research suggests that Kawasaki disease is associated with a response to a conventional antigen (rather than a superantigen) that involves both activation of the innate immune system and also features of an adaptive immune response. Identification of the exact nature of the immune process involved in Kawasaki disease could help guide research aimed at improving clinical management. Inflammation, or vasculitis , of the arteries and veins occurs throughout the body, usually caused by increased production of the cells of the immune system to a pathogen , or autoimmunity. Systemic vasculitides may be classified according to the type of cells involved in the proliferation, as well as the specific type of tissue damage occurring within the vein or arterial walls. Under this classification scheme for systemic vasculitis, Kawasaki disease is considered to be a necrotizing vasculitis (also called necrotizing angiitis), which may be identified histologically by the occurrence of necrosis ( tissue death), fibrosis , and proliferation of cells associated with inflammation in the inner layer of the vascular wall . Other diseases involving necrotizing vasculitis include polyarteritis nodosa , granulomatosis with polyangiitis , Henoch–Schönlein purpura , and eosinophilic granulomatosis with polyangiitis . Kawasaki disease may be further classified as a medium-sized vessel vasculitis, affecting medium- and small-sized blood vessels, such as the smaller cutaneous vasculature (veins and arteries in the skin) that range from 50 to 100 µm in diameter. Kawasaki disease is also considered to be a primary childhood vasculitis, a disorder associated with vasculitis that mainly affects children under the age of 18. A recent, consensus-based evaluation of vasculitides occurring primarily in children resulted in a classification scheme for these disorders, to distinguish them and suggest a more concrete set of diagnostic criteria for each. Within this classification of childhood vasculitides, Kawasaki disease is, again, a predominantly medium-sized vessel vasculitis. It can also be classed as an autoimmune form of vasculitis. It is not associated with anti-neutrophil cytoplasmic antibodies , unlike other vasculitic disorders associated with them (such as granulomatosis with polyangiitis , microscopic polyangiitis , and eosinophilic granulomatosis with polyangiitis ). This form of categorization is relevant for appropriate treatment. A physical examination will demonstrate many of the features listed above. Blood tests Other optional tests include: Biopsy is rarely performed, as it is not necessary for diagnosis. Based on clinical findings, a diagnostic distinction may be made between the 'classic' / 'typical' presentation of Kawasaki disease and 'incomplete' / 'atypical' presentation of a "suspected" form of the disease. Regarding 'incomplete' / 'atypical' presentation, American Heart Association guidelines state that Kawasaki disease "should be considered in the differential diagnosis of prolonged unexplained fever in childhood associated with any of the principal clinical features of the disease, and the diagnosis can be considered confirmed when coronary artery aneurysms are identified in such patients by echocardiography." A further distinction between 'incomplete' and 'atypical' subtypes may also be made in the presence of non-typical symptoms. For study purposes, including vaccine safety monitoring, an international case definition has been proposed to categorize 'definite' (i.e. complete/incomplete), 'probable' and 'possible' cases of Kawasaki disease. The broadness of the differential diagnosis is a challenge to timely diagnosis of Kawasaki disease. Infectious and noninfectious conditions requiring consideration include: measles and other viral infections (e.g. adenovirus , enterovirus ); staphylococcal and streptococcal toxin-mediated diseases such as scarlet fever and toxic shock syndrome; drug hypersensitivity reactions (including Stevens Johnson syndrome ); systemic onset juvenile idiopathic arthritis; Rocky Mountain spotted fever or other rickettsial infections; and leptospirosis . Infectious conditions that can mimic Kawasaki disease include periorbital cellulitis , peritonsillar abscess , retropharyngeal abscess , cervical lymphadenitis , parvovirus B19 , mononucleosis , rheumatic fever , meningitis , staphylococcal scalded skin syndrome , toxic epidermal necrolysis , and Lyme disease . In 2020, reports of a Kawasaki-like disease following exposure to SARS-CoV-2 , the virus responsible for COVID-19 , emerged in the US and Europe. The World Health Organization is examining possible links with COVID-19. This emerging condition was named 'paediatric multisystem inflammatory syndrome' by the Royal College of Paediatrics and Child Health , and 'multisystem inflammatory syndrome in children' by the Centers for Disease Control and Prevention . Guidance for diagnosis and reporting of cases has been issued by these organizations. Several reported cases suggest that this Kawasaki-like multisystem inflammatory syndrome is not limited to children; there is the possibility of an analogous disease in adults, which has been termed MIS-A. Some suspected patients have presented with positive test results for SARS-CoV-2 and reports suggest intravenous immunoglobulin, anticoagulation, tocilizumab, plasmapheresis and steroids are potential treatments. In 2020, reports of a Kawasaki-like disease following exposure to SARS-CoV-2 , the virus responsible for COVID-19 , emerged in the US and Europe. The World Health Organization is examining possible links with COVID-19. This emerging condition was named 'paediatric multisystem inflammatory syndrome' by the Royal College of Paediatrics and Child Health , and 'multisystem inflammatory syndrome in children' by the Centers for Disease Control and Prevention . Guidance for diagnosis and reporting of cases has been issued by these organizations. Several reported cases suggest that this Kawasaki-like multisystem inflammatory syndrome is not limited to children; there is the possibility of an analogous disease in adults, which has been termed MIS-A. Some suspected patients have presented with positive test results for SARS-CoV-2 and reports suggest intravenous immunoglobulin, anticoagulation, tocilizumab, plasmapheresis and steroids are potential treatments. Debate has occurred about whether Kawasaki disease should be viewed as a characteristic immune response to some infectious pathogen , as an autoimmune process, or as an autoinflammatory disease (i.e. involving innate rather than adaptive immune pathways). Overall, immunological research suggests that Kawasaki disease is associated with a response to a conventional antigen (rather than a superantigen) that involves both activation of the innate immune system and also features of an adaptive immune response. Identification of the exact nature of the immune process involved in Kawasaki disease could help guide research aimed at improving clinical management. Inflammation, or vasculitis , of the arteries and veins occurs throughout the body, usually caused by increased production of the cells of the immune system to a pathogen , or autoimmunity. Systemic vasculitides may be classified according to the type of cells involved in the proliferation, as well as the specific type of tissue damage occurring within the vein or arterial walls. Under this classification scheme for systemic vasculitis, Kawasaki disease is considered to be a necrotizing vasculitis (also called necrotizing angiitis), which may be identified histologically by the occurrence of necrosis ( tissue death), fibrosis , and proliferation of cells associated with inflammation in the inner layer of the vascular wall . Other diseases involving necrotizing vasculitis include polyarteritis nodosa , granulomatosis with polyangiitis , Henoch–Schönlein purpura , and eosinophilic granulomatosis with polyangiitis . Kawasaki disease may be further classified as a medium-sized vessel vasculitis, affecting medium- and small-sized blood vessels, such as the smaller cutaneous vasculature (veins and arteries in the skin) that range from 50 to 100 µm in diameter. Kawasaki disease is also considered to be a primary childhood vasculitis, a disorder associated with vasculitis that mainly affects children under the age of 18. A recent, consensus-based evaluation of vasculitides occurring primarily in children resulted in a classification scheme for these disorders, to distinguish them and suggest a more concrete set of diagnostic criteria for each. Within this classification of childhood vasculitides, Kawasaki disease is, again, a predominantly medium-sized vessel vasculitis. It can also be classed as an autoimmune form of vasculitis. It is not associated with anti-neutrophil cytoplasmic antibodies , unlike other vasculitic disorders associated with them (such as granulomatosis with polyangiitis , microscopic polyangiitis , and eosinophilic granulomatosis with polyangiitis ). This form of categorization is relevant for appropriate treatment. Children with Kawasaki disease should be hospitalized and cared for by a physician who has experience with this disease. In an academic medical center, care is often shared between pediatric cardiology , pediatric rheumatology , and pediatric infectious disease specialists (although no specific infectious agent has yet been identified). To prevent damage to coronary arteries, treatment should be started immediately following the diagnosis. [ citation needed ] Intravenous immunoglobulin (IVIG) is the standard treatment for Kawasaki disease and is administered in high doses with marked improvement usually noted within 24 hours. If the fever does not respond, an additional dose may be considered. In rare cases, a third dose may be given. IVIG is most useful within the first seven days of fever onset, to prevent coronary artery aneurysm. IVIG given within the first 10 days of the disease reduces the risk of damage to the coronary arteries in children, without serious adverse effects. A 2023 systematic review and meta-analysis revealed that no prediction models of IVIG resistance in patients with Kawasaki disease could accurately distinguish the resistance. Salicylate therapy, particularly aspirin, remains an important part of the treatment (though questioned by some) but salicylates alone are not as effective as IVIG. There is limited evidence to indicate whether children should continue to receive salicylate as part of their treatment. Aspirin therapy is started at high doses until the fever subsides, and then is continued at a low dose when the patient returns home, usually for two months to prevent blood clots from forming. Except for Kawasaki disease and a few other indications, aspirin is otherwise normally not recommended for children due to its association with Reye syndrome . Because children with Kawasaki disease will be taking aspirin for up to several months, vaccination against varicella and influenza is required, as these infections are most likely to cause Reye syndrome. High-dose aspirin is associated with anemia and does not confer benefit to disease outcomes. About 15-20% of children following the initial IVIG infusion show persistent or recurrent fever and are classified as IVIG-resistant. While the use of TNF alpha blockers (TNF-α) may reduce treatment resistance and the infusion reaction after treatment initiation, further research is needed. Due to the potential involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the development of the disease, a 2019 study found that the combination of ciclosporin and IVIG infusion can suppress coronary artery abnormalities. Further research is needed to determine which patients would respond best to this treatment. Corticosteroids have also been used, especially when other treatments fail or symptoms recur, but in a randomized controlled trial, the addition of corticosteroid to immune globulin and aspirin did not improve outcome. Additionally, corticosteroid use in the setting of Kawasaki disease is associated with increased risk of coronary artery aneurysm, so its use is generally contraindicated in this setting. In cases of Kawasaki disease refractory to IVIG, cyclophosphamide and plasma exchange have been investigated as possible treatments, with variable outcomes. However, a Cochrane review published in 2017 (updated in 2022) found that, in children, the use of corticosteroids in the acute phase of KD was associated with improved coronary artery abnormalities, shorter hospital stays, a decreased duration of clinical symptoms, and reduced inflammatory marker levels. Patient populations based in Asia, people with higher risk scores, and those receiving longer steroid treatment may have greater benefit from steroid use. With early treatment, rapid recovery from the acute symptoms can be expected, and the risk of coronary artery aneurysms is greatly reduced. Untreated, the acute symptoms of Kawasaki disease are self-limited ( i.e. the patient will recover eventually), but the risk of coronary artery involvement is much greater, even many years later. Many cases of myocardial infarction in young adults have now been attributed to Kawasaki disease that went undiagnosed during childhood. Overall, about 2% of patients die from complications of coronary vasculitis. [ citation needed ] Laboratory evidence of increased inflammation combined with demographic features (male sex, age less than six months or greater than eight years) and incomplete response to IVIG therapy create a profile of a high-risk patient with Kawasaki disease. The likelihood that an aneurysm will resolve appears to be determined in large measure by its initial size, in which the smaller aneurysms have a greater likelihood of regression. Other factors are positively associated with the regression of aneurysms, including being younger than a year old at the onset of Kawasaki disease, fusiform rather than saccular aneurysm morphology, and an aneurysm location in a distal coronary segment. The highest rate of progression to stenosis occurs among those who develop large aneurysms. The worst prognosis occurs in children with giant aneurysms. This severe outcome may require further treatment such as percutaneous transluminal angioplasty , coronary artery stenting , bypass grafting , and even cardiac transplantation . A relapse of symptoms may occur soon after initial treatment with IVIG. This usually requires rehospitalization and retreatment. Treatment with IVIG can cause allergic and nonallergic acute reactions, aseptic meningitis, fluid overload , and rarely, other serious reactions. Overall, life-threatening complications resulting from therapy for Kawasaki disease are exceedingly rare, especially compared with the risk of nontreatment. Evidence indicates Kawasaki disease produces altered lipid metabolism that persists beyond the clinical resolution of the disease. [ citation needed ] Rarely, recurrence can occur in Kawasaki disease with or without treatment. Kawasaki disease affects boys more than girls, with people of Asian ethnicity, particularly Japanese people. The higher incidence in Asian populations is thought to be linked to genetic susceptibility . Incidence rates vary between countries. Currently, Kawasaki disease is the most commonly diagnosed pediatric vasculitis in the world. By far, the highest incidence of Kawasaki disease occurs in Japan, with the most recent study placing the attack rate at 218.6 per 100,000 children less than five years of age (about one in 450 children). At this present attack rate, more than one in 150 children in Japan will develop Kawasaki disease during their lifetimes. [ citation needed ] However, its incidence in the United States is increasing. Kawasaki disease is predominantly a disease of young children, with 80% of patients younger than five years of age. About 2,000–4,000 cases are identified in the U.S. each year (9 to 19 per 100,000 children younger than five years of age). In the continental United States, Kawasaki disease is more common during the winter and early spring, boys with the disease outnumber girls by ≈1.5–1.7:1, and 76% of affected children are less than 5 years of age. In the United Kingdom, prior to 2000, it was diagnosed in fewer than one in every 25,000 people per year. Incidence of the disease doubled from 1991 to 2000, however, with four cases per 100,000 children in 1991 compared with a rise of eight cases per 100,000 in 2000. By 2017, this figure had risen to 12 in 100,000 people with 419 diagnosed cases of Kawasaki disease in the United Kingdom. In Japan, the rate is 240 in every 100,000 people. Coronary artery aneurysms due to Kawasaki disease are believed to account for 5% of acute coronary syndrome cases in adults under 40 years of age. The disease was first reported by Tomisaku Kawasaki in a four-year-old child with a rash and fever at the Red Cross Hospital in Tokyo in January 1961, and he later published a report on 50 similar cases. Later, Kawasaki and colleagues were persuaded of definite cardiac involvement when they studied and reported 23 cases, of which 11 (48%) patients had abnormalities detected by an electrocardiogram. In 1974, the first description of this disorder was published in the English-language literature. In 1976, Melish et al. described the same illness in 16 children in Hawaii. Melish and Kawasaki had independently developed the same diagnostic criteria for the disorder, which are still used today to make the diagnosis of classic Kawasaki disease. Dr. Kawasaki died on June 5, 2020, at the age of 95. A question was raised whether the disease only started during the period between 1960 and 1970, but later a preserved heart of a seven-year-old boy who died in 1870 was examined and showed three aneurysms of the coronary arteries with clots, as well as pathologic changes consistent with Kawasaki disease. Kawasaki disease is now recognized worldwide. Why cases began to emerge across all continents around the 1960s and 1970s is unclear. Possible explanations could include confusion with other diseases such as scarlet fever, and easier recognition stemming from modern healthcare factors such as the widespread use of antibiotics. In particular, old pathological descriptions from Western countries of infantile polyarteritis nodosa coincide with reports of fatal cases of Kawasaki disease. In the United States and other developed nations, Kawasaki disease appears to have replaced acute rheumatic fever as the most common cause of acquired heart disease in children.

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Acute hemorrhagic fever syndrome

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Ebola

Ebola , also known as Ebola virus disease ( EVD ) and Ebola hemorrhagic fever ( EHF ), is a viral hemorrhagic fever in humans and other primates , caused by ebolaviruses . Symptoms typically start anywhere between two days and three weeks after infection. The first symptoms are usually fever , sore throat , muscle pain , and headaches . These are usually followed by vomiting , diarrhoea , rash and decreased liver and kidney function, at which point some people begin to bleed both internally and externally. It kills between 25% and 90% of those infected – about 50% on average. Death is often due to shock from fluid loss , and typically occurs between six and 16 days after the first symptoms appear. Early treatment of symptoms increases the survival rate considerably compared to late start. An Ebola vaccine was approved by the US FDA in December 2019. The virus spreads through direct contact with body fluids , such as blood from infected humans or other animals, or from contact with items that have recently been contaminated with infected body fluids. There have been no documented cases, either in nature or under laboratory conditions, of spread through the air between humans or other primates . After recovering from Ebola, semen or breast milk may continue to carry the virus for anywhere between several weeks to several months. Fruit bats are believed to be the normal carrier in nature ; they are able to spread the virus without being affected by it. The symptoms of Ebola may resemble those of several other diseases, including malaria , cholera , typhoid fever , meningitis and other viral hemorrhagic fevers. Diagnosis is confirmed by testing blood samples for the presence of viral RNA , viral antibodies or the virus itself. Control of outbreaks requires coordinated medical services and community engagement, including rapid detection, contact tracing of those exposed, quick access to laboratory services, care for those infected, and proper disposal of the dead through cremation or burial. Prevention measures involve wearing proper protective clothing and washing hands when in close proximity to patients and while handling potentially infected bushmeat , as well as thoroughly cooking bushmeat. An Ebola vaccine was approved by the US FDA in December 2019. While there is no approved treatment for Ebola as of 2019 [ update ] , two treatments ( atoltivimab/maftivimab/odesivimab and ansuvimab ) are associated with improved outcomes. Supportive efforts also improve outcomes. These include oral rehydration therapy (drinking slightly sweetened and salty water) or giving intravenous fluids , and treating symptoms. In October 2020, atoltivimab/maftivimab/odesivimab (Inmazeb) was approved for medical use in the United States to treat the disease caused by Zaire ebolavirus . Ebola was first identified in 1976, in two simultaneous outbreaks, one in Nzara (a town in South Sudan ) and the other in Yambuku ( the Democratic Republic of the Congo ), a village near the Ebola River , for which the disease was named. Ebola outbreaks occur intermittently in tropical regions of sub-Saharan Africa . Between 1976 and 2012, according to the World Health Organization , there were 24 outbreaks of Ebola resulting in a total of 2,387 cases, and 1,590 deaths . The largest Ebola outbreak to date was an epidemic in West Africa from December 2013 to January 2016, with 28,646 cases and 11,323 deaths. On 29 March 2016, it was declared to no longer be an emergency. Other outbreaks in Africa began in the Democratic Republic of the Congo in May 2017, and 2018. In July 2019, the World Health Organization declared the Congo Ebola outbreak a world health emergency . The length of time between exposure to the virus and the development of symptoms ( incubation period ) is between 2 and 21 days, and usually between 4 and 10 days. However, recent estimates based on mathematical models predict that around 5% of cases may take longer than 21 days to develop. Symptoms usually begin with a sudden influenza -like stage characterised by fatigue , fever , weakness , decreased appetite , muscular pain , joint pain , headache, and sore throat. The fever is usually higher than 38.3 °C (101 °F) . This is often followed by nausea, vomiting, diarrhoea , abdominal pain, and sometimes hiccups . The combination of severe vomiting and diarrhoea often leads to severe dehydration . Next, shortness of breath and chest pain may occur, along with swelling , headaches , and confusion . In about half of the cases, the skin may develop a maculopapular rash , a flat red area covered with small bumps, five to seven days after symptoms begin. In some cases, internal and external bleeding may occur. This typically begins five to seven days after the first symptoms. All infected people show some decreased blood clotting . Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50% of cases. This may cause vomiting blood , coughing up of blood , or blood in stool . Bleeding into the skin may create petechiae , purpura , ecchymoses or haematomas (especially around needle injection sites). Bleeding into the whites of the eyes may also occur. Heavy bleeding is uncommon; if it occurs, it is usually in the gastrointestinal tract . The incidence of bleeding into the gastrointestinal tract was reported to be ~58% in the 2001 outbreak in Gabon, but in the 2014–15 outbreak in the US it was ~18%, possibly due to improved prevention of disseminated intravascular coagulation . Recovery may begin between seven and 14 days after first symptoms. Death, if it occurs, follows typically six to sixteen days from first symptoms and is often due to shock from fluid loss . In general, bleeding often indicates a worse outcome, and blood loss may result in death. People are often in a coma near the end of life. Those who survive often have ongoing muscular and joint pain, liver inflammation , and decreased hearing, and may have continued tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight. Problems with vision may develop. It is recommended that survivors of EVD wear condoms for at least twelve months after initial infection or until the semen of a male survivor tests negative for Ebola virus on two separate occasions. Survivors develop antibodies against Ebola that last at least 10 years, but it is unclear whether they are immune to additional infections. The length of time between exposure to the virus and the development of symptoms ( incubation period ) is between 2 and 21 days, and usually between 4 and 10 days. However, recent estimates based on mathematical models predict that around 5% of cases may take longer than 21 days to develop. Symptoms usually begin with a sudden influenza -like stage characterised by fatigue , fever , weakness , decreased appetite , muscular pain , joint pain , headache, and sore throat. The fever is usually higher than 38.3 °C (101 °F) . This is often followed by nausea, vomiting, diarrhoea , abdominal pain, and sometimes hiccups . The combination of severe vomiting and diarrhoea often leads to severe dehydration . Next, shortness of breath and chest pain may occur, along with swelling , headaches , and confusion . In about half of the cases, the skin may develop a maculopapular rash , a flat red area covered with small bumps, five to seven days after symptoms begin. In some cases, internal and external bleeding may occur. This typically begins five to seven days after the first symptoms. All infected people show some decreased blood clotting . Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50% of cases. This may cause vomiting blood , coughing up of blood , or blood in stool . Bleeding into the skin may create petechiae , purpura , ecchymoses or haematomas (especially around needle injection sites). Bleeding into the whites of the eyes may also occur. Heavy bleeding is uncommon; if it occurs, it is usually in the gastrointestinal tract . The incidence of bleeding into the gastrointestinal tract was reported to be ~58% in the 2001 outbreak in Gabon, but in the 2014–15 outbreak in the US it was ~18%, possibly due to improved prevention of disseminated intravascular coagulation . Recovery may begin between seven and 14 days after first symptoms. Death, if it occurs, follows typically six to sixteen days from first symptoms and is often due to shock from fluid loss . In general, bleeding often indicates a worse outcome, and blood loss may result in death. People are often in a coma near the end of life. Those who survive often have ongoing muscular and joint pain, liver inflammation , and decreased hearing, and may have continued tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight. Problems with vision may develop. It is recommended that survivors of EVD wear condoms for at least twelve months after initial infection or until the semen of a male survivor tests negative for Ebola virus on two separate occasions. Survivors develop antibodies against Ebola that last at least 10 years, but it is unclear whether they are immune to additional infections. EVD in humans is caused by four of six viruses of the genus Ebolavirus . The four are Bundibugyo virus (BDBV), Sudan virus (SUDV), Taï Forest virus (TAFV) and one simply called Ebola virus (EBOV, formerly Zaire Ebola virus). EBOV, species Zaire ebolavirus , is the most dangerous of the known EVD-causing viruses, and is responsible for the largest number of outbreaks. The fifth and sixth viruses, Reston virus (RESTV) and Bombali virus (BOMV), are not thought to cause disease in humans, but have caused disease in other primates. All five viruses are closely related to marburgviruses . Ebolaviruses contain single-stranded, non-infectious RNA genomes . Ebolavirus genomes contain seven genes including 3'-UTR - NP - VP35 - VP40 - GP - VP30 - VP24 - L - 5'-UTR . The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in sequence and the number and location of gene overlaps. As with all filoviruses , ebolavirus virions are filamentous particles that may appear in the shape of a shepherd's crook, of a "U" or of a "6," and they may be coiled, toroid or branched. In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm. Their life cycle is thought to begin with a virion attaching to specific cell-surface receptors such as C-type lectins , DC-SIGN , or integrins , which is followed by fusion of the viral envelope with cellular membranes . The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved. This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid . The Ebolavirus structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells. The viral RNA polymerase , encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-strand mRNAs , which are then translated into structural and nonstructural proteins. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny. Newly synthesised structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane . Virions bud off from the cell, gaining their envelopes from the cellular membrane from which they bud. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV's virulent characteristics. It is believed that between people, Ebola disease spreads only by direct contact with the blood or other body fluids of a person who has developed symptoms of the disease. Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and semen . The WHO states that only people who are very sick are able to spread Ebola disease in saliva , and the virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces and vomit. Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions. Ebola may be spread through large droplets ; however, this is believed to occur only when a person is very sick. This contamination can happen if a person is splashed with droplets. Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection. The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person. The Ebola virus may be able to persist for more than three months in the semen after recovery, which could lead to infections via sexual intercourse . Virus persistence in semen for over a year has been recorded in a national screening programme. Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again. The virus was also found in the eye of one patient in 2014, two months after it was cleared from his blood. Otherwise, people who have recovered are not infectious. The potential for widespread infections in countries with medical systems capable of observing correct medical isolation procedures is considered low. Usually when someone has symptoms of the disease, they are unable to travel without assistance. Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as embalming are at risk. Of the cases of Ebola infections in Guinea during the 2014 outbreak, 69% are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals. Health-care workers treating people with Ebola are at greatest risk of infection. The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly. This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly. There has been transmission in hospitals in some African countries that reuse hypodermic needles. Some health-care centres caring for people with the disease do not have running water. In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures. Human-to-human transmission of EBOV through the air has not been reported to occur during EVD outbreaks, and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from pigs to primates , but not from primates to primates. Spread of EBOV by water, or food other than bushmeat, has not been observed. No spread by mosquitos or other insects has been reported. Other possible methods of transmission are being studied. Airborne transmission among humans is theoretically possible due to the presence of Ebola virus particles in saliva, which can be discharged into the air with a cough or sneeze, but observational data from previous epidemics suggests the actual risk of airborne transmission is low. A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream. Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough. By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs. It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air. Although it is not entirely clear how Ebola initially spreads from animals to humans, the spread is believed to involve direct contact with an infected wild animal or fruit bat. Besides bats, other wild animals that are sometimes infected with EBOV include several species of monkeys such as baboons , great apes ( chimpanzees and gorillas ), and duikers (a species of antelope ). Animals may become infected when they eat fruit partially eaten by bats carrying the virus. Fruit production, animal behavior and other factors may trigger outbreaks among animal populations. Evidence indicates that both domestic dogs and pigs can also be infected with EBOV. Dogs do not appear to develop symptoms when they carry the virus, and pigs appear to be able to transmit the virus to at least some primates. Although some dogs in an area in which a human outbreak occurred had antibodies to EBOV, it is unclear whether they played a role in spreading the disease to people. The natural reservoir for Ebola has yet to be confirmed; however, bats are considered to be the most likely candidate. Three types of fruit bats ( Hypsignathus monstrosus , Epomops franqueti and Myonycteris torquata ) were found to possibly carry the virus without getting sick. As of 2013 [ update ] , whether other animals are involved in its spread is not known. Plants, arthropods , rodents , and birds have also been considered possible viral reservoirs. Bats were known to roost in the cotton factory in which the first cases of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980. Of 24 plant and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected. The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EBOV. In a 2002–2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo , immunoglobulin G (IgG) immune defense molecules indicative of Ebola infection were found in three bat species; at various periods of study, between 2.2 and 22.6% of bats were found to contain both RNA sequences and IgG molecules indicating Ebola infection. Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh , suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia. Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from regions of EBOV outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species Mus setulosus and Praomys ) and one shrew ( Sylvisorex ollula ) collected from the Central African Republic . However, further research efforts have not confirmed rodents as a reservoir. Traces of EBOV were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high rates of death in these species resulting from EBOV infection make it unlikely that these species represent a natural reservoir for the virus. Deforestation has been mentioned as a possible contributor to recent outbreaks, including the West African Ebola virus epidemic . Index cases of EVD have often been close to recently deforested lands. Ebolaviruses contain single-stranded, non-infectious RNA genomes . Ebolavirus genomes contain seven genes including 3'-UTR - NP - VP35 - VP40 - GP - VP30 - VP24 - L - 5'-UTR . The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in sequence and the number and location of gene overlaps. As with all filoviruses , ebolavirus virions are filamentous particles that may appear in the shape of a shepherd's crook, of a "U" or of a "6," and they may be coiled, toroid or branched. In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm. Their life cycle is thought to begin with a virion attaching to specific cell-surface receptors such as C-type lectins , DC-SIGN , or integrins , which is followed by fusion of the viral envelope with cellular membranes . The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved. This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid . The Ebolavirus structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells. The viral RNA polymerase , encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-strand mRNAs , which are then translated into structural and nonstructural proteins. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny. Newly synthesised structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane . Virions bud off from the cell, gaining their envelopes from the cellular membrane from which they bud. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV's virulent characteristics. It is believed that between people, Ebola disease spreads only by direct contact with the blood or other body fluids of a person who has developed symptoms of the disease. Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and semen . The WHO states that only people who are very sick are able to spread Ebola disease in saliva , and the virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces and vomit. Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions. Ebola may be spread through large droplets ; however, this is believed to occur only when a person is very sick. This contamination can happen if a person is splashed with droplets. Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection. The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person. The Ebola virus may be able to persist for more than three months in the semen after recovery, which could lead to infections via sexual intercourse . Virus persistence in semen for over a year has been recorded in a national screening programme. Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again. The virus was also found in the eye of one patient in 2014, two months after it was cleared from his blood. Otherwise, people who have recovered are not infectious. The potential for widespread infections in countries with medical systems capable of observing correct medical isolation procedures is considered low. Usually when someone has symptoms of the disease, they are unable to travel without assistance. Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as embalming are at risk. Of the cases of Ebola infections in Guinea during the 2014 outbreak, 69% are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals. Health-care workers treating people with Ebola are at greatest risk of infection. The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly. This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly. There has been transmission in hospitals in some African countries that reuse hypodermic needles. Some health-care centres caring for people with the disease do not have running water. In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures. Human-to-human transmission of EBOV through the air has not been reported to occur during EVD outbreaks, and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from pigs to primates , but not from primates to primates. Spread of EBOV by water, or food other than bushmeat, has not been observed. No spread by mosquitos or other insects has been reported. Other possible methods of transmission are being studied. Airborne transmission among humans is theoretically possible due to the presence of Ebola virus particles in saliva, which can be discharged into the air with a cough or sneeze, but observational data from previous epidemics suggests the actual risk of airborne transmission is low. A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream. Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough. By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs. It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air. Although it is not entirely clear how Ebola initially spreads from animals to humans, the spread is believed to involve direct contact with an infected wild animal or fruit bat. Besides bats, other wild animals that are sometimes infected with EBOV include several species of monkeys such as baboons , great apes ( chimpanzees and gorillas ), and duikers (a species of antelope ). Animals may become infected when they eat fruit partially eaten by bats carrying the virus. Fruit production, animal behavior and other factors may trigger outbreaks among animal populations. Evidence indicates that both domestic dogs and pigs can also be infected with EBOV. Dogs do not appear to develop symptoms when they carry the virus, and pigs appear to be able to transmit the virus to at least some primates. Although some dogs in an area in which a human outbreak occurred had antibodies to EBOV, it is unclear whether they played a role in spreading the disease to people. The natural reservoir for Ebola has yet to be confirmed; however, bats are considered to be the most likely candidate. Three types of fruit bats ( Hypsignathus monstrosus , Epomops franqueti and Myonycteris torquata ) were found to possibly carry the virus without getting sick. As of 2013 [ update ] , whether other animals are involved in its spread is not known. Plants, arthropods , rodents , and birds have also been considered possible viral reservoirs. Bats were known to roost in the cotton factory in which the first cases of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980. Of 24 plant and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected. The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EBOV. In a 2002–2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo , immunoglobulin G (IgG) immune defense molecules indicative of Ebola infection were found in three bat species; at various periods of study, between 2.2 and 22.6% of bats were found to contain both RNA sequences and IgG molecules indicating Ebola infection. Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh , suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia. Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from regions of EBOV outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species Mus setulosus and Praomys ) and one shrew ( Sylvisorex ollula ) collected from the Central African Republic . However, further research efforts have not confirmed rodents as a reservoir. Traces of EBOV were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high rates of death in these species resulting from EBOV infection make it unlikely that these species represent a natural reservoir for the virus. Deforestation has been mentioned as a possible contributor to recent outbreaks, including the West African Ebola virus epidemic . Index cases of EVD have often been close to recently deforested lands. Like other filoviruses , EBOV replicates very efficiently in many cells , producing large amounts of virus in monocytes , macrophages , dendritic cells and other cells including liver cells , fibroblasts , and adrenal gland cells . Viral replication triggers high levels of inflammatory chemical signals and leads to a septic state . EBOV is thought to infect humans through contact with mucous membranes or skin breaks. After infection, endothelial cells (cells lining the inside of blood vessels), liver cells, and several types of immune cells such as macrophages, monocytes , and dendritic cells are the main targets of attack. Following infection, immune cells carry the virus to nearby lymph nodes where further reproduction of the virus takes place. From there the virus can enter the bloodstream and lymphatic system and spread throughout the body. Macrophages are the first cells infected with the virus, and this infection results in programmed cell death . Other types of white blood cells , such as lymphocytes , also undergo programmed cell death leading to an abnormally low concentration of lymphocytes in the blood. This contributes to the weakened immune response seen in those infected with EBOV. Endothelial cells may be infected within three days after exposure to the virus. The breakdown of endothelial cells leading to blood vessel injury can be attributed to EBOV glycoproteins . This damage occurs due to the synthesis of Ebola virus glycoprotein (GP), which reduces the availability of specific integrins responsible for cell adhesion to the intercellular structure and causes liver damage, leading to improper clotting . The widespread bleeding that occurs in affected people causes swelling and shock due to loss of blood volume . The dysfunctional bleeding and clotting commonly seen in EVD has been attributed to increased activation of the extrinsic pathway of the coagulation cascade due to excessive tissue factor production by macrophages and monocytes. After infection, a secreted glycoprotein , small soluble glycoprotein (sGP or GP) is synthesised. EBOV replication overwhelms protein synthesis of infected cells and the host immune defences. The GP forms a trimeric complex , which tethers the virus to the endothelial cells. The sGP forms a dimeric protein that interferes with the signalling of neutrophils , another type of white blood cell. This enables the virus to evade the immune system by inhibiting early steps of neutrophil activation. [ medical citation needed ] Furthermore, the virus is capable of hijacking cellular metabolism. Studies have shown that Ebola virus-like particles can reprogram metabolism in both vascular and immune cells. Filoviral infection also interferes with proper functioning of the innate immune system . EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as interferon-alpha , interferon-beta , and interferon gamma . The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5 ) or outside of the cytosol (such as Toll-like receptor 3 (TLR3) , TLR7 , TLR8 and TLR9 ) recognise infectious molecules associated with the virus. On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signalling cascade that leads to the expression of type 1 interferons . The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighbouring cell. Once interferon has bound to its receptors on the neighbouring cell, the signalling proteins STAT1 and STAT2 are activated and move to the cell's nucleus . This triggers the expression of interferon-stimulated genes , which code for proteins with antiviral properties. EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signalling protein in the neighbouring cell from entering the nucleus. The VP35 protein directly inhibits the production of interferon-beta. By inhibiting these immune responses, EBOV may quickly spread throughout the body. Filoviral infection also interferes with proper functioning of the innate immune system . EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as interferon-alpha , interferon-beta , and interferon gamma . The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5 ) or outside of the cytosol (such as Toll-like receptor 3 (TLR3) , TLR7 , TLR8 and TLR9 ) recognise infectious molecules associated with the virus. On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signalling cascade that leads to the expression of type 1 interferons . The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighbouring cell. Once interferon has bound to its receptors on the neighbouring cell, the signalling proteins STAT1 and STAT2 are activated and move to the cell's nucleus . This triggers the expression of interferon-stimulated genes , which code for proteins with antiviral properties. EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signalling protein in the neighbouring cell from entering the nucleus. The VP35 protein directly inhibits the production of interferon-beta. By inhibiting these immune responses, EBOV may quickly spread throughout the body. When EVD is suspected, travel, work history, and exposure to wildlife are important factors with respect to further diagnostic efforts. Possible non-specific laboratory indicators of EVD include a low platelet count ; an initially decreased white blood cell count followed by an increased white blood cell count ; elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and abnormalities in blood clotting often consistent with disseminated intravascular coagulation (DIC) such as a prolonged prothrombin time , partial thromboplastin time , and bleeding time . Filovirions such as EBOV may be identified by their unique filamentous shapes in cell cultures examined with electron microscopy . The specific diagnosis of EVD is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture , detecting the viral RNA by polymerase chain reaction (PCR) and detecting proteins by enzyme-linked immunosorbent assay (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover. IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected six to 18 days after symptom onset. During an outbreak, isolation of the virus with cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are real-time PCR and ELISA. In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission. In 2015, a rapid antigen test which gives results in 15 minutes was approved for use by WHO. It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected. Early symptoms of EVD may be similar to those of other diseases common in Africa, including malaria and dengue fever . The symptoms are also similar to those of other viral haemorrhagic fevers such as Marburg virus disease , Crimean–Congo haemorrhagic fever , and Lassa fever . The complete differential diagnosis is extensive and requires consideration of many other infectious diseases such as typhoid fever , shigellosis , rickettsial diseases , cholera , sepsis , borreliosis , EHEC enteritis , leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , measles , and viral hepatitis among others. Non-infectious diseases that may result in symptoms similar to those of EVD include acute promyelocytic leukaemia , haemolytic uraemic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary haemorrhagic telangiectasia , Kawasaki disease , and warfarin poisoning. Possible non-specific laboratory indicators of EVD include a low platelet count ; an initially decreased white blood cell count followed by an increased white blood cell count ; elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and abnormalities in blood clotting often consistent with disseminated intravascular coagulation (DIC) such as a prolonged prothrombin time , partial thromboplastin time , and bleeding time . Filovirions such as EBOV may be identified by their unique filamentous shapes in cell cultures examined with electron microscopy . The specific diagnosis of EVD is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture , detecting the viral RNA by polymerase chain reaction (PCR) and detecting proteins by enzyme-linked immunosorbent assay (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover. IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected six to 18 days after symptom onset. During an outbreak, isolation of the virus with cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are real-time PCR and ELISA. In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission. In 2015, a rapid antigen test which gives results in 15 minutes was approved for use by WHO. It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected. Early symptoms of EVD may be similar to those of other diseases common in Africa, including malaria and dengue fever . The symptoms are also similar to those of other viral haemorrhagic fevers such as Marburg virus disease , Crimean–Congo haemorrhagic fever , and Lassa fever . The complete differential diagnosis is extensive and requires consideration of many other infectious diseases such as typhoid fever , shigellosis , rickettsial diseases , cholera , sepsis , borreliosis , EHEC enteritis , leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , measles , and viral hepatitis among others. Non-infectious diseases that may result in symptoms similar to those of EVD include acute promyelocytic leukaemia , haemolytic uraemic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary haemorrhagic telangiectasia , Kawasaki disease , and warfarin poisoning. An Ebola vaccine , rVSV-ZEBOV , was approved in the United States in December 2019. It appears to be fully effective ten days after being given. It was studied in Guinea between 2014 and 2016. More than 100,000 people have been vaccinated against Ebola as of 2019 [ update ] . The WHO reported that approximately 345,000 people were given the vaccine during the Kivu Ebola epidemic from 2018 to 2020. Community awareness of the benefits on survival chances of admitting cases early is important for the infected and infection control People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. Isolation refers to separating those who are sick from those who are not. Quarantine refers to separating those who may have been exposed to a disease until they either show signs of the disease or are no longer at risk. Quarantine, also known as enforced isolation, is usually effective in decreasing spread. Governments often quarantine areas where the disease is occurring or individuals who may transmit the disease outside of an initial area. In the United States, the law allows quarantine of those infected with ebolaviruses. Contact tracing is considered important to contain an outbreak. It involves finding everyone who had close contact with infected individuals and monitoring them for signs of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested and treated. Then the process is repeated, tracing the contacts' contacts. An Ebola vaccine , rVSV-ZEBOV , was approved in the United States in December 2019. It appears to be fully effective ten days after being given. It was studied in Guinea between 2014 and 2016. More than 100,000 people have been vaccinated against Ebola as of 2019 [ update ] . The WHO reported that approximately 345,000 people were given the vaccine during the Kivu Ebola epidemic from 2018 to 2020. Community awareness of the benefits on survival chances of admitting cases early is important for the infected and infection control People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. Isolation refers to separating those who are sick from those who are not. Quarantine refers to separating those who may have been exposed to a disease until they either show signs of the disease or are no longer at risk. Quarantine, also known as enforced isolation, is usually effective in decreasing spread. Governments often quarantine areas where the disease is occurring or individuals who may transmit the disease outside of an initial area. In the United States, the law allows quarantine of those infected with ebolaviruses. Contact tracing is considered important to contain an outbreak. It involves finding everyone who had close contact with infected individuals and monitoring them for signs of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested and treated. Then the process is repeated, tracing the contacts' contacts. As of 2019 [ update ] two treatments ( atoltivimab/maftivimab/odesivimab and ansuvimab ) are associated with improved outcomes. The U.S. Food and Drug Administration (FDA) advises people to be careful of advertisements making unverified or fraudulent claims of benefits supposedly gained from various anti-Ebola products. In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab with an indication for the treatment of infection caused by Zaire ebolavirus . Treatment is primarily supportive in nature. Early supportive care with rehydration and symptomatic treatment improves survival. Rehydration may be via the oral or intravenous route. These measures may include pain management , and treatment for nausea , fever , and anxiety . The World Health Organization (WHO) recommends avoiding aspirin or ibuprofen for pain management, due to the risk of bleeding associated with these medications. Blood products such as packed red blood cells , platelets , or fresh frozen plasma may also be used. Other regulators of coagulation have also been tried including heparin in an effort to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding. Antimalarial medications and antibiotics are often used before the diagnosis is confirmed, though there is no evidence to suggest such treatment helps. Several experimental treatments are being studied . Where hospital care is not possible, the WHO's guidelines for home care have been relatively successful. Recommendations include using towels soaked in a bleach solution when moving infected people or bodies and also applying bleach on stains. It is also recommended that the caregivers wash hands with bleach solutions and cover their mouth and nose with a cloth. Intensive care is often used in the developed world. This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop. Dialysis may be needed for kidney failure , and extracorporeal membrane oxygenation may be used for lung dysfunction. Treatment is primarily supportive in nature. Early supportive care with rehydration and symptomatic treatment improves survival. Rehydration may be via the oral or intravenous route. These measures may include pain management , and treatment for nausea , fever , and anxiety . The World Health Organization (WHO) recommends avoiding aspirin or ibuprofen for pain management, due to the risk of bleeding associated with these medications. Blood products such as packed red blood cells , platelets , or fresh frozen plasma may also be used. Other regulators of coagulation have also been tried including heparin in an effort to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding. Antimalarial medications and antibiotics are often used before the diagnosis is confirmed, though there is no evidence to suggest such treatment helps. Several experimental treatments are being studied . Where hospital care is not possible, the WHO's guidelines for home care have been relatively successful. Recommendations include using towels soaked in a bleach solution when moving infected people or bodies and also applying bleach on stains. It is also recommended that the caregivers wash hands with bleach solutions and cover their mouth and nose with a cloth. Intensive care is often used in the developed world. This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop. Dialysis may be needed for kidney failure , and extracorporeal membrane oxygenation may be used for lung dysfunction. EVD has a risk of death in those infected of between 25% and 90%. As of September 2014 [ update ] , the average risk of death among those infected is 50%. The highest risk of death was 90% in the 2002–2003 Republic of the Congo outbreak. Early admission significantly increases survival rates Death, if it occurs, follows typically six to sixteen days after symptoms appear and is often due to low blood pressure from fluid loss . Early supportive care to prevent dehydration may reduce the risk of death. If an infected person survives, recovery may be quick and complete. However, a large portion of survivors develop post-Ebola virus syndrome after the acute phase of the infection. Prolonged cases are often complicated by the occurrence of long-term problems, such as inflammation of the testicles , joint pains , fatigue, hearing loss, mood and sleep disturbances, muscular pain , abdominal pain, menstrual abnormalities , miscarriages , skin peeling , or hair loss . Inflammation and swelling of the uveal layer of the eye is the most common eye complication in survivors of Ebola virus disease. Eye symptoms, such as light sensitivity , excess tearing , and vision loss have been described. Ebola can stay in some body parts like the eyes, breasts, and testicles after infection. Sexual transmission after recovery has been suspected. If sexual transmission occurs following recovery it is believed to be a rare event. One case of a condition similar to meningitis has been reported many months after recovery, as of October 2015 [ update ] . If an infected person survives, recovery may be quick and complete. However, a large portion of survivors develop post-Ebola virus syndrome after the acute phase of the infection. Prolonged cases are often complicated by the occurrence of long-term problems, such as inflammation of the testicles , joint pains , fatigue, hearing loss, mood and sleep disturbances, muscular pain , abdominal pain, menstrual abnormalities , miscarriages , skin peeling , or hair loss . Inflammation and swelling of the uveal layer of the eye is the most common eye complication in survivors of Ebola virus disease. Eye symptoms, such as light sensitivity , excess tearing , and vision loss have been described. Ebola can stay in some body parts like the eyes, breasts, and testicles after infection. Sexual transmission after recovery has been suspected. If sexual transmission occurs following recovery it is believed to be a rare event. One case of a condition similar to meningitis has been reported many months after recovery, as of October 2015 [ update ] . The disease typically occurs in outbreaks in tropical regions of Sub-Saharan Africa . From 1976 (when it was first identified) through 2013, the WHO reported 2,387 confirmed cases with 1,590 overall fatalities. The largest outbreak to date was the Ebola virus epidemic in West Africa , which caused a large number of deaths in Guinea , Sierra Leone , and Liberia . The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The second major outbreak occurred in Zaire (now the Democratic Republic of the Congo , DRC), in 1995, affecting 315 and killing 254. In 2000, Uganda had an outbreak infecting 425 and killing 224; in this case, the Sudan virus was found to be the Ebola species responsible for the outbreak. In 2003, an outbreak in the DRC infected 143 and killed 128, a 90% death rate, the highest of a genus Ebolavirus outbreak to date. In 2004, a Russian scientist died from Ebola after sticking herself with an infected needle. Between April and August 2007, a fever epidemic in a four-village region of the DRC was confirmed in September to have been cases of Ebola. Many people who attended the recent funeral of a local village chief died. The 2007 outbreak eventually infected 264 individuals and killed 187. On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District in Western Uganda. After confirming samples tested by the United States National Reference Laboratories and the Centers for Disease Control, the World Health Organization (WHO) confirmed the presence of a new species of genus Ebolavirus , which was tentatively named Bundibugyo. The WHO reported 149 cases of this new strain and 37 of those led to deaths. The WHO confirmed two small outbreaks in Uganda in 2012, both caused by the Sudan variant. The first outbreak affected seven people, killing four, and the second affected 24, killing 17. On 17 August 2012, the Ministry of Health of the DRC reported an outbreak of the Ebola-Bundibugyo variant in the eastern region. Other than its discovery in 2007, this was the only time that this variant has been identified as responsible for an outbreak. The WHO revealed that the virus had sickened 57 people and killed 29. The probable cause of the outbreak was tainted bush meat hunted by local villagers around the towns of Isiro and Viadana. In 2014, an outbreak occurred in the DRC. Genome-sequencing showed that this outbreak was not related to the 2014–15 West Africa Ebola virus outbreak , but was the same EBOV species, the Zaire species. It began in August 2014, and was declared over in November with 66 cases and 49 deaths. This was the 7th outbreak in the DRC, three of which occurred during the period when the country was known as Zaire . In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea , a West African nation. Researchers traced the outbreak to a one-year-old child who died in December 2013. The disease rapidly spread to the neighbouring countries of Liberia and Sierra Leone . It was the largest Ebola outbreak ever documented, and the first recorded in the region. On 8 August 2014, the WHO declared the epidemic an international public health emergency. Urging the world to offer aid to the affected regions, its Director-General said, "Countries affected to date simply do not have the capacity to manage an outbreak of this size and complexity on their own. I urge the international community to provide this support on the most urgent basis possible." By mid-August 2014, Doctors Without Borders reported the situation in Liberia's capital, Monrovia , was "catastrophic" and "deteriorating daily". They reported that fears of Ebola among staff members and patients had shut down much of the city's health system, leaving many people without medical treatment for other conditions. In a 26 September statement, WHO said, "The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long." Intense contact tracing and strict isolation largely prevented further spread of the disease in the countries that had imported cases. It caused significant mortality, with a considerable case fatality rate . [note 1] By the end of the epidemic, 28,616 people had been infected; of these, 11,310 had died, for a case-fatality rate of 40%. As of 8 May 2016 [ update ] , 28,646 suspected cases and 11,323 deaths were reported; however, the WHO said that these numbers may be underestimated. Because they work closely with the body fluids of infected patients, healthcare workers were especially vulnerable to infection; in August 2014, the WHO reported that 10% of the dead were healthcare workers. In September 2014, it was estimated that the countries' capacity for treating Ebola patients was insufficient by the equivalent of 2,122 beds; by December there were a sufficient number of beds to treat and isolate all reported Ebola cases, although the uneven distribution of cases was causing serious shortfalls in some areas. On 28 January 2015, the WHO reported that for the first time since the week ending 29 June 2014, there had been fewer than 100 new confirmed cases reported in a week in the three most-affected countries. The response to the epidemic then moved to a second phase, as the focus shifted from slowing transmission to ending the epidemic. On 8 April 2015, the WHO reported only 30 confirmed cases, the lowest weekly total since the third week of May 2014. On 29 December 2015, 42 days after the last person tested negative for a second time, Guinea was declared free of Ebola transmission. At that time, a 90-day period of heightened surveillance was announced by that agency. "This is the first time that all three countries – Guinea, Liberia and Sierra Leone – have stopped the original chains of transmission ...", the organisation stated in a news release. A new case was detected in Sierra Leone on 14 January 2016. However, the outbreak was declared no longer an emergency on 29 March 2016. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 11 May 2017, the DRC Ministry of Public Health notified the WHO about an outbreak of Ebola. Four people died, and four people survived; five of these eight cases were laboratory-confirmed. A total of 583 contacts were monitored. On 2 July 2017, the WHO declared the end of the outbreak. On 14 May 2018, the World Health Organization reported that "the Democratic Republic of Congo reported 39 suspected, probable or confirmed cases of Ebola between 4 April and 13 May, including 19 deaths." Some 393 people identified as contacts of Ebola patients were being followed up. The outbreak centred on the Bikoro , Iboko, and Wangata areas in Equateur province, including in the large city of Mbandaka . The DRC Ministry of Public Health approved the use of an experimental vaccine. On 13 May 2018, WHO Director-General Tedros Adhanom Ghebreyesus visited Bikoro. Reports emerged that maps of the area were inaccurate, not so much hampering medical providers as epidemiologists and officials trying to assess the outbreak and containment efforts. The 2018 outbreak in the DRC was declared over on 24 July 2018. On 1 August 2018, the world's 10th Ebola outbreak was declared in North Kivu province of the Democratic Republic of the Congo. It was the first Ebola outbreak in a military conflict zone, with thousands of refugees in the area. By November 2018, nearly 200 Congolese had died of Ebola, about half of them from the city of Beni , where armed groups are fighting over the region's mineral wealth, impeding medical relief efforts. By March 2019, this became the second largest Ebola outbreak ever recorded, with more than 1,000 cases and insecurity continuing to be the major resistance to providing an adequate response. As of 4 June 2019 [ update ] , the WHO reported 2025 confirmed and probable cases with 1357 deaths. In June 2019, two people died of Ebola in neighbouring Uganda . In July 2019, an infected man travelled to Goma , home to more than two million people. One week later, on 17 July 2019, the WHO declared the Ebola outbreak a global health emergency , the fifth time such a declaration has been made by the organisation. A government spokesman said that half of the Ebola cases are unidentified, and he added that the current outbreak could last up to three years. On 25 June 2020, the second biggest EVD outbreak ever was declared over. On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in Mbandaka , Équateur Province , a region along the Congo River. Genome sequencing suggests that this outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, is unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified; four of the people had died. It is expected that more people will be identified as surveillance activities increase. By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. The 11th EVD outbreak was officially declared over on 19 November 2020. By the time the Équateur outbreak ended, it had 130 confirmed cases with 75 recoveries and 55 deaths. On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 23 April 2022, a case of Ebola was confirmed in the DRC in the Equateur province. The case was a 31-year-old man whose symptoms began on 5 April, but did not seek treatment for over a week. On 21 April, he was admitted to an Ebola treatment centre and died later that day. By 24 May 2022, there were 5 recorded deaths in the DRC. On 15 August, the fifth case was buried, and the outbreak was declared over, 42 days after, on 4 July 2022. In September 2022, Uganda reported 7 cases infected with the Ebola Sudan strain , but by mid-October the count had increased to 63. In November 2022, the outbreak in Uganda continued - still without a vaccine. On 10 January 2023, the outbreak was considered over after no new cases had been reported for 42 days; the outbreak killed nearly 80 people. The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The second major outbreak occurred in Zaire (now the Democratic Republic of the Congo , DRC), in 1995, affecting 315 and killing 254. In 2000, Uganda had an outbreak infecting 425 and killing 224; in this case, the Sudan virus was found to be the Ebola species responsible for the outbreak. In 2003, an outbreak in the DRC infected 143 and killed 128, a 90% death rate, the highest of a genus Ebolavirus outbreak to date. In 2004, a Russian scientist died from Ebola after sticking herself with an infected needle. Between April and August 2007, a fever epidemic in a four-village region of the DRC was confirmed in September to have been cases of Ebola. Many people who attended the recent funeral of a local village chief died. The 2007 outbreak eventually infected 264 individuals and killed 187. On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District in Western Uganda. After confirming samples tested by the United States National Reference Laboratories and the Centers for Disease Control, the World Health Organization (WHO) confirmed the presence of a new species of genus Ebolavirus , which was tentatively named Bundibugyo. The WHO reported 149 cases of this new strain and 37 of those led to deaths. The WHO confirmed two small outbreaks in Uganda in 2012, both caused by the Sudan variant. The first outbreak affected seven people, killing four, and the second affected 24, killing 17. On 17 August 2012, the Ministry of Health of the DRC reported an outbreak of the Ebola-Bundibugyo variant in the eastern region. Other than its discovery in 2007, this was the only time that this variant has been identified as responsible for an outbreak. The WHO revealed that the virus had sickened 57 people and killed 29. The probable cause of the outbreak was tainted bush meat hunted by local villagers around the towns of Isiro and Viadana. In 2014, an outbreak occurred in the DRC. Genome-sequencing showed that this outbreak was not related to the 2014–15 West Africa Ebola virus outbreak , but was the same EBOV species, the Zaire species. It began in August 2014, and was declared over in November with 66 cases and 49 deaths. This was the 7th outbreak in the DRC, three of which occurred during the period when the country was known as Zaire . In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea , a West African nation. Researchers traced the outbreak to a one-year-old child who died in December 2013. The disease rapidly spread to the neighbouring countries of Liberia and Sierra Leone . It was the largest Ebola outbreak ever documented, and the first recorded in the region. On 8 August 2014, the WHO declared the epidemic an international public health emergency. Urging the world to offer aid to the affected regions, its Director-General said, "Countries affected to date simply do not have the capacity to manage an outbreak of this size and complexity on their own. I urge the international community to provide this support on the most urgent basis possible." By mid-August 2014, Doctors Without Borders reported the situation in Liberia's capital, Monrovia , was "catastrophic" and "deteriorating daily". They reported that fears of Ebola among staff members and patients had shut down much of the city's health system, leaving many people without medical treatment for other conditions. In a 26 September statement, WHO said, "The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long." Intense contact tracing and strict isolation largely prevented further spread of the disease in the countries that had imported cases. It caused significant mortality, with a considerable case fatality rate . [note 1] By the end of the epidemic, 28,616 people had been infected; of these, 11,310 had died, for a case-fatality rate of 40%. As of 8 May 2016 [ update ] , 28,646 suspected cases and 11,323 deaths were reported; however, the WHO said that these numbers may be underestimated. Because they work closely with the body fluids of infected patients, healthcare workers were especially vulnerable to infection; in August 2014, the WHO reported that 10% of the dead were healthcare workers. In September 2014, it was estimated that the countries' capacity for treating Ebola patients was insufficient by the equivalent of 2,122 beds; by December there were a sufficient number of beds to treat and isolate all reported Ebola cases, although the uneven distribution of cases was causing serious shortfalls in some areas. On 28 January 2015, the WHO reported that for the first time since the week ending 29 June 2014, there had been fewer than 100 new confirmed cases reported in a week in the three most-affected countries. The response to the epidemic then moved to a second phase, as the focus shifted from slowing transmission to ending the epidemic. On 8 April 2015, the WHO reported only 30 confirmed cases, the lowest weekly total since the third week of May 2014. On 29 December 2015, 42 days after the last person tested negative for a second time, Guinea was declared free of Ebola transmission. At that time, a 90-day period of heightened surveillance was announced by that agency. "This is the first time that all three countries – Guinea, Liberia and Sierra Leone – have stopped the original chains of transmission ...", the organisation stated in a news release. A new case was detected in Sierra Leone on 14 January 2016. However, the outbreak was declared no longer an emergency on 29 March 2016. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 11 May 2017, the DRC Ministry of Public Health notified the WHO about an outbreak of Ebola. Four people died, and four people survived; five of these eight cases were laboratory-confirmed. A total of 583 contacts were monitored. On 2 July 2017, the WHO declared the end of the outbreak. On 14 May 2018, the World Health Organization reported that "the Democratic Republic of Congo reported 39 suspected, probable or confirmed cases of Ebola between 4 April and 13 May, including 19 deaths." Some 393 people identified as contacts of Ebola patients were being followed up. The outbreak centred on the Bikoro , Iboko, and Wangata areas in Equateur province, including in the large city of Mbandaka . The DRC Ministry of Public Health approved the use of an experimental vaccine. On 13 May 2018, WHO Director-General Tedros Adhanom Ghebreyesus visited Bikoro. Reports emerged that maps of the area were inaccurate, not so much hampering medical providers as epidemiologists and officials trying to assess the outbreak and containment efforts. The 2018 outbreak in the DRC was declared over on 24 July 2018. On 1 August 2018, the world's 10th Ebola outbreak was declared in North Kivu province of the Democratic Republic of the Congo. It was the first Ebola outbreak in a military conflict zone, with thousands of refugees in the area. By November 2018, nearly 200 Congolese had died of Ebola, about half of them from the city of Beni , where armed groups are fighting over the region's mineral wealth, impeding medical relief efforts. By March 2019, this became the second largest Ebola outbreak ever recorded, with more than 1,000 cases and insecurity continuing to be the major resistance to providing an adequate response. As of 4 June 2019 [ update ] , the WHO reported 2025 confirmed and probable cases with 1357 deaths. In June 2019, two people died of Ebola in neighbouring Uganda . In July 2019, an infected man travelled to Goma , home to more than two million people. One week later, on 17 July 2019, the WHO declared the Ebola outbreak a global health emergency , the fifth time such a declaration has been made by the organisation. A government spokesman said that half of the Ebola cases are unidentified, and he added that the current outbreak could last up to three years. On 25 June 2020, the second biggest EVD outbreak ever was declared over. On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in Mbandaka , Équateur Province , a region along the Congo River. Genome sequencing suggests that this outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, is unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified; four of the people had died. It is expected that more people will be identified as surveillance activities increase. By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. The 11th EVD outbreak was officially declared over on 19 November 2020. By the time the Équateur outbreak ended, it had 130 confirmed cases with 75 recoveries and 55 deaths.On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 23 April 2022, a case of Ebola was confirmed in the DRC in the Equateur province. The case was a 31-year-old man whose symptoms began on 5 April, but did not seek treatment for over a week. On 21 April, he was admitted to an Ebola treatment centre and died later that day. By 24 May 2022, there were 5 recorded deaths in the DRC. On 15 August, the fifth case was buried, and the outbreak was declared over, 42 days after, on 4 July 2022. In September 2022, Uganda reported 7 cases infected with the Ebola Sudan strain , but by mid-October the count had increased to 63. In November 2022, the outbreak in Uganda continued - still without a vaccine. On 10 January 2023, the outbreak was considered over after no new cases had been reported for 42 days; the outbreak killed nearly 80 people. Ebolavirus is classified as a biosafety level 4 agent, as well as a Category A bioterrorism agent by the Centers for Disease Control and Prevention. It has the potential to be weaponised for use in biological warfare , and was investigated by Biopreparat for such use, but might be difficult to prepare as a weapon of mass destruction because the virus becomes ineffective quickly in open air. Fake emails pretending to be Ebola information from the WHO or the Mexican government have, in 2014, been misused to spread computer malware. The BBC reported in 2015 that "North Korean state media has suggested the disease was created by the U.S. military as a biological weapon." Richard Preston 's 1995 best-selling book, The Hot Zone , dramatised the Ebola outbreak in Reston, Virginia. William Close 's 1995 Ebola: A Documentary Novel of Its First Explosion and 2002 Ebola: Through the Eyes of the People focused on individuals' reactions to the 1976 Ebola outbreak in Zaire. Tom Clancy 's 1996 novel, Executive Orders , involves a Middle Eastern terrorist attack on the United States using an airborne form of a deadly Ebola virus strain named "Ebola Mayinga" (see Mayinga N'Seka ). As the Ebola virus epidemic in West Africa developed in 2014, a number of popular self-published and well-reviewed books containing sensational and misleading information about the disease appeared in electronic and printed formats. The authors of some such books admitted that they lacked medical credentials and were not technically qualified to give medical advice. The World Health Organization and the United Nations stated that such misinformation had contributed to the spread of the disease. Ebolavirus is classified as a biosafety level 4 agent, as well as a Category A bioterrorism agent by the Centers for Disease Control and Prevention. It has the potential to be weaponised for use in biological warfare , and was investigated by Biopreparat for such use, but might be difficult to prepare as a weapon of mass destruction because the virus becomes ineffective quickly in open air. Fake emails pretending to be Ebola information from the WHO or the Mexican government have, in 2014, been misused to spread computer malware. The BBC reported in 2015 that "North Korean state media has suggested the disease was created by the U.S. military as a biological weapon." Richard Preston 's 1995 best-selling book, The Hot Zone , dramatised the Ebola outbreak in Reston, Virginia. William Close 's 1995 Ebola: A Documentary Novel of Its First Explosion and 2002 Ebola: Through the Eyes of the People focused on individuals' reactions to the 1976 Ebola outbreak in Zaire. Tom Clancy 's 1996 novel, Executive Orders , involves a Middle Eastern terrorist attack on the United States using an airborne form of a deadly Ebola virus strain named "Ebola Mayinga" (see Mayinga N'Seka ). As the Ebola virus epidemic in West Africa developed in 2014, a number of popular self-published and well-reviewed books containing sensational and misleading information about the disease appeared in electronic and printed formats. The authors of some such books admitted that they lacked medical credentials and were not technically qualified to give medical advice. The World Health Organization and the United Nations stated that such misinformation had contributed to the spread of the disease. Ebola has a high mortality rate among primates. Frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas. Outbreaks of Ebola may have been responsible for an 88% decline in tracking indices of observed chimpanzee populations in the 420 km 2 Lossi Sanctuary between 2002 and 2003. Transmission among chimpanzees through meat consumption constitutes a significant risk factor, whereas contact between the animals, such as touching dead bodies and grooming, is not. Recovered gorilla carcasses have contained multiple Ebola virus strains, suggesting multiple introductions of the virus. Bodies decompose quickly and carcasses are not infectious after three to four days. Contact between gorilla groups is rare, suggesting that transmission among gorilla groups is unlikely, and that outbreaks result from transmission between viral reservoirs and animal populations. In 2012, it was demonstrated that the virus can travel without contact from pigs to nonhuman primates, although the same study failed to achieve transmission in that manner between primates. Dogs may become infected with EBOV but not develop symptoms. Dogs in some parts of Africa scavenge for food, and they sometimes eat EBOV-infected animals and also the corpses of humans. A 2005 survey of dogs during an EBOV outbreak found that although they remain asymptomatic, about 32 percent of dogs closest to an outbreak showed a seroprevalence for EBOV versus nine percent of those farther away. The authors concluded that there were "potential implications for preventing and controlling human outbreaks." In late 1989, Hazelton Research Products' Reston Quarantine Unit in Reston, Virginia , had an outbreak of fatal illness amongst certain lab monkeys. This lab outbreak was initially diagnosed as simian haemorrhagic fever virus (SHFV) and occurred amongst a shipment of crab-eating macaque monkeys imported from the Philippines. Hazelton's veterinary pathologist in Reston sent tissue samples from dead animals to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland , where an ELISA test indicated the antibodies present in the tissue were a response to Ebola virus and not SHFV. An electron microscopist from USAMRIID discovered filoviruses similar in appearance, in crystalloid aggregates and as single filaments with a shepherd's hook, to Ebola in the tissue samples sent from Hazelton Research Products' Reston Quarantine Unit. A US Army team headquartered at USAMRIID euthanised the surviving monkeys, and brought all the dead monkeys to Fort Detrick for study by the Army's veterinary pathologists and virologists, and eventual disposal under safe conditions. Blood samples were taken from 178 animal handlers during the incident. Of those, six animal handlers eventually seroconverted , including one who had cut himself with a bloody scalpel. Despite its status as a Level‑4 organism and its apparent pathogenicity in monkeys, when the handlers did not become ill, the CDC concluded that the virus had a very low pathogenicity to humans. The Philippines and the United States had no previous cases of Ebola infection, and upon further isolation, researchers concluded it was another strain of Ebola, or a new filovirus of Asian origin, which they named Reston ebolavirus (RESTV) after the location of the incident. Reston virus (RESTV) can be transmitted to pigs. Since the initial outbreak it has since been found in nonhuman primates in Pennsylvania, Texas, and Italy, where the virus had infected pigs. According to the WHO, routine cleaning and disinfection of pig (or monkey) farms with sodium hypochlorite or detergents should be effective in inactivating the Reston ebolavirus . Pigs that have been infected with RESTV tend to show symptoms of the disease. Ebola has a high mortality rate among primates. Frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas. Outbreaks of Ebola may have been responsible for an 88% decline in tracking indices of observed chimpanzee populations in the 420 km 2 Lossi Sanctuary between 2002 and 2003. Transmission among chimpanzees through meat consumption constitutes a significant risk factor, whereas contact between the animals, such as touching dead bodies and grooming, is not. Recovered gorilla carcasses have contained multiple Ebola virus strains, suggesting multiple introductions of the virus. Bodies decompose quickly and carcasses are not infectious after three to four days. Contact between gorilla groups is rare, suggesting that transmission among gorilla groups is unlikely, and that outbreaks result from transmission between viral reservoirs and animal populations. In 2012, it was demonstrated that the virus can travel without contact from pigs to nonhuman primates, although the same study failed to achieve transmission in that manner between primates. Dogs may become infected with EBOV but not develop symptoms. Dogs in some parts of Africa scavenge for food, and they sometimes eat EBOV-infected animals and also the corpses of humans. A 2005 survey of dogs during an EBOV outbreak found that although they remain asymptomatic, about 32 percent of dogs closest to an outbreak showed a seroprevalence for EBOV versus nine percent of those farther away. The authors concluded that there were "potential implications for preventing and controlling human outbreaks."In late 1989, Hazelton Research Products' Reston Quarantine Unit in Reston, Virginia , had an outbreak of fatal illness amongst certain lab monkeys. This lab outbreak was initially diagnosed as simian haemorrhagic fever virus (SHFV) and occurred amongst a shipment of crab-eating macaque monkeys imported from the Philippines. Hazelton's veterinary pathologist in Reston sent tissue samples from dead animals to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland , where an ELISA test indicated the antibodies present in the tissue were a response to Ebola virus and not SHFV. An electron microscopist from USAMRIID discovered filoviruses similar in appearance, in crystalloid aggregates and as single filaments with a shepherd's hook, to Ebola in the tissue samples sent from Hazelton Research Products' Reston Quarantine Unit. A US Army team headquartered at USAMRIID euthanised the surviving monkeys, and brought all the dead monkeys to Fort Detrick for study by the Army's veterinary pathologists and virologists, and eventual disposal under safe conditions. Blood samples were taken from 178 animal handlers during the incident. Of those, six animal handlers eventually seroconverted , including one who had cut himself with a bloody scalpel. Despite its status as a Level‑4 organism and its apparent pathogenicity in monkeys, when the handlers did not become ill, the CDC concluded that the virus had a very low pathogenicity to humans. The Philippines and the United States had no previous cases of Ebola infection, and upon further isolation, researchers concluded it was another strain of Ebola, or a new filovirus of Asian origin, which they named Reston ebolavirus (RESTV) after the location of the incident. Reston virus (RESTV) can be transmitted to pigs. Since the initial outbreak it has since been found in nonhuman primates in Pennsylvania, Texas, and Italy, where the virus had infected pigs. According to the WHO, routine cleaning and disinfection of pig (or monkey) farms with sodium hypochlorite or detergents should be effective in inactivating the Reston ebolavirus . Pigs that have been infected with RESTV tend to show symptoms of the disease. As of July 2015 [ update ] , no medication has been proven safe and effective for treating Ebola. By the time the Ebola virus epidemic in West Africa began in 2013, there were at least nine different candidate treatments. Several trials were conducted in late 2014, and early 2015, but some were abandoned due to lack of efficacy or lack of people to study. As of August 2019 [ update ] , two experimental treatments known as atoltivimab/maftivimab/odesivimab and ansuvimab were found to be 90% effective. The diagnostic tests currently available require specialised equipment and highly trained personnel. Since there are few suitable testing centres in West Africa, this leads to delay in diagnosis. On 29 November 2014, a new 15-minute Ebola test was reported that if successful, "not only gives patients a better chance of survival, but it prevents transmission of the virus to other people." The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas. On 29 December 2014, the U.S. Food and Drug Administration (FDA) approved the LightMix Ebola Zaire rRT-PCR test for patients with symptoms of Ebola. Animal models and in particular non-human primates are being used to study different aspects of Ebola virus disease. Developments in organ-on-a-chip technology have led to a chip-based model for Ebola haemorrhagic syndrome. As of July 2015 [ update ] , no medication has been proven safe and effective for treating Ebola. By the time the Ebola virus epidemic in West Africa began in 2013, there were at least nine different candidate treatments. Several trials were conducted in late 2014, and early 2015, but some were abandoned due to lack of efficacy or lack of people to study. As of August 2019 [ update ] , two experimental treatments known as atoltivimab/maftivimab/odesivimab and ansuvimab were found to be 90% effective. The diagnostic tests currently available require specialised equipment and highly trained personnel. Since there are few suitable testing centres in West Africa, this leads to delay in diagnosis. On 29 November 2014, a new 15-minute Ebola test was reported that if successful, "not only gives patients a better chance of survival, but it prevents transmission of the virus to other people." The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas. On 29 December 2014, the U.S. Food and Drug Administration (FDA) approved the LightMix Ebola Zaire rRT-PCR test for patients with symptoms of Ebola. Animal models and in particular non-human primates are being used to study different aspects of Ebola virus disease. Developments in organ-on-a-chip technology have led to a chip-based model for Ebola haemorrhagic syndrome.

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Acute hemorrhagic fever syndrome

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Hantavirus pulmonary syndrome

Hantavirus pulmonary syndrome ( HPS ) is one of two potentially fatal syndromes of zoonotic origin caused by species of hantavirus . These include Black Creek Canal virus (BCCV), New York orthohantavirus (NYV), Monongahela virus (MGLV), Sin Nombre orthohantavirus (SNV), and certain other members of hantavirus genera that are native to the United States and Canada. Specific rodents are the principal hosts of the hantaviruses including the hispid cotton rat ( Sigmodon hispidus ) in southern Florida , which is the principal host of Black Creek Canal virus. The deer mouse ( Peromyscus maniculatus ) in Canada and the Western United States is the principal host of Sin Nombre virus . The white-footed mouse ( Peromyscus leucopus ) in the eastern United States is the principal host of New York virus. In South America , the long-tailed mouse ( Oligoryzomys longicaudatus ) and other species of the genus Oligoryzomys have been documented as the reservoir for Andes virus . Initially, HPS has an incubation phase of 2–4 weeks, in which patients remain asymptomatic. Subsequently, patients can experience 3–5 days of flu-like prodromal phase symptoms, including fever , cough, muscle pain , headache, lethargy, shortness of breath , nausea, vomiting and diarrhea. In the following 5–7 day cardiopulmonary phase, the patient's condition rapidly deteriorates into acute respiratory failure , characterized by the sudden onset of shortness of breath with rapidly evolving pulmonary edema , as well as cardiac failure , with hypotension, tachycardia and shock. In this phase, patients may develop acute respiratory distress syndrome . It is often fatal despite mechanical ventilation and intervention with diuretics . [ citation needed ] After the cardiopulmonary phase, patients can enter a diuretic phase of 2–3 days characterized by symptom improvement and diuresis . Subsequent convalescence can last months to years. As of 2017, patient mortality in the US from HPS is 36%. The virus can be transmitted to humans by a direct bite or inhalation of aerosolized virus, shed from stool, urine, or saliva from a natural reservoir rodent. In general, droplet and/or fomite transfer has not been shown in the hantaviruses in either the pulmonary or hemorrhagic forms. The preferred method for diagnosis of Hantavirus Pulmonary Syndrome is serological testing which identifies both acute (IgM) and remote infections (IgG); however, PCR may also be used to identify early infections. Rodent control in and around the home or dwellings remains the primary prevention strategy, as well as eliminating contact with rodents in the workplace and at campsites. Closed storage sheds and cabins are often ideal sites for rodent infestations. Airing out of such spaces prior to use is recommended. People are advised to avoid direct contact with rodent droppings and wear a mask while cleaning such areas to avoid inhalation of aerosolized rodent secretions. There is no cure or vaccine for HPS. Treatment involves supportive therapy, including mechanical ventilation with supplemental oxygen during the critical respiratory-failure stage of the illness. Although ribavirin can be used to treat hantavirus infections, it is not recommended as a treatment for HPS due to unclear clinical efficacy and likelihood of medication side effects. Early recognition of HPS and admission to an intensive care setting offers the best prognosis . Hantavirus pulmonary syndrome was first recognized during the 1993 outbreak in the Four Corners region of the southwestern United States . It was identified by Dr. Bruce Tempest. It was originally called Four Corners disease , but the name was changed to Sin Nombre virus after complaints by Native Americans that the name "Four Corners" stigmatized the region. It has since been identified throughout the United States. [ citation needed ]

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Acute hemorrhagic fever syndrome

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Acute hemorrhagic edema of infancy

Acute hemorrhagic edema of infancy (AHEI) is a type of leukocytoclastic vasculitis that is not fatal. Although it causes fever, large palpable purpuric skin lesions, and edema , it is a harmless condition. AHEI's appearance is frequently similar to that of Henoch-Schönlein purpura . Because AHEI is a self-limiting disease, conservative treatment is common. Snow described acute hemorrhagic edema of infancy in the United States in 1913. Finkelstein described it in Europe in 1938, and it has been recognized in European literature since then under various names. Synonyms include Finkelstein disease, Seidlmayer syndrome, Infantile postinfectious iris-like purpura and oedema, and Purpura en cocarde avec oedema. AHEI is associated with a variety of organisms, including adenovirus , varicella-zoster virus , cytomegalovirus , herpes simplex virus , tuberculosis , streptococci , and staphylococci . The typical clinical picture is edema on the cheeks, auricles , and extremities along with purpuric skin lesions. It has a violent onset, a brief and benign course, and recovers spontaneously after 1 to 3 weeks. Mild fever has been reported in the majority of patients. AHEI typically begins with palpable hemorrhagic skin lesions and petechiae , which can progress to medallion-like lesions 1 to 6 cm in diameter. The rashes are usually sharply edged, and the centers of the iris-like lesions are rarely normal skin color. The extremities, including the ears, chin, eyelids, malar region, and scrotal area, are particularly affected. The trunk is usually unaffected. It has been described as a bullous variation with tense hemorrhagic blisters. Lesions, particularly those on the ears, can become necrotic and leave a scar. Edema primarily affects the extremities, especially the backs of the hands and feet. It is frequently asymmetric and begins distally. It can spread to the forearms and legs, but it can also appear on the face, eyelids, earlobes, and even the scrotum. Edema can be painful. AHEI can sometimes appear without fever or edema but without purpura .

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Acute hemorrhagic fever syndrome

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Intracerebral hemorrhage

Intracerebral hemorrhage ( ICH ), also known as hemorrhagic stroke , is a sudden bleeding into the tissues of the brain (i.e. the parenchyma), into its ventricles , or into both. An ICH is a type of bleeding within the skull and one kind of stroke (ischemic stroke being the other). Symptoms can vary dramatically depending on the severity (how much blood), acuity (over what timeframe), and location (anatomically) but can include headache , one-sided weakness , numbness, tingling, or paralysis , speech problems, vision or hearing problems, memory loss, attention problems, coordination problems, balance problems, dizziness or lightheadedness or vertigo , nausea/vomiting, seizures, decreased level of consciousness or total loss of consciousness , neck stiffness , and fever . Hemorrhagic stroke may occur on the background of alterations to the blood vessels in the brain, such as cerebral arteriolosclerosis , cerebral amyloid angiopathy , cerebral arteriovenous malformation , brain trauma , brain tumors and an intracranial aneurysm , which can cause intraparenchymal or subarachnoid hemorrhage. The biggest risk factors for spontaneous bleeding are high blood pressure and amyloidosis . Other risk factors include alcoholism , low cholesterol , blood thinners , and cocaine use. Diagnosis is typically by CT scan . Treatment should typically be carried out in an intensive care unit due to strict blood pressure goals and frequent use of both pressors and antihypertensive agents. Anticoagulation should be reversed if possible and blood sugar kept in the normal range. A procedure to place an external ventricular drain may be used to treat hydrocephalus or increased intracranial pressure , however, the use of corticosteroids is frequently avoided. Sometimes surgery to directly remove the blood can be therapeutic. Cerebral bleeding affects about 2.5 per 10,000 people each year. It occurs more often in males and older people. About 44% of those affected die within a month. A good outcome occurs in about 20% of those affected. Intracerebral hemorrhage, a type of hemorrhagic stroke, was first distinguished from ischemic strokes due to insufficient blood flow, so called "leaks and plugs", in 1823. The incidence of intracerebral hemorrhage is estimated at 24.6 cases per 100,000 person years with the incidence rate being similar in men and women. The incidence is much higher in the elderly, especially those who are 85 or older, who are 9.6 times more likely to have an intracerebral hemorrhage as compared to those of middle age. It accounts for 20% of all cases of cerebrovascular disease in the United States, behind cerebral thrombosis (40%) and cerebral embolism (30%). Intraparenchymal hemorrhage (IPH) is one form of intracerebral bleeding in which there is bleeding within brain parenchyma . Intraparenchymal hemorrhage accounts for approximately 8-13% of all strokes and results from a wide spectrum of disorders. It is more likely to result in death or major disability than ischemic stroke or subarachnoid hemorrhage , and therefore constitutes an immediate medical emergency . Intracerebral hemorrhages and accompanying edema may disrupt or compress adjacent brain tissue , leading to neurological dysfunction. Substantial displacement of brain parenchyma may cause elevation of intracranial pressure (ICP) and potentially fatal herniation syndromes . Intraventricular hemorrhage (IVH), also known asintraventricular bleeding, is a bleeding into the brain's ventricular system , where the cerebrospinal fluid is produced and circulates through towards the subarachnoid space . It can result from physical trauma or from hemorrhagic stroke . 30% of intraventricular hemorrhage (IVH) are primary, confined to the ventricular system and typically caused by intraventricular trauma, aneurysm, vascular malformations, or tumors, particularly of the choroid plexus. However 70% of IVH are secondary in nature, resulting from an expansion of an existing intraparenchymal or subarachnoid hemorrhage. Intraventricular hemorrhage has been found to occur in 35% of moderate to severe traumatic brain injuries . Thus the hemorrhage usually does not occur without extensive associated damage, and so the outcome is rarely good. Intraparenchymal hemorrhage (IPH) is one form of intracerebral bleeding in which there is bleeding within brain parenchyma . Intraparenchymal hemorrhage accounts for approximately 8-13% of all strokes and results from a wide spectrum of disorders. It is more likely to result in death or major disability than ischemic stroke or subarachnoid hemorrhage , and therefore constitutes an immediate medical emergency . Intracerebral hemorrhages and accompanying edema may disrupt or compress adjacent brain tissue , leading to neurological dysfunction. Substantial displacement of brain parenchyma may cause elevation of intracranial pressure (ICP) and potentially fatal herniation syndromes .Intraventricular hemorrhage (IVH), also known asintraventricular bleeding, is a bleeding into the brain's ventricular system , where the cerebrospinal fluid is produced and circulates through towards the subarachnoid space . It can result from physical trauma or from hemorrhagic stroke . 30% of intraventricular hemorrhage (IVH) are primary, confined to the ventricular system and typically caused by intraventricular trauma, aneurysm, vascular malformations, or tumors, particularly of the choroid plexus. However 70% of IVH are secondary in nature, resulting from an expansion of an existing intraparenchymal or subarachnoid hemorrhage. Intraventricular hemorrhage has been found to occur in 35% of moderate to severe traumatic brain injuries . Thus the hemorrhage usually does not occur without extensive associated damage, and so the outcome is rarely good. People with intracerebral bleeding have symptoms that correspond to the functions controlled by the area of the brain that is damaged by the bleed. These localizing signs and symptoms can include hemiplegia (or weakness localized to one side of the body) and paresthesia (loss of sensation) including hemisensory loss (if localized to one side of the body). These symptoms are usually rapid in onset, sometimes occurring in minutes, but not as rapid as the symptom onset in ischemic stroke . While the duration of onset not be as rapid, it is important that patients go to the emergency department as soon as they notice any symptoms as early detection and management of stroke may lead to better outcomes post-stroke than delayed identification. A mnemonic to remember the warning signs of stroke is FAST (facial droop, arm weakness, speech difficulty, and time to call emergency services), as advocated by the Department of Health (United Kingdom) and the Stroke Association , the American Stroke Association , the National Stroke Association (US), the Los Angeles Prehospital Stroke Screen (LAPSS) and the Cincinnati Prehospital Stroke Scale (CPSS). Use of these scales is recommended by professional guidelines. FAST is less reliable in the recognition of posterior circulation stroke. Other symptoms include those that indicate a rise in intracranial pressure caused by a large mass (due to hematoma expansion) putting pressure on the brain. These symptoms include headaches , nausea, vomiting, a depressed level of consciousness, stupor and death. Continued elevation in the intracranial pressure and the accompanying mass effect may eventually cause brain herniation (when different parts of the brain are displaced or shifted to new areas in relation to the skull and surrounding dura mater supporting structures). Brain herniation is associated with hyperventilation , extensor rigidity , pupillary asymmetry, pyramidal signs , coma and death. Hemorrhage into the basal ganglia or thalamus causes contralateral hemiplegia due to damage to the internal capsule . Other possible symptoms include gaze palsies or hemisensory loss. Intracerebral hemorrhage into the cerebellum may cause ataxia , vertigo , incoordination of limbs and vomiting. Some cases of cerebellar hemorrhage lead to blockage of the fourth ventricle with subsequent impairment of drainage of cerebrospinal fluid from the brain. The ensuing hydrocephalus , or fluid buildup in the ventricles of the brain leads to a decreased level of consciousness, total loss of consciousness , coma , and persistent vegetative state . Brainstem hemorrhage most commonly occurs in the pons and is associated with shortness of breath , cranial nerve palsies , pinpoint (but reactive) pupils, gaze palsies, facial weakness, coma , and persistent vegetative state (if there is damage to the reticular activating system ). Intracerebral bleeds are the second most common cause of stroke , accounting for 10% of hospital admissions for stroke. High blood pressure raises the risks of spontaneous intracerebral hemorrhage by two to six times. More common in adults than in children, intraparenchymal bleeds are usually due to penetrating head trauma , but can also be due to depressed skull fractures . Acceleration-deceleration trauma, rupture of an aneurysm or arteriovenous malformation (AVM), and bleeding within a tumor are additional causes. Amyloid angiopathy is not an uncommon cause of intracerebral hemorrhage in patients over the age of 55. A very small proportion is due to cerebral venous sinus thrombosis . [ citation needed ] Risk factors for ICH include: Hypertension is the strongest risk factor associated with intracerebral hemorrhage and long term control of elevated blood pressure has been shown to reduce the incidence of hemorrhage. Cerebral amyloid angiopathy , a disease characterized by deposition of amyloid beta peptides in the walls of the small blood vessels of the brain, leading to weakened blood vessel walls and an increased risk of bleeding; is also an important risk factor for the development of intracerebral hemorrhage. Other risk factors include advancing age (usually with a concomitant increase of cerebral amyloid angiopathy risk in the elderly), use of anticoagulants or antiplatelet medications , the presence of cerebral microbleeds, chronic kidney disease , and low low density lipoprotein (LDL) levels (usually below 70). The direct oral anticoagulants (DOACs) such as the factor Xa inhibitors or direct thrombin inhibitors are thought to have a lower risk of intracerebral hemorrhage as compared to the vitamin K antagonists such as warfarin . Cigarette smoking may be a risk factor but the association is weak. Traumautic intracerebral hematomas are divided into acute and delayed. Acute intracerebral hematomas occur at the time of the injury while delayed intracerebral hematomas have been reported from as early as 6 hours post injury to as long as several weeks. [ citation needed ]Both computed tomography angiography (CTA) and magnetic resonance angiography (MRA) have been proved to be effective in diagnosing intracranial vascular malformations after ICH. So frequently, a CT angiogram will be performed in order to exclude a secondary cause of hemorrhage or to detect a "spot sign". Intraparenchymal hemorrhage can be recognized on CT scans because blood appears brighter than other tissue and is separated from the inner table of the skull by brain tissue. The tissue surrounding a bleed is often less dense than the rest of the brain because of edema , and therefore shows up darker on the CT scan. The oedema surrounding the haemorrhage would rapidly increase in size in the first 48 hours, and reached its maximum extent at day 14. The bigger the size of the haematoma, the larger its surrounding oedema. Brain oedema formation is due to the breakdown of red blood cells, where haemoglobin and other contents of red blood cells are released. The release of these red blood cells contents causes toxic effect on the brain and causes brain oedema. Besides, the breaking down of blood-brain barrier also contributes to the odema formation. Apart from CT scans, haematoma progression of intracerebral haemorrhage can be monitored using transcranial ultrasound. Ultrasound probe can be placed at the temporal lobe to estimate the volume of haematoma within the brain, thus identifying those with active bleeding for further intervention to stop the bleeding. Using ultrasound can also reduces radiation risk to the subject from CT scans. When due to high blood pressure , intracerebral hemorrhages typically occur in the putamen (50%) or thalamus (15%), cerebrum (10–20%), cerebellum (10–13%), pons (7–15%), or elsewhere in the brainstem (1–6%). When due to high blood pressure , intracerebral hemorrhages typically occur in the putamen (50%) or thalamus (15%), cerebrum (10–20%), cerebellum (10–13%), pons (7–15%), or elsewhere in the brainstem (1–6%). Treatment depends substantially on the type of ICH. Rapid CT scan and other diagnostic measures are used to determine proper treatment, which may include both medication and surgery. Rapid lowering of the blood pressure using antihypertensive therapy for those with hypertensive emergency can have higher functional recovery at 90 days post intracerebral haemorrhage, when compared to those who undergone other treatments such as mannitol administration, reversal of anticoagulation (those previously on anticoagulant treatment for other conditions), surgery to evacuate the haematoma, and standard rehabilitation care in hospital, while showing similar rate of death at 12%. Early lowering of the blood pressure can reduce the volume of the haematoma, but may not have any effect against the oedema surrounding the haematoma. Reducing the blood pressure rapidly does not cause brain ischemia in those who have intracerebral haemorrhage. The American Heart Association and American Stroke Association guidelines in 2015 recommended decreasing the blood pressure to a SBP of 140 mmHg. However, later reviews found unclear difference between intensive and less intensive blood pressure control. Giving Factor VIIa within 4 hours limits the bleeding and formation of a hematoma . However, it also increases the risk of thromboembolism . It thus overall does not result in better outcomes in those without hemophilia. Frozen plasma , vitamin K , protamine , or platelet transfusions may be given in case of a coagulopathy . Platelets however appear to worsen outcomes in those with spontaneous intracerebral bleeding on antiplatelet medication. The specific reversal agents idarucizumab and andexanet alfa may be used to stop continued intracerebral hemorrhage in people taking directly oral acting anticoagulants (such as factor Xa inhibitors or direct thrombin inhibitors). However, if these specialized medications are not available, prothrombin complex concentrate may also be used. Only 7% of those with ICH are presented with clinical features of seizures while up to 25% of those have subclinical seizures. Seizures are not associated with an increased risk of death or disability. Meanwhile, anticonvulsant administration can increase the risk of death. Therefore, anticonvulsants are only reserved for those that have shown obvious clinical features of seizures or seizure activity on electroencephalography (EEG). H2 antagonists or proton pump inhibitors are commonly given to try to prevent stress ulcers , a condition linked with ICH. Corticosteroids were thought to reduce swelling. However, in large controlled studies, corticosteroids have been found to increase mortality rates and are no longer recommended. Surgery is required if the hematoma is greater than 3 cm (1 in) , if there is a structural vascular lesion or lobar hemorrhage in a young patient. A catheter may be passed into the brain vasculature to close off or dilate blood vessels , avoiding invasive surgical procedures. Aspiration by stereotactic surgery or endoscopic drainage may be used in basal ganglia hemorrhages, although successful reports are limited. A craniectomy holds promise of reduced mortality, but the effects of long‐term neurological outcome remain controversial. Rapid lowering of the blood pressure using antihypertensive therapy for those with hypertensive emergency can have higher functional recovery at 90 days post intracerebral haemorrhage, when compared to those who undergone other treatments such as mannitol administration, reversal of anticoagulation (those previously on anticoagulant treatment for other conditions), surgery to evacuate the haematoma, and standard rehabilitation care in hospital, while showing similar rate of death at 12%. Early lowering of the blood pressure can reduce the volume of the haematoma, but may not have any effect against the oedema surrounding the haematoma. Reducing the blood pressure rapidly does not cause brain ischemia in those who have intracerebral haemorrhage. The American Heart Association and American Stroke Association guidelines in 2015 recommended decreasing the blood pressure to a SBP of 140 mmHg. However, later reviews found unclear difference between intensive and less intensive blood pressure control. Giving Factor VIIa within 4 hours limits the bleeding and formation of a hematoma . However, it also increases the risk of thromboembolism . It thus overall does not result in better outcomes in those without hemophilia. Frozen plasma , vitamin K , protamine , or platelet transfusions may be given in case of a coagulopathy . Platelets however appear to worsen outcomes in those with spontaneous intracerebral bleeding on antiplatelet medication. The specific reversal agents idarucizumab and andexanet alfa may be used to stop continued intracerebral hemorrhage in people taking directly oral acting anticoagulants (such as factor Xa inhibitors or direct thrombin inhibitors). However, if these specialized medications are not available, prothrombin complex concentrate may also be used. Only 7% of those with ICH are presented with clinical features of seizures while up to 25% of those have subclinical seizures. Seizures are not associated with an increased risk of death or disability. Meanwhile, anticonvulsant administration can increase the risk of death. Therefore, anticonvulsants are only reserved for those that have shown obvious clinical features of seizures or seizure activity on electroencephalography (EEG). H2 antagonists or proton pump inhibitors are commonly given to try to prevent stress ulcers , a condition linked with ICH. Corticosteroids were thought to reduce swelling. However, in large controlled studies, corticosteroids have been found to increase mortality rates and are no longer recommended. Surgery is required if the hematoma is greater than 3 cm (1 in) , if there is a structural vascular lesion or lobar hemorrhage in a young patient. A catheter may be passed into the brain vasculature to close off or dilate blood vessels , avoiding invasive surgical procedures. Aspiration by stereotactic surgery or endoscopic drainage may be used in basal ganglia hemorrhages, although successful reports are limited. A craniectomy holds promise of reduced mortality, but the effects of long‐term neurological outcome remain controversial. About 8 to 33% of those with intracranial haemorrhage have neurological deterioration within the first 24 hours of hospital admission, where a large proportion of them happens within 6 to 12 hours. Rate of haematoma expansion, perihaematoma odema volume and the presence of fever can affect the chances of getting neurological complications. The risk of death from an intraparenchymal bleed in traumatic brain injury is especially high when the injury occurs in the brain stem . Intraparenchymal bleeds within the medulla oblongata are almost always fatal, because they cause damage to cranial nerve X, the vagus nerve , which plays an important role in blood circulation and breathing. This kind of hemorrhage can also occur in the cortex or subcortical areas, usually in the frontal or temporal lobes when due to head injury, and sometimes in the cerebellum . Larger volumes of hematoma at hospital admission as well as greater expansion of the hematoma on subsequent evaluation (usually occurring within 6 hours of symptom onset) are associated with a worse prognosis. Perihematomal edema, or secondary edema surrounding the hematoma, is associated with secondary brain injury, worsening neurological function and is associated with poor outcomes. Intraventricular hemorrhage, or bleeding into the ventricles of the brain, which may occur in 30–50% of patients, is also associated with long-term disability and a poor prognosis. Brain herniation is associated with poor prognoses. For spontaneous intracerebral hemorrhage seen on CT scan, the death rate ( mortality ) is 34–50% by 30 days after the injury, and half of the deaths occur in the first 2 days. Even though the majority of deaths occur in the first few days after ICH, survivors have a long-term excess mortality rate of 27% compared to the general population. Of those who survive an intracerebral hemorrhage, 12–39% are independent with regard to self-care; others are disabled to varying degrees and require supportive care.

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Acute hemorrhagic fever syndrome

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Subdural hematoma

A subdural hematoma ( SDH ) is a type of bleeding in which a collection of blood —usually but not always associated with a traumatic brain injury —gathers between the inner layer of the dura mater and the arachnoid mater of the meninges surrounding the brain . It usually results from tears in bridging veins that cross the subdural space . Subdural hematomas may cause an increase in the pressure inside the skull , which in turn can cause compression of and damage to delicate brain tissue. Acute subdural hematomas are often life-threatening. Chronic subdural hematomas have a better prognosis if properly managed. In contrast, epidural hematomas are usually caused by tears in arteries , resulting in a build-up of blood between the dura mater and the skull . The third type of brain hemorrhage, known as a subarachnoid hemorrhage (SAH), causes bleeding into the subarachnoid space between the arachnoid mater and the pia mater . SAH are often seen in trauma settings, or after rupture of intracranial aneurysms. [ citation needed ]The symptoms of a subdural hematoma have a slower onset than those of epidural hematomas because the lower-pressure veins involved bleed more slowly than arteries. Signs and symptoms of acute hematomas may appear in minutes, if not immediately, but can also be delayed as much as two weeks. Symptoms of chronic subdural hematomas are usually delayed more than three weeks after injury. If the bleeds are large enough to put pressure on the brain, signs of increased intracranial pressure or brain damage will be present. Other symptoms of subdural hematoma can include any combination of the following: Subdural hematomas are most often caused by head injury , in which rapidly changing velocities within the skull may stretch and tear small bridging veins . Much more common than epidural hemorrhages , subdural hemorrhages generally result from shearing injuries due to various rotational or linear forces. There are claims that they can occur in cases of shaken baby syndrome , although there is no scientific evidence for this. They are also commonly seen in the elderly and in people with an alcohol use disorder who have evidence of cerebral atrophy . Cerebral atrophy increases the length the bridging veins have to traverse between the two meningeal layers, thus increasing the likelihood of shearing forces causing a tear. It is also more common in patients on anticoagulants or antiplatelet medications , such as warfarin and aspirin , respectively. People on these medications can have a subdural hematoma after a relatively minor traumatic event. Another cause can be a reduction in cerebrospinal fluid pressure, which can reduce pressure in the subarachnoid space, pulling the arachnoid away from the dura mater and leading to a rupture of the blood vessels. Factors increasing the risk of a subdural hematoma include very young or very old age . As the brain shrinks with age, the subdural space enlarges and the veins that traverse the space must cover a wider distance, making them more vulnerable to tears. The elderly also have more brittle veins, making chronic subdural bleeds more common. Infants, too, have larger subdural spaces and are more predisposed to subdural bleeds than are young adults. It is often claimed that subdural hematoma is a common finding in shaken baby syndrome, although there is no science to support this. In juveniles, an arachnoid cyst is a risk factor for subdural hematoma. Other risk factors include taking blood thinners (anticoagulants), long-term excessive alcohol consumption , dementia , and cerebrospinal fluid leaks . Factors increasing the risk of a subdural hematoma include very young or very old age . As the brain shrinks with age, the subdural space enlarges and the veins that traverse the space must cover a wider distance, making them more vulnerable to tears. The elderly also have more brittle veins, making chronic subdural bleeds more common. Infants, too, have larger subdural spaces and are more predisposed to subdural bleeds than are young adults. It is often claimed that subdural hematoma is a common finding in shaken baby syndrome, although there is no science to support this. In juveniles, an arachnoid cyst is a risk factor for subdural hematoma. Other risk factors include taking blood thinners (anticoagulants), long-term excessive alcohol consumption , dementia , and cerebrospinal fluid leaks . Acute subdural hematoma is usually caused by external trauma that creates tension in the wall of a bridging vein as it passes between the arachnoid and dural layers of the brain's lining—i.e., the subdural space. The circumferential arrangement of collagen surrounding the vein makes it susceptible to such tearing. [ citation needed ] Intracerebral hemorrhage and ruptured cortical vessels (blood vessels on the surface of the brain) can also cause subdural hematoma. In these cases, blood usually accumulates between the two layers of the dura mater. This can cause ischemic brain damage by two mechanisms: one, pressure on the cortical blood vessels, and two, vasoconstriction due to the substances released from the hematoma, which causes further ischemia by restricting blood flow to the brain. When the brain is denied adequate blood flow, a biochemical cascade known as the ischemic cascade is unleashed, and may ultimately lead to brain cell death . Subdural hematomas grow continually larger as a result of the pressure they place on the brain: As intracranial pressure rises, blood is squeezed into the dural venous sinuses , raising the dural venous pressure and resulting in more bleeding from the ruptured bridging veins. They stop growing only when the pressure of the hematoma equalizes with the intracranial pressure, as the space for expansion shrinks. In chronic subdural hematomas, blood accumulates in the dural space as a result of damage to the dural border cells. The resulting inflammation leads to new membrane formation through fibrosis and produces fragile and leaky blood vessels through angiogenesis , permitting the leakage of red blood cells , white blood cells , and plasma into the hematoma cavity. Traumatic tearing of the arachnoid mater also causes leakage of cerebrospinal fluid into the hematoma cavity, increasing the size of the hematoma over time. Excessive fibrinolysis also causes continuous bleeding. [ citation needed ] Pro-inflammatory mediators active in the hematoma expansion process include Interleukin 1α ( IL1A ), Interleukin 6 , and Interleukin 8 , while the anti-inflammatory mediator is Interleukin 10 . Mediators that promote angiogenesis are angiopoietin and vascular endothelial growth factor (VEGF). Prostaglandin E2 promotes the expression of VEGF. Matrix metalloproteinases remove surrounding collagen, providing space for new blood vessels to grow. Craniotomy for unruptured intracranial aneurysm is another risk factor for the development of chronic subdural hematoma. The incision in the arachnoid membrane during the operation causes cerebrospinal fluid to leak into the subdural space, leading to inflammation. This complication usually resolves on its own. Acute subdural hematoma is usually caused by external trauma that creates tension in the wall of a bridging vein as it passes between the arachnoid and dural layers of the brain's lining—i.e., the subdural space. The circumferential arrangement of collagen surrounding the vein makes it susceptible to such tearing. [ citation needed ] Intracerebral hemorrhage and ruptured cortical vessels (blood vessels on the surface of the brain) can also cause subdural hematoma. In these cases, blood usually accumulates between the two layers of the dura mater. This can cause ischemic brain damage by two mechanisms: one, pressure on the cortical blood vessels, and two, vasoconstriction due to the substances released from the hematoma, which causes further ischemia by restricting blood flow to the brain. When the brain is denied adequate blood flow, a biochemical cascade known as the ischemic cascade is unleashed, and may ultimately lead to brain cell death . Subdural hematomas grow continually larger as a result of the pressure they place on the brain: As intracranial pressure rises, blood is squeezed into the dural venous sinuses , raising the dural venous pressure and resulting in more bleeding from the ruptured bridging veins. They stop growing only when the pressure of the hematoma equalizes with the intracranial pressure, as the space for expansion shrinks. In chronic subdural hematomas, blood accumulates in the dural space as a result of damage to the dural border cells. The resulting inflammation leads to new membrane formation through fibrosis and produces fragile and leaky blood vessels through angiogenesis , permitting the leakage of red blood cells , white blood cells , and plasma into the hematoma cavity. Traumatic tearing of the arachnoid mater also causes leakage of cerebrospinal fluid into the hematoma cavity, increasing the size of the hematoma over time. Excessive fibrinolysis also causes continuous bleeding. [ citation needed ] Pro-inflammatory mediators active in the hematoma expansion process include Interleukin 1α ( IL1A ), Interleukin 6 , and Interleukin 8 , while the anti-inflammatory mediator is Interleukin 10 . Mediators that promote angiogenesis are angiopoietin and vascular endothelial growth factor (VEGF). Prostaglandin E2 promotes the expression of VEGF. Matrix metalloproteinases remove surrounding collagen, providing space for new blood vessels to grow. Craniotomy for unruptured intracranial aneurysm is another risk factor for the development of chronic subdural hematoma. The incision in the arachnoid membrane during the operation causes cerebrospinal fluid to leak into the subdural space, leading to inflammation. This complication usually resolves on its own. It is important that a person receive medical assessment, including a complete neurological examination, after any head trauma. A CT scan or MRI scan will usually detect significant subdural hematomas. [ citation needed ] Subdural hematomas occur most often around the tops and sides of the frontal and parietal lobes . They also occur in the posterior cranial fossa , and near the falx cerebri and tentorium cerebelli . Unlike epidural hematomas, which cannot expand past the sutures of the skull , subdural hematomas can expand along the inside of the skull, creating a concave shape that follows the curve of the brain, stopping only at dural reflections like the tentorium cerebelli and falx cerebri. [ citation needed ] On a CT scan, subdural hematomas are classically crescent-shaped, with a concave surface away from the skull. However, they can have a convex appearance, especially in the early stages of bleeding. This may cause difficulty in distinguishing between subdural and epidural hemorrhages. A more reliable indicator of subdural hemorrhage is its involvement of a larger portion of the cerebral hemisphere. Subdural blood can also be seen as a layering density along the tentorium cerebelli. This can be a chronic, stable process, since the feeding system is low-pressure. In such cases, subtle signs of bleeding—such as effacement of sulci or medial displacement of the junction between gray matter and white matter —may be apparent. [ citation needed ] Fresh subdural bleeding is hyperdense , but becomes more hypodense over time due to dissolution of cellular elements. After 3–14 days, the bleeding becomes isodense with brain tissue and may therefore be missed. Subsequently, it will become more hypodense than brain tissue. Subdural hematomas are classified as acute , subacute, or chronic , depending on the speed of their onset. Acute bleeds often develop after high-speed acceleration or deceleration injuries. They are most severe if associated with cerebral contusions . Though much faster than chronic subdural bleeds, acute subdural bleeding is usually venous and therefore slower than the arterial bleeding of an epidural hemorrhage. Acute subdural hematomas due to trauma are the most lethal of all head injuries and have a high mortality rate if they are not rapidly treated with surgical decompression. The mortality rate is higher than that of epidural hematomas and diffuse brain injuries because the force required to cause subdural hematomas tends to cause other severe injuries as well. Chronic subdural bleeds develop over a period of days to weeks, often after minor head trauma, though a cause is not identifiable in 50% of patients. They may not be discovered until they present clinically months or years after a head injury. The bleeding from a chronic hematoma is slow and usually stops by itself. Because these hematomas progress slowly, they can more often be stopped before they cause significant damage, especially if they are less than a centimeter wide. In one study, only 22% of patients with chronic subdural bleeds had outcomes worse than "good" or "complete recovery". Chronic subdural hematomas are common in the elderly. Subdural hematomas are classified as acute , subacute, or chronic , depending on the speed of their onset. Acute bleeds often develop after high-speed acceleration or deceleration injuries. They are most severe if associated with cerebral contusions . Though much faster than chronic subdural bleeds, acute subdural bleeding is usually venous and therefore slower than the arterial bleeding of an epidural hemorrhage. Acute subdural hematomas due to trauma are the most lethal of all head injuries and have a high mortality rate if they are not rapidly treated with surgical decompression. The mortality rate is higher than that of epidural hematomas and diffuse brain injuries because the force required to cause subdural hematomas tends to cause other severe injuries as well. Chronic subdural bleeds develop over a period of days to weeks, often after minor head trauma, though a cause is not identifiable in 50% of patients. They may not be discovered until they present clinically months or years after a head injury. The bleeding from a chronic hematoma is slow and usually stops by itself. Because these hematomas progress slowly, they can more often be stopped before they cause significant damage, especially if they are less than a centimeter wide. In one study, only 22% of patients with chronic subdural bleeds had outcomes worse than "good" or "complete recovery". Chronic subdural hematomas are common in the elderly. Treatment of a subdural hematoma depends on its size and rate of growth. Some small subdural hematomas can be managed by careful monitoring as the blood clot is eventually resorbed naturally. Others can be treated by inserting a small catheter through a hole drilled through the skull and sucking out the hematoma. [ citation needed ] Large or symptomatic hematomas require a craniotomy . A surgeon opens the skull and then the dura mater; removes the clot with suction or irrigation; and identifies and controls sites of bleeding. The injured vessels must be repaired. Postoperative complications can include increased intracranial pressure , brain edema , new or recurrent bleeding, infection , and seizures . In patients with a chronic subdural hematoma but no history of seizures, it is unclear whether anticonvulsants are harmful or beneficial. Those with chronic subudural haematoma (CSDH) with few or no symptoms or have high risk of complication during surgery may be treated conservatively with medications such as atorvastatin, dexamethasone, and mannitol, although supporting conservative treatment is still weak. HMG-CoA reductase inhibitor such as Atorvastatin can reduce the haematoma volume and improving neurological function in eight weeks. HMG-CoA reductase inhibitor may also reduce risk of recurrences in CSDH. Dexamethasone, when used together with surgical drainage, may reduce the recurrence rate of subdural haematoma. Even with surgical evacuation of chronic subdural haematoma, the recurrence rate is high, ranging from 7 to 20%. Acute subdural hematomas have one of the highest mortality rates of all head injuries, with 50 to 90 percent of cases resulting in death, depending on the underlying brain injury. About 20 to 30 percent of patients recover brain function. Higher Glasgow Coma Scale score, younger age and responsive pupils are associated with better outcomes in acute subdural hematomas, while the time between the injury and the surgical evacuation, or the type of surgery, do not have a statistically significant impact on the outcomes. Additionally, chronic subdural hematomas (CSDHs) have a relatively high mortality rate (up to 16.7% in patients over the age of 65); however, they have an even higher rate of recurrence (as mentioned in the previous section). For the aforementioned reasons, researchers have developed predictive grading scales to identify patients at high risk of CSDH recurrence, one of which is the Puerto Rico Recurrence Scale developed by Mignucci-Jiménez et al.

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Acute hemorrhagic fever syndrome

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Yellow fever

Yellow fever is a viral disease of typically short duration . In most cases, symptoms include fever , chills , loss of appetite , nausea , muscle pains—particularly in the back—and headaches . Symptoms typically improve within five days. In about 15% of people, within a day of improving the fever comes back, abdominal pain occurs, and liver damage begins causing yellow skin . If this occurs, the risk of bleeding and kidney problems is increased. The disease is caused by the yellow fever virus and is spread by the bite of an infected mosquito . It infects humans, other primates , and several types of mosquitoes. In cities, it is spread primarily by Aedes aegypti , a type of mosquito found throughout the tropics and subtropics . The virus is an RNA virus of the genus Flavivirus . The disease may be difficult to tell apart from other illnesses, especially in the early stages. To confirm a suspected case, blood-sample testing with a polymerase chain reaction is required. A safe and effective vaccine against yellow fever exists, and some countries require vaccinations for travelers. Other efforts to prevent infection include reducing the population of the transmitting mosquitoes. In areas where yellow fever is common, early diagnosis of cases and immunization of large parts of the population are important to prevent outbreaks . Once a person is infected, management is symptomatic; no specific measures are effective against the virus. Death occurs in up to half of those who get severe disease. In 2013, yellow fever was estimated to have caused 130,000 severe infections and 78,000 deaths in Africa. Approximately 90 percent of an estimated 200,000 cases of yellow fever per year occur in Africa. Nearly a billion people live in an area of the world where the disease is common. It is common in tropical areas of the continents of South America and Africa, but not in Asia. Since the 1980s, the number of cases of yellow fever has been increasing. This is believed to be due to fewer people being immune, more people living in cities, people moving frequently, and changing climate increasing the habitat for mosquitoes. The disease originated in Africa and spread to the Americas starting in the 17th century with the European trafficking of enslaved Africans from sub-Saharan Africa. Since the 17th century, several major outbreaks of the disease have occurred in the Americas, Africa, and Europe. In the 18th and 19th centuries, yellow fever was considered one of the most dangerous infectious diseases ; numerous epidemics swept through major cities of the US and in other parts of the world. In 1927, yellow fever virus became the first human virus to be isolated. Yellow fever begins after an incubation period of three to six days. Most cases cause only mild infection with fever, headache, chills, back pain, fatigue, loss of appetite, muscle pain, nausea, and vomiting. In these cases, the infection lasts only three to six days. But in 15% of cases, people enter a second, toxic phase of the disease characterized by recurring fever, this time accompanied by jaundice due to liver damage , as well as abdominal pain . Bleeding in the mouth, nose, eyes, and the gastrointestinal tract cause vomit containing blood , hence one of the names in Spanish for yellow fever, vómito negro ("black vomit"). There may also be kidney failure, hiccups, and delirium. Among those who develop jaundice, the fatality rate is 20 to 50%, while the overall fatality rate is about 3 to 7.5%. Severe cases may have a mortality rate greater than 50%. Surviving the infection provides lifelong immunity , and normally results in no permanent organ damage. Yellow fever can lead to death for 20% to 50% of those who develop severe disease. Jaundice, fatigue, heart rhythm problems, seizures and internal bleeding may also appear as complications of yellow fever during recovery time. Yellow fever can lead to death for 20% to 50% of those who develop severe disease. Jaundice, fatigue, heart rhythm problems, seizures and internal bleeding may also appear as complications of yellow fever during recovery time. Yellow fever is caused by Yellow fever virus (YFV), an enveloped RNA virus 40–50 nm in width, the type species and namesake of the family Flaviviridae . It was the first illness shown to be transmissible by filtered human serum and transmitted by mosquitoes, by American doctor Walter Reed around 1900. The positive- sense , single-stranded RNA is around 10,862 nucleotides long and has a single open reading frame encoding a polyprotein . Host proteases cut this polyprotein into three structural (C, prM, E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration corresponds to the arrangement of the protein coding genes in the genome . Minimal YFV 3 ′ UTR region is required for stalling of the host 5 ′ -3 ′ exonuclease XRN1. The UTR contains PKS3 pseudoknot structure, which serves as a molecular signal to stall the exonuclease and is the only viral requirement for subgenomic flavivirus RNA (sfRNA) production. The sfRNAs are a result of incomplete degradation of the viral genome by the exonuclease and are important for viral pathogenicity. Yellow fever belongs to the group of hemorrhagic fevers . The viruses infect, amongst others, monocytes , macrophages , Schwann cells , and dendritic cells . They attach to the cell surfaces via specific receptors and are taken up by an endosomal vesicle . Inside the endosome , the decreased pH induces the fusion of the endosomal membrane with the virus envelope . The capsid enters the cytosol , decays, and releases the genome. Receptor binding, as well as membrane fusion, are catalyzed by the protein E, which changes its conformation at low pH, causing a rearrangement of the 90 homo dimers to 60 homo trimers . After entering the host cell, the viral genome is replicated in the rough endoplasmic reticulum (ER) and in the so-called vesicle packets. At first, an immature form of the virus particle is produced inside the ER, whose M-protein is not yet cleaved to its mature form, so is denoted as precursor M (prM) and forms a complex with protein E. The immature particles are processed in the Golgi apparatus by the host protein furin , which cleaves prM to M. This releases E from the complex, which can now take its place in the mature, infectious virion . Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti , but other mostly Aedes mosquitoes such as the tiger mosquito ( Aedes albopictus ) can also serve as a vector for this virus. Like other arboviruses , which are transmitted by mosquitoes, yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or another primate. Viruses reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect epithelial cells and replicate there. From there, they reach the haemocoel (the blood system of mosquitoes) and from there the salivary glands . When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person. Transovarial transmissionial and transstadial transmission of yellow fever virus within A. aegypti , that is, the transmission from a female mosquito to its eggs and then larvae, are indicated. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease. Three epidemiologically different infectious cycles occur in which the virus is transmitted from mosquitoes to humans or other primates. In the "urban cycle", only the yellow fever mosquito A. aegypti is involved. It is well adapted to urban areas, and can also transmit other diseases, including Zika fever , dengue fever , and chikungunya . The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except for an outbreak in Bolivia in 1999, this urban cycle no longer exists in South America. Besides the urban cycle, both in Africa and South America, a sylvatic cycle (forest or jungle cycle) is present, where Aedes africanus (in Africa) or mosquitoes of the genus Haemagogus and Sabethes (in South America) serve as vectors. In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way unvaccinated humans can become infected, which explains the low incidence of yellow fever cases on the continent. People who become infected in the jungle can carry the virus to urban areas, where A. aegypti acts as a vector. Because of this sylvatic cycle, yellow fever cannot be eradicated except by eradicating the mosquitoes that serve as vectors. In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles. Different mosquitoes of the genus Aedes are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa. Concern exists about yellow fever spreading to southeast Asia, where its vector A. aegypti already occurs. Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti , but other mostly Aedes mosquitoes such as the tiger mosquito ( Aedes albopictus ) can also serve as a vector for this virus. Like other arboviruses , which are transmitted by mosquitoes, yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or another primate. Viruses reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect epithelial cells and replicate there. From there, they reach the haemocoel (the blood system of mosquitoes) and from there the salivary glands . When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person. Transovarial transmissionial and transstadial transmission of yellow fever virus within A. aegypti , that is, the transmission from a female mosquito to its eggs and then larvae, are indicated. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease. Three epidemiologically different infectious cycles occur in which the virus is transmitted from mosquitoes to humans or other primates. In the "urban cycle", only the yellow fever mosquito A. aegypti is involved. It is well adapted to urban areas, and can also transmit other diseases, including Zika fever , dengue fever , and chikungunya . The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except for an outbreak in Bolivia in 1999, this urban cycle no longer exists in South America. Besides the urban cycle, both in Africa and South America, a sylvatic cycle (forest or jungle cycle) is present, where Aedes africanus (in Africa) or mosquitoes of the genus Haemagogus and Sabethes (in South America) serve as vectors. In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way unvaccinated humans can become infected, which explains the low incidence of yellow fever cases on the continent. People who become infected in the jungle can carry the virus to urban areas, where A. aegypti acts as a vector. Because of this sylvatic cycle, yellow fever cannot be eradicated except by eradicating the mosquitoes that serve as vectors. In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles. Different mosquitoes of the genus Aedes are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa. Concern exists about yellow fever spreading to southeast Asia, where its vector A. aegypti already occurs. After transmission from a mosquito, the viruses replicate in the lymph nodes and infect dendritic cells in particular. From there, they reach the liver and infect hepatocytes (probably indirectly via Kupffer cells ), which leads to eosinophilic degradation of these cells and to the release of cytokines . Apoptotic masses known as Councilman bodies appear in the cytoplasm of hepatocytes. Fatality may occur when cytokine storm , shock , and multiple organ failure follow. Yellow fever is most frequently a clinical diagnosis , based on symptomatology and travel history. Mild cases of the disease can only be confirmed virologically. Since mild cases of yellow fever can also contribute significantly to regional outbreaks, every suspected case of yellow fever (involving symptoms of fever, pain, nausea, and vomiting 6–10 days after leaving the affected area) is treated seriously. If yellow fever is suspected, the virus cannot be confirmed until 6–10 days following the illness. A direct confirmation can be obtained by reverse transcription polymerase chain reaction , where the genome of the virus is amplified. Another direct approach is the isolation of the virus and its growth in cell culture using blood plasma ; this can take 1–4 weeks. Serologically, an enzyme-linked immunosorbent assay during the acute phase of the disease using specific IgM against yellow fever or an increase in specific IgG titer (compared to an earlier sample) can confirm yellow fever. Together with clinical symptoms, the detection of IgM or a four-fold increase in IgG titer is considered sufficient indication for yellow fever. As these tests can cross-react with other flaviviruses, such as dengue virus , these indirect methods cannot conclusively prove yellow fever infection. Liver biopsy can verify inflammation and necrosis of hepatocytes and detect viral antigens . Because of the bleeding tendency of yellow fever patients, a biopsy is only advisable post mortem to confirm the cause of death. In a differential diagnosis , infections with yellow fever must be distinguished from other feverish illnesses such as malaria . Other viral hemorrhagic fevers , such as Ebola virus , Lassa virus , Marburg virus , and Junin virus , must be excluded as the cause. Personal prevention of yellow fever includes vaccination and avoidance of mosquito bites in areas where yellow fever is endemic. Institutional measures for prevention of yellow fever include vaccination programmes and measures to control mosquitoes. Programmes for distribution of mosquito nets for use in homes produce reductions in cases of both malaria and yellow fever. Use of EPA-registered insect repellent is recommended when outdoors. Exposure for even a short time is enough for a potential mosquito bite. Long-sleeved clothing, long pants, and socks are useful for prevention. The application of larvicides to water-storage containers can help eliminate potential mosquito breeding sites. EPA-registered insecticide spray decreases the transmission of yellow fever. Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. The World Health Organization (WHO) now states that a single dose of vaccine is sufficient to confer lifelong immunity against yellow fever disease. The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler . The WHO recommends routine vaccination for people living in affected areas between the 9th and 12th month after birth. Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases. The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI alliance and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected. Demand for yellow fever vaccine has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes. Recent upsurges in yellow fever outbreaks in Angola (2015), the Democratic Republic of Congo (2016), Uganda (2016), and more recently in Nigeria and Brazil in 2017 have further increased demand, while straining global vaccine supply. Therefore, to vaccinate susceptible populations in preventive mass immunization campaigns during outbreaks, fractional dosing of the vaccine is being considered as a dose-sparing strategy to maximize limited vaccine supplies. Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations. The first practical use of fractional dose yellow fever vaccination was in response to a large yellow fever outbreak in the Democratic Republic of the Congo in mid-2016. Available evidence shows that fractional dose yellow fever vaccination induces a level of immune response similar to that of the standard full dose. In March 2017, the WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil. In March 2018, Brazil shifted its policy and announced it planned to vaccinate all 77.5 million currently unvaccinated citizens by April 2019. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Control of the yellow fever mosquito A. aegypti is of major importance, especially because the same mosquito can also transmit dengue fever and chikungunya disease. A. aegypti breeds preferentially in water, for example, in installations by inhabitants of areas with precarious drinking water supplies, or in domestic refuse, especially tires, cans, and plastic bottles. These conditions are common in urban areas in developing countries. Two main strategies are employed to reduce A. aegypti populations. One approach is to kill the developing larvae. Measures are taken to reduce the water accumulations in which the larvae develop. Larvicides are used, along with larvae-eating fish and copepods , which reduce the number of larvae. For many years, copepods of the genus Mesocyclops have been used in Vietnam for preventing dengue fever. This eradicated the mosquito vector in several areas. Similar efforts may prove effective against yellow fever. Pyriproxyfen is recommended as a chemical larvicide, mainly because it is safe for humans and effective in small doses. The second strategy is to reduce populations of the adult yellow fever mosquito. Lethal ovitraps can reduce Aedes populations, using lesser amounts of pesticide because it targets the pest directly. Curtains and lids of water tanks can be sprayed with insecticides, but application inside houses is not recommended by the WHO. Insecticide-treated mosquito nets are effective, just as they are against the Anopheles mosquito that carries malaria. Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. The World Health Organization (WHO) now states that a single dose of vaccine is sufficient to confer lifelong immunity against yellow fever disease. The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler . The WHO recommends routine vaccination for people living in affected areas between the 9th and 12th month after birth. Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases. The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI alliance and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected. Demand for yellow fever vaccine has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes. Recent upsurges in yellow fever outbreaks in Angola (2015), the Democratic Republic of Congo (2016), Uganda (2016), and more recently in Nigeria and Brazil in 2017 have further increased demand, while straining global vaccine supply. Therefore, to vaccinate susceptible populations in preventive mass immunization campaigns during outbreaks, fractional dosing of the vaccine is being considered as a dose-sparing strategy to maximize limited vaccine supplies. Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations. The first practical use of fractional dose yellow fever vaccination was in response to a large yellow fever outbreak in the Democratic Republic of the Congo in mid-2016. Available evidence shows that fractional dose yellow fever vaccination induces a level of immune response similar to that of the standard full dose. In March 2017, the WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil. In March 2018, Brazil shifted its policy and announced it planned to vaccinate all 77.5 million currently unvaccinated citizens by April 2019. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Control of the yellow fever mosquito A. aegypti is of major importance, especially because the same mosquito can also transmit dengue fever and chikungunya disease. A. aegypti breeds preferentially in water, for example, in installations by inhabitants of areas with precarious drinking water supplies, or in domestic refuse, especially tires, cans, and plastic bottles. These conditions are common in urban areas in developing countries. Two main strategies are employed to reduce A. aegypti populations. One approach is to kill the developing larvae. Measures are taken to reduce the water accumulations in which the larvae develop. Larvicides are used, along with larvae-eating fish and copepods , which reduce the number of larvae. For many years, copepods of the genus Mesocyclops have been used in Vietnam for preventing dengue fever. This eradicated the mosquito vector in several areas. Similar efforts may prove effective against yellow fever. Pyriproxyfen is recommended as a chemical larvicide, mainly because it is safe for humans and effective in small doses. The second strategy is to reduce populations of the adult yellow fever mosquito. Lethal ovitraps can reduce Aedes populations, using lesser amounts of pesticide because it targets the pest directly. Curtains and lids of water tanks can be sprayed with insecticides, but application inside houses is not recommended by the WHO. Insecticide-treated mosquito nets are effective, just as they are against the Anopheles mosquito that carries malaria. As with other Flavivirus infections, no cure is known for yellow fever. Hospitalization is advisable and intensive care may be necessary because of rapid deterioration in some cases. Certain acute treatment methods lack efficacy: passive immunization after the emergence of symptoms is probably without effect; ribavirin and other antiviral drugs , as well as treatment with interferons , are ineffective in yellow fever patients. Symptomatic treatment includes rehydration and pain relief with drugs such as paracetamol (acetaminophen). However, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are often avoided because of an increased risk of gastrointestinal bleeding due to their anticoagulant effects. Yellow fever is common in tropical and subtropical areas of South America and Africa. Worldwide, about 600 million people live in endemic areas. The WHO estimates 200,000 cases of yellow fever worldwide each year. About 15% of people infected with yellow fever progress to a severe form of the illness, and up to half of those will die, as there is no cure for yellow fever. An estimated 90% of yellow fever infections occur on the African continent. In 2016, a large outbreak originated in Angola and spread to neighboring countries before being contained by a massive vaccination campaign. In March and April 2016, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first appearance of the disease in Asia in recorded history. Phylogenetic analysis has identified seven genotypes of yellow fever viruses, and they are assumed to be differently adapted to humans and to the vector A. aegypti . Five genotypes (Angola, Central/East Africa, East Africa, West Africa I, and West Africa II) occur only in Africa. West Africa genotype I is found in Nigeria and the surrounding region. West Africa genotype I appears to be especially infectious, as it is often associated with major outbreaks. The three genotypes found outside of Nigeria and Angola occur in areas where outbreaks are rare. Two outbreaks, in Kenya (1992–1993) and Sudan (2003 and 2005), involved the East African genotype, which had remained undetected in the previous 40 years. In South America, two genotypes have been identified (South American genotypes I and II). Based on phylogenetic analysis these two genotypes appear to have originated in West Africa and were first introduced into Brazil. The date of introduction of the predecessor African genotype which gave rise to the South American genotypes appears to be 1822 (95% confidence interval 1701 to 1911). The historical record shows an outbreak of yellow fever occurred in Recife, Brazil, between 1685 and 1690. The disease seems to have disappeared, with the next outbreak occurring in 1849. It was likely introduced with the trafficking of slaves through the slave trade from Africa. Genotype I has been divided into five subclades, A through E. In late 2016, a large outbreak began in Minas Gerais state of Brazil that was characterized as a sylvatic or jungle epizootic . Real-time phylogenetic investigations at the epicentre of the outbreak revealed that the outbreak was caused by the introduction of a virus lineage from the Amazon region into the southeast region around July 2016, spreading rapidly across several neotropical monkey species, including brown howler monkeys, which serve as a sentinel species for yellow fever. No cases had been transmitted between humans by the A. aegypti mosquito, which can sustain urban outbreaks that can spread rapidly. In April 2017, the sylvatic outbreak continued moving toward the Brazilian coast, where most people were unvaccinated. By the end of May the outbreak appeared to be declining after more than 3,000 suspected cases, 758 confirmed and 264 deaths confirmed to be yellow fever. The Health Ministry launched a vaccination campaign and was concerned about spread during the Carnival season in February and March. The CDC issued a Level 2 alert (practice enhanced precautions.) A Bayesian analysis of genotypes I and II has shown that genotype I accounts for virtually all the current infections in Brazil , Colombia , Venezuela , and Trinidad and Tobago , while genotype II accounted for all cases in Peru . Genotype I originated in the northern Brazilian region around 1908 (95% highest posterior density interval [HPD]: 1870–1936). Genotype II originated in Peru in 1920 (95% HPD: 1867–1958). The estimated rate of mutation for both genotypes was about 5 × 10 −4 substitutions/site/year, similar to that of other RNA viruses. The main vector ( A. aegypti ) also occurs in tropical and subtropical regions of Asia, the Pacific, and Australia, but yellow fever had never occurred there until jet travel introduced 11 cases from the 2016 Angola and DR Congo yellow fever outbreak in Africa. Proposed explanations include: But none is considered satisfactory. Another proposal is the absence of a slave trade to Asia on the scale of that to the Americas. The trans-Atlantic slave trade probably introduced yellow fever into the Western Hemisphere from Africa. An estimated 90% of yellow fever infections occur on the African continent. In 2016, a large outbreak originated in Angola and spread to neighboring countries before being contained by a massive vaccination campaign. In March and April 2016, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first appearance of the disease in Asia in recorded history. Phylogenetic analysis has identified seven genotypes of yellow fever viruses, and they are assumed to be differently adapted to humans and to the vector A. aegypti . Five genotypes (Angola, Central/East Africa, East Africa, West Africa I, and West Africa II) occur only in Africa. West Africa genotype I is found in Nigeria and the surrounding region. West Africa genotype I appears to be especially infectious, as it is often associated with major outbreaks. The three genotypes found outside of Nigeria and Angola occur in areas where outbreaks are rare. Two outbreaks, in Kenya (1992–1993) and Sudan (2003 and 2005), involved the East African genotype, which had remained undetected in the previous 40 years. In South America, two genotypes have been identified (South American genotypes I and II). Based on phylogenetic analysis these two genotypes appear to have originated in West Africa and were first introduced into Brazil. The date of introduction of the predecessor African genotype which gave rise to the South American genotypes appears to be 1822 (95% confidence interval 1701 to 1911). The historical record shows an outbreak of yellow fever occurred in Recife, Brazil, between 1685 and 1690. The disease seems to have disappeared, with the next outbreak occurring in 1849. It was likely introduced with the trafficking of slaves through the slave trade from Africa. Genotype I has been divided into five subclades, A through E. In late 2016, a large outbreak began in Minas Gerais state of Brazil that was characterized as a sylvatic or jungle epizootic . Real-time phylogenetic investigations at the epicentre of the outbreak revealed that the outbreak was caused by the introduction of a virus lineage from the Amazon region into the southeast region around July 2016, spreading rapidly across several neotropical monkey species, including brown howler monkeys, which serve as a sentinel species for yellow fever. No cases had been transmitted between humans by the A. aegypti mosquito, which can sustain urban outbreaks that can spread rapidly. In April 2017, the sylvatic outbreak continued moving toward the Brazilian coast, where most people were unvaccinated. By the end of May the outbreak appeared to be declining after more than 3,000 suspected cases, 758 confirmed and 264 deaths confirmed to be yellow fever. The Health Ministry launched a vaccination campaign and was concerned about spread during the Carnival season in February and March. The CDC issued a Level 2 alert (practice enhanced precautions.) A Bayesian analysis of genotypes I and II has shown that genotype I accounts for virtually all the current infections in Brazil , Colombia , Venezuela , and Trinidad and Tobago , while genotype II accounted for all cases in Peru . Genotype I originated in the northern Brazilian region around 1908 (95% highest posterior density interval [HPD]: 1870–1936). Genotype II originated in Peru in 1920 (95% HPD: 1867–1958). The estimated rate of mutation for both genotypes was about 5 × 10 −4 substitutions/site/year, similar to that of other RNA viruses. The main vector ( A. aegypti ) also occurs in tropical and subtropical regions of Asia, the Pacific, and Australia, but yellow fever had never occurred there until jet travel introduced 11 cases from the 2016 Angola and DR Congo yellow fever outbreak in Africa. Proposed explanations include: But none is considered satisfactory. Another proposal is the absence of a slave trade to Asia on the scale of that to the Americas. The trans-Atlantic slave trade probably introduced yellow fever into the Western Hemisphere from Africa. The evolutionary origins of yellow fever most likely lie in Africa, with transmission of the disease from nonhuman primates to humans. The virus is thought to have originated in East or Central Africa and spread from there to West Africa. As it was endemic in Africa, local populations had developed some immunity to it. When an outbreak of yellow fever would occur in an African community where colonists resided, most Europeans died, while the indigenous Africans usually developed nonlethal symptoms resembling influenza . This phenomenon, in which certain populations develop immunity to yellow fever due to prolonged exposure in their childhood, is known as acquired immunity . The virus, as well as the vector A. aegypti, were probably transferred to North and South America with the trafficking of slaves from Africa, part of the Columbian exchange following European exploration and colonization. However, some researchers have argued that yellow fever might have existed in the Americas during the pre-Columbian period as mosquitoes of the genus Haemagogus , which is indigenous to the Americas, have been known to carry the disease. The first definitive outbreak of yellow fever in the New World was in 1647 on the island of Barbados . An outbreak was recorded by Spanish colonists in 1648 in the Yucatán Peninsula , where the indigenous Mayan people called the illness xekik ("blood vomit"). In 1685, Brazil suffered its first epidemic in Recife . The first mention of the disease by the name "yellow fever" occurred in 1744. However, Dr. Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis. McNeill argues that the environmental and ecological disruption caused by the introduction of sugar plantations created the conditions for mosquito and viral reproduction, and subsequent outbreaks of yellow fever. Deforestation reduced populations of insectivorous birds and other creatures that fed on mosquitoes and their eggs. In Colonial times and during the Napoleonic Wars , the West Indies were known as a particularly dangerous posting for soldiers due to yellow fever being endemic in the area. The mortality rate in British garrisons in Jamaica was seven times that of garrisons in Canada, mostly because of yellow fever and other tropical diseases. Both English and French forces posted there were seriously affected by the "yellow jack" . Wanting to regain control of the lucrative sugar trade in Saint-Domingue (Hispaniola), and with an eye on regaining France's New World empire, Napoleon sent an army under the command of his brother-in-law General Charles Leclerc to Saint-Domingue to seize control after a slave revolt. The historian J. R. McNeill asserts that yellow fever accounted for about 35,000 to 45,000 casualties of these forces during the fighting. Only one third of the French troops survived for withdrawal and return to France. Napoleon gave up on the island and his plans for North America, selling the Louisiana Purchase to the US in 1803. In 1804, Haiti proclaimed its independence as the second republic in the Western Hemisphere. Considerable debate exists over whether the number of deaths caused by disease in the Haitian Revolution was exaggerated. Although yellow fever is most prevalent in tropical-like climates, the northern United States were not exempted from the fever. The first outbreak in English-speaking North America occurred in New York City in 1668. English colonists in Philadelphia and the French in the Mississippi River Valley recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia, Baltimore , and New York City in the 18th and 19th centuries. The disease traveled along steamboat routes from New Orleans, causing some 100,000–150,000 deaths in total. The yellow fever epidemic of 1793 in Philadelphia, which was then the capital of the United States, resulted in the deaths of several thousand people, more than 9% of the population. One of these deaths was James Hutchinson , a physician helping to treat the population of the city. The national government fled the city to Trenton, New Jersey, including President George Washington . The southern city of New Orleans was plagued with major epidemics during the 19th century, most notably in 1833 and 1853. A major epidemic occurred in both New Orleans and Shreveport, Louisiana in 1873. Its residents called the disease "yellow jack". Urban epidemics continued in the United States until 1905, with the last outbreak affecting New Orleans. At least 25 major outbreaks took place in the Americas during the 18th and 19th centuries, including particularly serious ones in Cartagena, Chile , in 1741; Cuba in 1762 and 1900; Santo Domingo in 1803; and Memphis, Tennessee , in 1878. In the early 19th century, the prevalence of yellow fever in the Caribbean "led to serious health problems" and alarmed the United States Navy as numerous deaths and sickness curtailed naval operations and destroyed morale. One episode began in April 1822 when the frigate USS Macedonian left Boston and became part of Commodore James Biddle's West India Squadron. Unbeknownst to all, they were about to embark on a cruise to disaster and their assignment "would prove a cruise through hell". Secretary of the Navy Smith Thompson had assigned the squadron to guard United States merchant shipping and suppress piracy. During their time on deployment from 26 May to 3 August 1822, 76 of the Macedonian's officers and men died, including John Cadle, surgeon USN. Seventy-four of these deaths were attributed to yellow fever. Biddle reported that another 52 of his crew were on sick-list. In their report to the secretary of the Navy, Biddle and Surgeon's Mate Charles Chase stated the cause as "fever". As a consequence of this loss, Biddle noted that his squadron was forced to return to Norfolk Navy Yard early. Upon arrival, the Macedonian's crew were provided medical care and quarantined at Craney Island, Virginia. In 1853, Cloutierville, Louisiana , had a late-summer outbreak of yellow fever that quickly killed 68 of the 91 inhabitants. A local doctor concluded that some unspecified infectious agent had arrived in a package from New Orleans. In 1854, 650 residents of Savannah, Georgia , died from yellow fever. In 1858, St. Matthew's German Evangelical Lutheran Church in Charleston, South Carolina , had 308 yellow fever deaths, reducing the congregation by half. A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern Virginia in June 1855. The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of Norfolk and Portsmouth . In 1873, Shreveport, Louisiana , lost 759 citizens in an 80-day period to a yellow fever epidemic, with over 400 additional victims eventually succumbing. The total death toll from August through November was approximately 1,200. In 1878, about 20,000 people died in a widespread epidemic in the Mississippi River Valley. That year, Memphis had an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge epidemic of yellow fever. The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but passengers were not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi River for the next two months before unloading her passengers. Major outbreaks have also occurred in southern Europe. Gibraltar lost many lives to outbreaks in 1804, 1814, and 1828. Barcelona suffered the loss of several thousand citizens during an outbreak in 1821. The Duke de Richelieu deployed 30,000 French troops to the border between France and Spain in the Pyrenees Mountains , to establish a cordon sanitaire in order to prevent the epidemic from spreading from Spain into France. Ezekiel Stone Wiggins , known as the Ottawa Prophet, proposed that the cause of a yellow fever epidemic in Jacksonville, Florida , in 1888, was astrological. The planets were in the same line as the sun and earth and this produced, besides Cyclones, Earthquakes, etc., a denser atmosphere holding more carbon and creating microbes. Mars had an uncommonly dense atmosphere, but its inhabitants were probably protected from the fever by their newly discovered canals , which were perhaps made to absorb carbon and prevent the disease. In 1848, Josiah C. Nott suggested that yellow fever was spread by insects such as moths or mosquitoes, basing his ideas on the pattern of transmission of the disease. Carlos Finlay , a Cuban-Spanish doctor and scientist, proposed in 1881 that yellow fever might be transmitted by previously infected mosquitoes rather than by direct contact from person to person, as had long been believed. Since the losses from yellow fever in the Spanish–American War in the 1890s were extremely high, U.S. Army doctors began research experiments with a team led by Walter Reed , and composed of doctors James Carroll , Aristides Agramonte , and Jesse William Lazear . They successfully proved Finlay's "mosquito hypothesis". Yellow fever was the first virus shown to be transmitted by mosquitoes. The physician William Gorgas applied these insights and eradicated yellow fever from Havana . He also campaigned against yellow fever during the construction of the Panama Canal . A previous effort of canal building by the French had failed in part due to mortality from the high incidence of yellow fever and malaria, which killed many workers. Although Reed has received much of the credit in United States history books for "beating" yellow fever, he had fully credited Finlay with the discovery of the yellow fever vector, and how it might be controlled. Reed often cited Finlay's papers in his own articles, and also credited him for the discovery in his personal correspondence. The acceptance of Finlay's work was one of the most important and far-reaching effects of the U.S. Army Yellow Fever Commission of 1900. Applying methods first suggested by Finlay, the United States government and Army eradicated yellow fever in Cuba and later in Panama, allowing completion of the Panama Canal. While Reed built on the research of Finlay, historian François Delaporte notes that yellow fever research was a contentious issue. Scientists, including Finlay and Reed, became successful by building on the work of less prominent scientists, without always giving them the credit they were due. Reed's research was essential in the fight against yellow fever. He is also credited for using the first type of medical consent form during his experiments in Cuba, an attempt to ensure that participants knew they were taking a risk by being part of testing. Like Cuba and Panama, Brazil also led a highly successful sanitation campaign against mosquitoes and yellow fever. Beginning in 1903, the campaign led by Oswaldo Cruz , then director general of public health, resulted not only in eradicating the disease but also in reshaping the physical landscape of Brazilian cities such as Rio de Janeiro. During rainy seasons, Rio de Janeiro had regularly suffered floods, as water from the bay surrounding the city overflowed into Rio's narrow streets. Coupled with the poor drainage systems found throughout Rio, this created swampy conditions in the city's neighborhoods. Pools of stagnant water stood year-long in city streets and proved to be a fertile ground for disease-carrying mosquitoes. Thus, under Cruz's direction, public health units known as "mosquito inspectors" fiercely worked to combat yellow fever throughout Rio by spraying, exterminating rats, improving drainage, and destroying unsanitary housing. Ultimately, the city's sanitation and renovation campaigns reshaped Rio de Janeiro's neighborhoods. Its poor residents were pushed from city centers to Rio's suburbs, or to towns found in the outskirts of the city. In later years, Rio's most impoverished inhabitants would come to reside in favelas . During 1920–1923, the Rockefeller Foundation 's International Health Board undertook an expensive and successful yellow fever eradication campaign in Mexico. The IHB gained the respect of Mexico's federal government because of the success. The eradication of yellow fever strengthened the relationship between the US and Mexico, which had not been very good in the years prior. The eradication of yellow fever was also a major step toward better global health. In 1927, scientists isolated the yellow fever virus in West Africa. Following this, two vaccines were developed in the 1930s. Max Theiler led the completion of the 17D yellow fever vaccine in 1937, for which he was subsequently awarded the Nobel Prize in Physiology or Medicine . That vaccine, 17D, is still in use, although newer vaccines, based on vero cells , are in development (as of 2018). Using vector control and strict vaccination programs, the urban cycle of yellow fever was nearly eradicated from South America. Since 1943, only a single urban outbreak in Santa Cruz de la Sierra , Bolivia, has occurred. Since the 1980s, however, the number of yellow fever cases has been increasing again, and A. aegypti has returned to the urban centers of South America. This is partly due to limitations on available insecticides, as well as habitat dislocations caused by climate change. It is also because the vector control program was abandoned. Although no new urban cycle has yet been established, scientists believe this could happen again at any point. An outbreak in Paraguay in 2008 was thought to be urban in nature, but this ultimately proved not to be the case. In Africa, virus eradication programs have mostly relied upon vaccination. These programs have largely been unsuccessful because they were unable to break the sylvatic cycle involving wild primates. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the future spread of the virus more likely. The evolutionary origins of yellow fever most likely lie in Africa, with transmission of the disease from nonhuman primates to humans. The virus is thought to have originated in East or Central Africa and spread from there to West Africa. As it was endemic in Africa, local populations had developed some immunity to it. When an outbreak of yellow fever would occur in an African community where colonists resided, most Europeans died, while the indigenous Africans usually developed nonlethal symptoms resembling influenza . This phenomenon, in which certain populations develop immunity to yellow fever due to prolonged exposure in their childhood, is known as acquired immunity . The virus, as well as the vector A. aegypti, were probably transferred to North and South America with the trafficking of slaves from Africa, part of the Columbian exchange following European exploration and colonization. However, some researchers have argued that yellow fever might have existed in the Americas during the pre-Columbian period as mosquitoes of the genus Haemagogus , which is indigenous to the Americas, have been known to carry the disease. The first definitive outbreak of yellow fever in the New World was in 1647 on the island of Barbados . An outbreak was recorded by Spanish colonists in 1648 in the Yucatán Peninsula , where the indigenous Mayan people called the illness xekik ("blood vomit"). In 1685, Brazil suffered its first epidemic in Recife . The first mention of the disease by the name "yellow fever" occurred in 1744. However, Dr. Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis. McNeill argues that the environmental and ecological disruption caused by the introduction of sugar plantations created the conditions for mosquito and viral reproduction, and subsequent outbreaks of yellow fever. Deforestation reduced populations of insectivorous birds and other creatures that fed on mosquitoes and their eggs. In Colonial times and during the Napoleonic Wars , the West Indies were known as a particularly dangerous posting for soldiers due to yellow fever being endemic in the area. The mortality rate in British garrisons in Jamaica was seven times that of garrisons in Canada, mostly because of yellow fever and other tropical diseases. Both English and French forces posted there were seriously affected by the "yellow jack" . Wanting to regain control of the lucrative sugar trade in Saint-Domingue (Hispaniola), and with an eye on regaining France's New World empire, Napoleon sent an army under the command of his brother-in-law General Charles Leclerc to Saint-Domingue to seize control after a slave revolt. The historian J. R. McNeill asserts that yellow fever accounted for about 35,000 to 45,000 casualties of these forces during the fighting. Only one third of the French troops survived for withdrawal and return to France. Napoleon gave up on the island and his plans for North America, selling the Louisiana Purchase to the US in 1803. In 1804, Haiti proclaimed its independence as the second republic in the Western Hemisphere. Considerable debate exists over whether the number of deaths caused by disease in the Haitian Revolution was exaggerated. Although yellow fever is most prevalent in tropical-like climates, the northern United States were not exempted from the fever. The first outbreak in English-speaking North America occurred in New York City in 1668. English colonists in Philadelphia and the French in the Mississippi River Valley recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia, Baltimore , and New York City in the 18th and 19th centuries. The disease traveled along steamboat routes from New Orleans, causing some 100,000–150,000 deaths in total. The yellow fever epidemic of 1793 in Philadelphia, which was then the capital of the United States, resulted in the deaths of several thousand people, more than 9% of the population. One of these deaths was James Hutchinson , a physician helping to treat the population of the city. The national government fled the city to Trenton, New Jersey, including President George Washington . The southern city of New Orleans was plagued with major epidemics during the 19th century, most notably in 1833 and 1853. A major epidemic occurred in both New Orleans and Shreveport, Louisiana in 1873. Its residents called the disease "yellow jack". Urban epidemics continued in the United States until 1905, with the last outbreak affecting New Orleans. At least 25 major outbreaks took place in the Americas during the 18th and 19th centuries, including particularly serious ones in Cartagena, Chile , in 1741; Cuba in 1762 and 1900; Santo Domingo in 1803; and Memphis, Tennessee , in 1878. In the early 19th century, the prevalence of yellow fever in the Caribbean "led to serious health problems" and alarmed the United States Navy as numerous deaths and sickness curtailed naval operations and destroyed morale. One episode began in April 1822 when the frigate USS Macedonian left Boston and became part of Commodore James Biddle's West India Squadron. Unbeknownst to all, they were about to embark on a cruise to disaster and their assignment "would prove a cruise through hell". Secretary of the Navy Smith Thompson had assigned the squadron to guard United States merchant shipping and suppress piracy. During their time on deployment from 26 May to 3 August 1822, 76 of the Macedonian's officers and men died, including John Cadle, surgeon USN. Seventy-four of these deaths were attributed to yellow fever. Biddle reported that another 52 of his crew were on sick-list. In their report to the secretary of the Navy, Biddle and Surgeon's Mate Charles Chase stated the cause as "fever". As a consequence of this loss, Biddle noted that his squadron was forced to return to Norfolk Navy Yard early. Upon arrival, the Macedonian's crew were provided medical care and quarantined at Craney Island, Virginia. In 1853, Cloutierville, Louisiana , had a late-summer outbreak of yellow fever that quickly killed 68 of the 91 inhabitants. A local doctor concluded that some unspecified infectious agent had arrived in a package from New Orleans. In 1854, 650 residents of Savannah, Georgia , died from yellow fever. In 1858, St. Matthew's German Evangelical Lutheran Church in Charleston, South Carolina , had 308 yellow fever deaths, reducing the congregation by half. A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern Virginia in June 1855. The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of Norfolk and Portsmouth . In 1873, Shreveport, Louisiana , lost 759 citizens in an 80-day period to a yellow fever epidemic, with over 400 additional victims eventually succumbing. The total death toll from August through November was approximately 1,200. In 1878, about 20,000 people died in a widespread epidemic in the Mississippi River Valley. That year, Memphis had an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge epidemic of yellow fever. The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but passengers were not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi River for the next two months before unloading her passengers. Major outbreaks have also occurred in southern Europe. Gibraltar lost many lives to outbreaks in 1804, 1814, and 1828. Barcelona suffered the loss of several thousand citizens during an outbreak in 1821. The Duke de Richelieu deployed 30,000 French troops to the border between France and Spain in the Pyrenees Mountains , to establish a cordon sanitaire in order to prevent the epidemic from spreading from Spain into France. Ezekiel Stone Wiggins , known as the Ottawa Prophet, proposed that the cause of a yellow fever epidemic in Jacksonville, Florida , in 1888, was astrological. The planets were in the same line as the sun and earth and this produced, besides Cyclones, Earthquakes, etc., a denser atmosphere holding more carbon and creating microbes. Mars had an uncommonly dense atmosphere, but its inhabitants were probably protected from the fever by their newly discovered canals , which were perhaps made to absorb carbon and prevent the disease. In 1848, Josiah C. Nott suggested that yellow fever was spread by insects such as moths or mosquitoes, basing his ideas on the pattern of transmission of the disease. Carlos Finlay , a Cuban-Spanish doctor and scientist, proposed in 1881 that yellow fever might be transmitted by previously infected mosquitoes rather than by direct contact from person to person, as had long been believed. Since the losses from yellow fever in the Spanish–American War in the 1890s were extremely high, U.S. Army doctors began research experiments with a team led by Walter Reed , and composed of doctors James Carroll , Aristides Agramonte , and Jesse William Lazear . They successfully proved Finlay's "mosquito hypothesis". Yellow fever was the first virus shown to be transmitted by mosquitoes. The physician William Gorgas applied these insights and eradicated yellow fever from Havana . He also campaigned against yellow fever during the construction of the Panama Canal . A previous effort of canal building by the French had failed in part due to mortality from the high incidence of yellow fever and malaria, which killed many workers. Although Reed has received much of the credit in United States history books for "beating" yellow fever, he had fully credited Finlay with the discovery of the yellow fever vector, and how it might be controlled. Reed often cited Finlay's papers in his own articles, and also credited him for the discovery in his personal correspondence. The acceptance of Finlay's work was one of the most important and far-reaching effects of the U.S. Army Yellow Fever Commission of 1900. Applying methods first suggested by Finlay, the United States government and Army eradicated yellow fever in Cuba and later in Panama, allowing completion of the Panama Canal. While Reed built on the research of Finlay, historian François Delaporte notes that yellow fever research was a contentious issue. Scientists, including Finlay and Reed, became successful by building on the work of less prominent scientists, without always giving them the credit they were due. Reed's research was essential in the fight against yellow fever. He is also credited for using the first type of medical consent form during his experiments in Cuba, an attempt to ensure that participants knew they were taking a risk by being part of testing. Like Cuba and Panama, Brazil also led a highly successful sanitation campaign against mosquitoes and yellow fever. Beginning in 1903, the campaign led by Oswaldo Cruz , then director general of public health, resulted not only in eradicating the disease but also in reshaping the physical landscape of Brazilian cities such as Rio de Janeiro. During rainy seasons, Rio de Janeiro had regularly suffered floods, as water from the bay surrounding the city overflowed into Rio's narrow streets. Coupled with the poor drainage systems found throughout Rio, this created swampy conditions in the city's neighborhoods. Pools of stagnant water stood year-long in city streets and proved to be a fertile ground for disease-carrying mosquitoes. Thus, under Cruz's direction, public health units known as "mosquito inspectors" fiercely worked to combat yellow fever throughout Rio by spraying, exterminating rats, improving drainage, and destroying unsanitary housing. Ultimately, the city's sanitation and renovation campaigns reshaped Rio de Janeiro's neighborhoods. Its poor residents were pushed from city centers to Rio's suburbs, or to towns found in the outskirts of the city. In later years, Rio's most impoverished inhabitants would come to reside in favelas . During 1920–1923, the Rockefeller Foundation 's International Health Board undertook an expensive and successful yellow fever eradication campaign in Mexico. The IHB gained the respect of Mexico's federal government because of the success. The eradication of yellow fever strengthened the relationship between the US and Mexico, which had not been very good in the years prior. The eradication of yellow fever was also a major step toward better global health. In 1927, scientists isolated the yellow fever virus in West Africa. Following this, two vaccines were developed in the 1930s. Max Theiler led the completion of the 17D yellow fever vaccine in 1937, for which he was subsequently awarded the Nobel Prize in Physiology or Medicine . That vaccine, 17D, is still in use, although newer vaccines, based on vero cells , are in development (as of 2018). Using vector control and strict vaccination programs, the urban cycle of yellow fever was nearly eradicated from South America. Since 1943, only a single urban outbreak in Santa Cruz de la Sierra , Bolivia, has occurred. Since the 1980s, however, the number of yellow fever cases has been increasing again, and A. aegypti has returned to the urban centers of South America. This is partly due to limitations on available insecticides, as well as habitat dislocations caused by climate change. It is also because the vector control program was abandoned. Although no new urban cycle has yet been established, scientists believe this could happen again at any point. An outbreak in Paraguay in 2008 was thought to be urban in nature, but this ultimately proved not to be the case. In Africa, virus eradication programs have mostly relied upon vaccination. These programs have largely been unsuccessful because they were unable to break the sylvatic cycle involving wild primates. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the future spread of the virus more likely. In the hamster model of yellow fever, early administration of the antiviral ribavirin is an effective treatment of many pathological features of the disease. Ribavirin treatment during the first five days after virus infection improved survival rates, reduced tissue damage in the liver and spleen , prevented hepatocellular steatosis , and normalised levels of alanine aminotransferase, a liver damage marker. The mechanism of action of ribavirin in reducing liver pathology in yellow fever virus infection may be similar to its activity in treatment of hepatitis C , a related virus. Because ribavirin had failed to improve survival in a virulent rhesus model of yellow fever infection, it had been previously discounted as a possible therapy. Infection was reduced in mosquitoes with the wMel strain of Wolbachia . Yellow fever has been researched by several countries as a potential biological weapon .

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Acute hemorrhagic fever syndrome

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Myelodysplastic syndrome

A myelodysplastic syndrome ( MDS ) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue , shortness of breath , bleeding disorders , anemia , or frequent infections . Some types may develop into acute myeloid leukemia . Risk factors include previous chemotherapy or radiation therapy , exposure to certain chemicals such as tobacco smoke , pesticides , and benzene , and exposure to heavy metals such as mercury or lead . Problems with blood cell formation result in some combination of low red blood cell , platelet , and white blood cell counts. Some types of MDS cause an increase in the production of immature blood cells (called blasts ), in the bone marrow or blood . The different types of MDS are identified based on the specific characteristics of the changes in the blood cells and bone marrow. Treatments may include supportive care , drug therapy, and hematopoietic stem cell transplantation . Supportive care may include blood transfusions , medications to increase the making of red blood cells , and antibiotics . Drug therapy may include the medications lenalidomide , antithymocyte globulin , and azacitidine . Some people can be cured by chemotherapy followed by a stem-cell transplant from a donor. About seven per 100,000 people are affected by MDS; about four per 100,000 people newly acquire the condition each year. The typical age of onset is 70 years. The prognosis depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells. The average survival time following diagnosis is 2.5 years. MDS was first recognized in the early 1900s; it came to be called myelodysplastic syndrome in 1976. Signs and symptoms are nonspecific and generally related to the blood cytopenias: Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count: Although some risk exists for developing acute myelogenous leukemia , about 50% of deaths occur as a result of bleeding or infection. However, leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment. Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea , and pallor , but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important factor in the person's medical history . Fever, weight loss and splenomegaly should point to a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) rather than pure myelodysplastic process. Some people have a history of exposure to chemotherapy (especially alkylating agents such as melphalan , cyclophosphamide , busulfan , and chlorambucil ) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Xylene and benzene exposures have been associated with myelodysplasia. Vietnam veterans exposed to Agent Orange are at risk of developing MDS. A link may exist between the development of MDS "in atomic-bomb survivors 40 to 60 years after radiation exposure" (in this case, referring to people who were in close proximity to the dropping of the atomic bombs in Hiroshima and Nagasaki during World War II). Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia . MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as radiation , benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late toxicity of cancer therapy (therapy associated MDS, t-MDS). MDS after exposure to radiation or alkylating agents such as busulfan, nitrosourea , or procarbazine , typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure to DNA topoisomerase II inhibitors occurs after a shorter latency of only 1–3 years and can have a 11q23 translocation. Other pre-existing bone-marrow disorders such as acquired aplastic anemia following immunosuppressive treatment and Fanconi anemia can evolve into MDS. MDS is thought to arise from mutations in the multipotent bone-marrow stem cell , but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and a significant increase in levels of apoptotic cell death occurs in bone-marrow cells. Clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone-marrow myeloblasts rises over a particular cutoff (20% for WHO and 30% for FAB ), then transformation to acute myelogenous leukemia (AML) is said to have occurred. The progression of MDS to AML is a good example of the multistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into a cancer cell. Although recognition of leukemic transformation was historically important (see History ), a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML, but rather from the cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion , MDS patients rarely experience injury from severe anemia. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). Long-term transfusion of packed red blood cells leads to iron overload . The recognition of epigenetic changes in DNA structure in MDS has explained the success of two (namely the hypomethylating agents 5-azacytidine and decitabine ) of three (the third is lenalidomide ) commercially available medications approved by the U.S. Food and Drug Administration to treat MDS. Proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth and cytopenias. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus , thereby restoring normal blood counts and retarding the progression of MDS to acute leukemia . Some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in MDS. Hematopoietic stem cell aging is thought to be associated with the accrual of multiple genetic and epigenetic aberrations leading to the suggestion that MDS is, in part, related to an inability to adequately cope with DNA damage . An emerging perspective is that the underlying mechanism of MDS could be a defect in one or more pathways that are involved in repairing damaged DNA . In MDS an increased frequency of chromosomal breaks indicates defects in DNA repair processes. Also elevated levels of 8-oxoguanine were found in the DNA of a significant proportion of MDS patients, indicating that the base excision repair pathway that is involved in handling oxidative DNA damages may be defective in these cases. Since at least 1974, the deletion in the long arm of chromosome 5 has been known to be associated with dysplastic abnormalities of hematopoietic stem cells. By 2005, lenalidomide , a chemotherapy drug, was recognized to be effective in MDS patients with the 5q- syndrome , and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low IPSS risk, and transfusion dependence respond best to lenalidomide. Typically, prognosis for these patients is favorable, with a 63-month median survival. Lenalidomide has dual action, by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion. [ citation needed ] Mutations in splicing factors have been found in 40–80% of people with MDS, with a higher incidence of mutations detected in people who have more ring sideroblasts . Mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) occur in 10–20% of patients with myelodysplastic syndrome, and confer a worsened prognosis in low-risk MDS. Because the incidence of IDH1/2 mutations increases as the disease malignancy increases, these findings together suggest that IDH1/2 mutations are important drivers of progression of MDS to a more malignant disease state. GATA2 deficiency is a group of disorders caused by a defect, familial, or sporadic inactivating mutations , in one of the two GATA2 genes . These autosomal dominant mutations cause a reduction in the cellular levels of the gene's product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development , maintenance, and functionality of blood-forming , lymph-forming , and other tissue-forming stem cells . In consequence of these mutations, cellular levels of GATA2 are low and individuals develop over time hematological, immunological, lymphatic, or other presentations. Prominent among these presentations is MDS that often progresses to acute myelocytic leukemia, or less commonly, chronic myelomonocytic leukemia . Transient myeloproliferative disease is the abnormal proliferation of a clone of noncancerous megakaryoblasts in the liver and bone marrow. The disease is restricted to individuals with Down syndrome or genetic changes similar to those in Down syndrome, develops during pregnancy or shortly after birth, and resolves within 3 months, or in about 10% of cases, progresses to acute megakaryoblastic leukemia . The recognition of epigenetic changes in DNA structure in MDS has explained the success of two (namely the hypomethylating agents 5-azacytidine and decitabine ) of three (the third is lenalidomide ) commercially available medications approved by the U.S. Food and Drug Administration to treat MDS. Proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth and cytopenias. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus , thereby restoring normal blood counts and retarding the progression of MDS to acute leukemia . Some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in MDS. Hematopoietic stem cell aging is thought to be associated with the accrual of multiple genetic and epigenetic aberrations leading to the suggestion that MDS is, in part, related to an inability to adequately cope with DNA damage . An emerging perspective is that the underlying mechanism of MDS could be a defect in one or more pathways that are involved in repairing damaged DNA . In MDS an increased frequency of chromosomal breaks indicates defects in DNA repair processes. Also elevated levels of 8-oxoguanine were found in the DNA of a significant proportion of MDS patients, indicating that the base excision repair pathway that is involved in handling oxidative DNA damages may be defective in these cases. Since at least 1974, the deletion in the long arm of chromosome 5 has been known to be associated with dysplastic abnormalities of hematopoietic stem cells. By 2005, lenalidomide , a chemotherapy drug, was recognized to be effective in MDS patients with the 5q- syndrome , and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low IPSS risk, and transfusion dependence respond best to lenalidomide. Typically, prognosis for these patients is favorable, with a 63-month median survival. Lenalidomide has dual action, by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion. [ citation needed ]Mutations in splicing factors have been found in 40–80% of people with MDS, with a higher incidence of mutations detected in people who have more ring sideroblasts . Mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) occur in 10–20% of patients with myelodysplastic syndrome, and confer a worsened prognosis in low-risk MDS. Because the incidence of IDH1/2 mutations increases as the disease malignancy increases, these findings together suggest that IDH1/2 mutations are important drivers of progression of MDS to a more malignant disease state. GATA2 deficiency is a group of disorders caused by a defect, familial, or sporadic inactivating mutations , in one of the two GATA2 genes . These autosomal dominant mutations cause a reduction in the cellular levels of the gene's product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development , maintenance, and functionality of blood-forming , lymph-forming , and other tissue-forming stem cells . In consequence of these mutations, cellular levels of GATA2 are low and individuals develop over time hematological, immunological, lymphatic, or other presentations. Prominent among these presentations is MDS that often progresses to acute myelocytic leukemia, or less commonly, chronic myelomonocytic leukemia . Transient myeloproliferative disease is the abnormal proliferation of a clone of noncancerous megakaryoblasts in the liver and bone marrow. The disease is restricted to individuals with Down syndrome or genetic changes similar to those in Down syndrome, develops during pregnancy or shortly after birth, and resolves within 3 months, or in about 10% of cases, progresses to acute megakaryoblastic leukemia . The elimination of other causes of cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome, so differentiating MDS from anemia, thrombocytopenia, and leukopenia is important. [ citation needed ] A typical diagnostic investigation includes: The features generally used to define an MDS are blood cytopenias, ineffective hematopoiesis, dyserythropoiesis , dysgranulopoiesis, dysmegakaropoiesis, and increased myeloblasts. Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains ( PAS ) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by: Other stains can help in special cases (PAS and naphthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy. On the bone-marrow biopsy, high-grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors , which are islands of immature precursors cells (myeloblasts and promyelocytes) localized to the center of the intertrabecular space rather than adjacent to the trabeculae or surrounding arterioles . This morphology can be difficult to differentiate from treated leukemia and recovering immature normal marrow elements. Also, topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia ( RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands . [ citation needed ] Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also, congenital diseases such as congenital dyserythropoietic anemia (CDA I through IV) have been recognized, Pearson's syndrome (sideroblastic anemia) , Jordans anomaly – vacuolization in all cell lines may be seen in Chanarin-Dorfman syndrome , aminolevulinic acid enzyme deficiency and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines; however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity , and other poisons. [ citation needed ] All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes , and platelets or their progenitor cells, megakaryocytes). [ citation needed ] In the late 1990s, a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others. In 2008, the WHO developed a new classification scheme that is based more on genetic findings, but morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy are still the screening tests used to decide which classification is best and which cytogenetic aberrations may be related. [ citation needed ] The list of dysplastic syndromes under the new WHO system includes: Note : not all physicians concur with this reclassification, because the underlying pathology of this disease is not well understood. The WHO has proposed a criterion for diagnosis and classification of MDS that may apply to most cases. However, occasional cases are difficult to classify into defined categories because of one or more unusual features: [ citation needed ]Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also, congenital diseases such as congenital dyserythropoietic anemia (CDA I through IV) have been recognized, Pearson's syndrome (sideroblastic anemia) , Jordans anomaly – vacuolization in all cell lines may be seen in Chanarin-Dorfman syndrome , aminolevulinic acid enzyme deficiency and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines; however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity , and other poisons. [ citation needed ] All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes , and platelets or their progenitor cells, megakaryocytes). [ citation needed ]In the late 1990s, a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others. In 2008, the WHO developed a new classification scheme that is based more on genetic findings, but morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy are still the screening tests used to decide which classification is best and which cytogenetic aberrations may be related. [ citation needed ] The list of dysplastic syndromes under the new WHO system includes: Note : not all physicians concur with this reclassification, because the underlying pathology of this disease is not well understood. The WHO has proposed a criterion for diagnosis and classification of MDS that may apply to most cases. However, occasional cases are difficult to classify into defined categories because of one or more unusual features: [ citation needed ]In the late 1990s, a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others. In 2008, the WHO developed a new classification scheme that is based more on genetic findings, but morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy are still the screening tests used to decide which classification is best and which cytogenetic aberrations may be related. [ citation needed ] The list of dysplastic syndromes under the new WHO system includes: Note : not all physicians concur with this reclassification, because the underlying pathology of this disease is not well understood.The WHO has proposed a criterion for diagnosis and classification of MDS that may apply to most cases. However, occasional cases are difficult to classify into defined categories because of one or more unusual features: [ citation needed ]The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to AML. The IPSS scoring system can help triage patients for more aggressive treatment (i.e. bone marrow transplant ) as well as help determine the best timing of this therapy. Supportive care with blood products and hematopoietic growth factors (e.g. erythropoietin ) is the mainstay of therapy. The regulatory environment for the use of erythropoietins is evolving, according to a recent US Medicare National coverage determination . However, no comment on the use of hematopoietic growth factors for MDS was made in that document. Agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS: Chemotherapy with the hypomethylating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML. Lenalidomide was approved by the FDA in December 2005 only for use in the 5q- syndrome . In the United States, treatment of MDS with lenalidomide costs about $9,200 per month. The chemotherapy may be supported by other drugs like all-trans retinoic acid (ATRA), however the evidence of benefit is not clear. HLA -matched allogeneic stem cell transplantation , particularly in younger (i.e. less than 40 years of age) and more severely affected patients, offers the potential for curative therapy. The success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tend to have a more favorable outcome with transplantation. Iron overload can develop in MDS as a result of the RBC transfusions , which are a major part of the supportive care for anemic MDS patients. Although the specific therapies patients receive may alleviate the RBC transfusion need in some cases, many MDS patients may not respond to these treatments, thus may develop secondary hemochromatosis due to iron overload from repeated RBC transfusions. Patients requiring relatively large numbers of RBC transfusions can experience the adverse effect of chronic iron overload on their liver, heart, and endocrine functions. For patients requiring many RBC transfusions, serum ferritin levels, number of RBC transfusions received, and associated organ dysfunction (heart, liver, and pancreas) should be monitored to determine iron levels. Monitoring serum ferritin may also be useful, aiming to decrease ferritin levels to < 1000 µg/L .Currently, two iron chelators are available in the US, deferoxamine for intravenous use and deferasirox for oral use. These options now provide potentially useful drugs for treating the iron overload problem. A third chelating agent is available in Europe, deferiprone , for oral use, but is not available in the US. [ citation needed ] Clinical trials in MDS patients are ongoing, with iron chelating agents to address the question of whether iron chelation alters the natural history of patients with MDS who are transfusion dependent. Reversal of some of the consequences of iron overload in MDS by iron chelation therapy has been shown. Both the MDS Foundation and the National Comprehensive Cancer Network MDS Guidelines Panel have recommended that chelation therapy be considered to decrease iron overload in selected MDS patients. Evidence also suggests a potential value exists to iron chelation in patients who will undergo a stem-cell transplant. Although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction in some patients), recently a safety warning by the FDA and Novartis was added to deferasirox treatment guidelines. Following postmarketing use of deferasirox, rare cases of acute kidney failure or liver failure occurred, some resulting in death. Due to this, patients should be closely monitored on deferasirox therapy prior to the start of therapy and regularly thereafter. [ citation needed ]Iron overload can develop in MDS as a result of the RBC transfusions , which are a major part of the supportive care for anemic MDS patients. Although the specific therapies patients receive may alleviate the RBC transfusion need in some cases, many MDS patients may not respond to these treatments, thus may develop secondary hemochromatosis due to iron overload from repeated RBC transfusions. Patients requiring relatively large numbers of RBC transfusions can experience the adverse effect of chronic iron overload on their liver, heart, and endocrine functions. For patients requiring many RBC transfusions, serum ferritin levels, number of RBC transfusions received, and associated organ dysfunction (heart, liver, and pancreas) should be monitored to determine iron levels. Monitoring serum ferritin may also be useful, aiming to decrease ferritin levels to < 1000 µg/L .Currently, two iron chelators are available in the US, deferoxamine for intravenous use and deferasirox for oral use. These options now provide potentially useful drugs for treating the iron overload problem. A third chelating agent is available in Europe, deferiprone , for oral use, but is not available in the US. [ citation needed ] Clinical trials in MDS patients are ongoing, with iron chelating agents to address the question of whether iron chelation alters the natural history of patients with MDS who are transfusion dependent. Reversal of some of the consequences of iron overload in MDS by iron chelation therapy has been shown. Both the MDS Foundation and the National Comprehensive Cancer Network MDS Guidelines Panel have recommended that chelation therapy be considered to decrease iron overload in selected MDS patients. Evidence also suggests a potential value exists to iron chelation in patients who will undergo a stem-cell transplant. Although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction in some patients), recently a safety warning by the FDA and Novartis was added to deferasirox treatment guidelines. Following postmarketing use of deferasirox, rare cases of acute kidney failure or liver failure occurred, some resulting in death. Due to this, patients should be closely monitored on deferasirox therapy prior to the start of therapy and regularly thereafter. [ citation needed ]The outlook in MDS is variable, with about 30% of patients progressing to refractory AML. The median survival time varies from years to months, depending on type. Stem-cell transplantation offers possible cure, with survival rates of 50% at 3 years, although older patients do poorly. Indicators of a good prognosis : Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (< 20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; and in vitro marrow culture with a nonleukemic growth pattern Indicators of a poor prognosis : Advanced age; severe neutropenia or thrombocytopenia; high blast count in the bone marrow (20–29%) or blasts in the blood; Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section; completely or mostly abnormal karyotypes, or complex marrow chromosome abnormalities and in vitro bone marrow culture with a leukemic growth pattern Karyotype prognostic factors: Good: normal, -Y, del(5q), del(20q) Intermediate or variable: +8, other single or double anomalies Poor: complex (>3 chromosomal aberrations); chromosome 7 anomalies The IPSS is the most commonly used tool in MDS to predict long-term outcome. Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or virtual karyotype . The best prognosis is seen with RA and RARS, where some nontransplant patients live more than a decade (typical is on the order of three to five years, although long-term remission is possible if a bone-marrow transplant is successful). The worst outlook is with RAEB-T, where the mean life expectancy is less than one year. About one-quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated diseases. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997. This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias. Although not yet formally incorporated in the generally accepted classification systems, molecular profiling of myelodysplastic syndrome genomes has increased the understanding of prognostic molecular factors for this disease. For example, in low-risk MDS, IDH1 and IDH2 mutations are associated with significantly worsened survival. Although not yet formally incorporated in the generally accepted classification systems, molecular profiling of myelodysplastic syndrome genomes has increased the understanding of prognostic molecular factors for this disease. For example, in low-risk MDS, IDH1 and IDH2 mutations are associated with significantly worsened survival. The exact number of people with MDS is not known because it can go undiagnosed and no tracking of the syndrome is mandated. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The number of new cases each year is probably increasing as the average age of the population increases, and some authors propose that the number of new cases in those over 70 may be as high as 15 per 100,000 per year. The typical age at diagnosis of MDS is between 60 and 75 years; a few people are younger than 50, and diagnoses are rare in children. Males are slightly more commonly affected than females. [ citation needed ]Since the early 20th century, some people with acute myelogenous leukemia were begun to be recognized to have a preceding period of anemia and abnormal blood cell production. These conditions were lumped together with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS. [ citation needed ] In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. This French-American-British classification was published in 1976, and revised in 1982. It was used by pathologists and clinicians for almost 20 years. Cases were classified into five categories: (A table comparing these is available from the Cleveland Clinic . )In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. This French-American-British classification was published in 1976, and revised in 1982. It was used by pathologists and clinicians for almost 20 years. Cases were classified into five categories: (A table comparing these is available from the Cleveland Clinic . )

Wiki

Acute hemorrhagic fever syndrome

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Dressler syndrome

Dressler syndrome is a secondary form of pericarditis that occurs in the setting of injury to the heart or the pericardium (the outer lining of the heart). It consists of fever, pleuritic pain, pericarditis and/or pericardial effusion. Dressler syndrome is also known as postmyocardial infarction syndrome and the term is sometimes used to refer to post-pericardiotomy pericarditis . It was first characterized by William Dressler at Maimonides Medical Center in 1956. It should not be confused with Dressler's syndrome of haemoglobinuria named for Lucas Dressler , who characterized it in 1854. Dressler syndrome was historically a phenomenon complicating about 7% of myocardial infarctions, but in the era of percutaneous coronary intervention , it is very uncommon. The disease consists of persistent low-grade fever , chest pain (usually pleuritic ), pericarditis (usually evidenced by a pericardial friction rub, chest pain worsening when recumbent, and diffuse ST elevation with PR segment depression), and/or pericardial effusion . The symptoms tend to occur 2–3 weeks after myocardial infarction but can also be delayed a few months. It tends to subside in a few days, and very rarely leads to pericardial tamponade . Elevated ESR is an objective but nonspecific laboratory finding.It is believed to result from an autoimmune inflammatory reaction to myocardial neo- antigens formed as a result of the MI . Similar pericarditis can be associated with any pericardiotomy or trauma to the pericardium or heart surgery which is called a postcardiotomy syndrome . [ citation needed ]Dressler syndrome needs to be differentiated from pulmonary embolism, another identifiable cause of pleuritic (and non-pleuritic) chest pain in people who have been hospitalized and/or undergone surgical procedures within the preceding weeks. [ citation needed ] ischaemic heart disease.Dressler syndrome needs to be differentiated from pulmonary embolism, another identifiable cause of pleuritic (and non-pleuritic) chest pain in people who have been hospitalized and/or undergone surgical procedures within the preceding weeks. [ citation needed ] ischaemic heart disease.Dressler syndrome is best treated with high-dose aspirin. In some resistant cases, corticosteroids can be used but are not preferred (avoided) in the first month due to the high frequency of impaired ventricular healing leading to an increased rate of ventricular rupture. Other NSAIDs , though once used to treat Dressler syndrome, are less advocated and should be avoided in patients with ischemic heart disease. One NSAID in particular, indomethacin, can inhibit new collagen deposition, thus impairing the healing process for the infarcted region. Other NSAIDS should be used only in cases refractory to aspirin. Heparin should be avoided because it can lead to hemorrhage into the pericardial sac, leading to tamponade. The only time heparin could be used with pericarditis is with coexisting acute MI, in order to prevent further thrombus formation.

Wiki

Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/Crimean–Congo_hemorrhagic_fever/html

Crimean–Congo hemorrhagic fever

Crimean–Congo hemorrhagic fever ( CCHF ) is a viral disease . Symptoms of CCHF may include fever , muscle pains , headache , vomiting, diarrhea , and bleeding into the skin . Onset of symptoms is less than two weeks following exposure. Complications may include liver failure . Survivors generally recover around two weeks after onset. The CCHF virus is typically spread by tick bites or close contact with the blood, secretions, organs or other bodily fluids of infected persons or animals. Groups that are at high risk of infection are farmers and those who work in slaughterhouses . The virus can also spread between people via body fluids . Diagnosis can be made by detecting antibodies , the virus's RNA , or viral proteins (antigens). It is a type of viral hemorrhagic fever . There are no FDA - or WHO -approved therapeutics for CCHF, and a vaccine is not commercially available. Prevention involves avoiding tick bites, following safe practices in meat processing plants, and observing universal healthcare precautions. Treatment is typically with supportive care , and the medication ribavirin may also help. CCHF cases are observed in a wide geographic range including Africa , Russia , the Balkans , the Middle East , and Asia . Typically small outbreaks are seen in areas where the virus is endemic. In 2013 Iran , Russia, Turkey , and Uzbekistan documented more than 50 cases. The fatality rate is typically between 10 and 40%, though fatalities as high as 80% have been observed in some outbreaks. The virus was first observed in Crimea in the 1940s and was later identified as the same agent of what had been called Congo Hemorrhagic Fever. In the past 20 years, CCHF outbreaks have been reported in eastern Europe, particularly in the former Soviet Union , throughout the Mediterranean, in northwestern China , central Asia, southern Europe, Africa, the Middle East, and the Indian subcontinent . CCHF is on WHO's priority list for Research and Development and the US National Institute of Allergy and Infectious Diseases (NIH/NIAID) priority A list, as a disease posing the highest level of risk to national security and public health.The clinical illness associated with CCHFV (the CCHF virus) is a severe form of hemorrhagic fever . Following infection by a tick bite, the incubation period is typically two to three days but can last as long as nine days, while the incubation period following contact with infected blood or tissues is usually five to six days with a documented maximum of 13 days. The onset of symptoms ushering in the pre-hemorrhagic phase is sudden, with fever, myalgia (muscle ache), dizziness, neck pain and stiffness, backache, headache, sore eyes and photophobia (sensitivity to light). Typical symptoms include nausea, vomiting (which may progress to severe bleeding and can be fatal if not treated), diarrhea, abdominal pain and sore throat early in the acute infection phase, followed by sharp mood swings, agitations and confusion. After several days, agitation may be replaced by sleepiness, depression and lassitude, and the abdominal pain may localize to the upper right quadrant, with detectable liver enlargement. As the illness progresses into the hemorrhagic phase, large areas of severe bruising, severe nosebleeds, and uncontrolled bleeding at injection sites can be seen, beginning on about the fourth day of illness and lasting for about two weeks. Other clinical signs include tachycardia (fast heart rate), lymphadenopathy (enlarged lymph nodes), and a petechiae (a rash caused by bleeding into the skin) on internal mucosal surfaces, such as in the mouth and throat, and on the skin. The petechiae may give way to larger rashes called ecchymoses, and other haemorrhagic phenomena. There is usually evidence of hepatitis, and severely ill patients may experience rapid kidney deterioration, liver failure or pulmonary failure after the fifth day of illness. In documented outbreaks of CCHF, fatality rates in hospitalized patients have ranged from 9% to as high as 70%, though the WHO notes a typical range of 10–40%, with death often occurring in the second week of illness. In patients who recover, improvement generally begins on the ninth or tenth day after the onset of illness. The long-term effects of CCHF infection have not been studied well enough in survivors to determine whether or not specific complications exist. However, recovery is slow.The Crimean–Congo hemorrhagic fever orthonairovirus (CCHFV) is a member of the genus Orthonairovirus , family Nairoviridae of RNA viruses . The virions are 80–120 nanometers (nm) in diameter and are pleomorphic . There are no host ribosomes within the virion. Each virion contains three distinct RNA sequences, which together make up the viral genome. The envelope is single layered and is formed from a lipid bilayer 5 nm thick. It has no external protrusions. The envelope proteins form small projections ~5–10 nm long. The nucleocapsids are filamentous and circular with a length of 200–3000 nm. Viral entry is thought to be clathrin-mediated with the cell surface protein nucleolin playing a role. The genome is circular, negative-sense RNA in three parts – Small (S), Medium (M) and Large (L). The L segment is 11–14.4 kilobases in length while the M and S segments are 4.4–6.3 and 1.7–2.1 kilobases long respectively. The L segment encodes the RNA polymerase , the M segment encodes the envelope glycoproteins (Gc and Gn), and the S segment encodes the nucleocapsid protein. The mutation rates for the three parts of the genome were estimated to be: 1.09 × 10 −4 , 1.52 × 10 −4 and 0.58 × 10 −4 substitutions/site/year for the S, M, and L segments respectively. CCHFV is the most genetically diverse of the arboviruses : its nucleotide sequences frequently differ between different strains, ranging from a 20% variability for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area; closely related viruses have been isolated from widely separated regions, suggesting that viral dispersion has occurred possibly by ticks carried on migratory birds or through international livestock trade. Reassortment among genome segments during coinfection of ticks or vertebrates seems likely to have played a role in generating diversity in this virus. [ citation needed ] Based on the sequence data, seven genotypes of CCHFV have been recognised: Africa 1 ( Senegal ), Africa 2 ( Democratic Republic of the Congo and South Africa), Africa 3 (southern and western Africa), Europe 1 ( Albania , Bulgaria , Kosovo , Russia and Turkey ), Europe 2 ( Greece ), Asia 1 ( the Middle East , Iran and Pakistan ) and Asia 2 ( China , Kazakhstan , Tajikistan and Uzbekistan ). [ citation needed ] Ticks are both "environmental reservoir" and vector for the virus, carrying it from wild animals to domestic animals and humans. Tick species identified as infected with the virus include Argas reflexus , Hyalomma anatolicum , Hyalomma detritum , Hyalomma marginatum marginatum and Rhipicephalus sanguineus . [ citation needed ] At least 31 different species of ticks from the genera Haemaphysalis and Hyalomma in southeastern Iran have been found to carry the virus. Wild animals and small mammals, particularly European hare , Middle-African hedgehogs and multimammate rats are the "amplifying hosts" of the virus. Birds are generally resistant to CCHF, with the exception of ostriches . Domestic animals like sheep, goats and cattle can develop high titers of virus in their blood, but tend not to fall ill. The "sporadic infection" of humans is usually caused by a Hyalomma tick bite. Animals can transmit the virus to humans, but this would usually be as part of a disease cluster . When clusters of illness occur, it is typically after people treat, butcher or eat infected livestock, particularly ruminants and ostriches . Outbreaks have occurred in abattoirs and other places where workers have been exposed to infected human or animal blood and fomites [ citation needed ] Humans can infect humans and outbreaks also occur in clinical facilities through infected blood and unclean medical instruments. The Crimean–Congo hemorrhagic fever orthonairovirus (CCHFV) is a member of the genus Orthonairovirus , family Nairoviridae of RNA viruses . The virions are 80–120 nanometers (nm) in diameter and are pleomorphic . There are no host ribosomes within the virion. Each virion contains three distinct RNA sequences, which together make up the viral genome. The envelope is single layered and is formed from a lipid bilayer 5 nm thick. It has no external protrusions. The envelope proteins form small projections ~5–10 nm long. The nucleocapsids are filamentous and circular with a length of 200–3000 nm. Viral entry is thought to be clathrin-mediated with the cell surface protein nucleolin playing a role. The genome is circular, negative-sense RNA in three parts – Small (S), Medium (M) and Large (L). The L segment is 11–14.4 kilobases in length while the M and S segments are 4.4–6.3 and 1.7–2.1 kilobases long respectively. The L segment encodes the RNA polymerase , the M segment encodes the envelope glycoproteins (Gc and Gn), and the S segment encodes the nucleocapsid protein. The mutation rates for the three parts of the genome were estimated to be: 1.09 × 10 −4 , 1.52 × 10 −4 and 0.58 × 10 −4 substitutions/site/year for the S, M, and L segments respectively. CCHFV is the most genetically diverse of the arboviruses : its nucleotide sequences frequently differ between different strains, ranging from a 20% variability for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area; closely related viruses have been isolated from widely separated regions, suggesting that viral dispersion has occurred possibly by ticks carried on migratory birds or through international livestock trade. Reassortment among genome segments during coinfection of ticks or vertebrates seems likely to have played a role in generating diversity in this virus. [ citation needed ] Based on the sequence data, seven genotypes of CCHFV have been recognised: Africa 1 ( Senegal ), Africa 2 ( Democratic Republic of the Congo and South Africa), Africa 3 (southern and western Africa), Europe 1 ( Albania , Bulgaria , Kosovo , Russia and Turkey ), Europe 2 ( Greece ), Asia 1 ( the Middle East , Iran and Pakistan ) and Asia 2 ( China , Kazakhstan , Tajikistan and Uzbekistan ). [ citation needed ]The genome is circular, negative-sense RNA in three parts – Small (S), Medium (M) and Large (L). The L segment is 11–14.4 kilobases in length while the M and S segments are 4.4–6.3 and 1.7–2.1 kilobases long respectively. The L segment encodes the RNA polymerase , the M segment encodes the envelope glycoproteins (Gc and Gn), and the S segment encodes the nucleocapsid protein. The mutation rates for the three parts of the genome were estimated to be: 1.09 × 10 −4 , 1.52 × 10 −4 and 0.58 × 10 −4 substitutions/site/year for the S, M, and L segments respectively. CCHFV is the most genetically diverse of the arboviruses : its nucleotide sequences frequently differ between different strains, ranging from a 20% variability for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area; closely related viruses have been isolated from widely separated regions, suggesting that viral dispersion has occurred possibly by ticks carried on migratory birds or through international livestock trade. Reassortment among genome segments during coinfection of ticks or vertebrates seems likely to have played a role in generating diversity in this virus. [ citation needed ] Based on the sequence data, seven genotypes of CCHFV have been recognised: Africa 1 ( Senegal ), Africa 2 ( Democratic Republic of the Congo and South Africa), Africa 3 (southern and western Africa), Europe 1 ( Albania , Bulgaria , Kosovo , Russia and Turkey ), Europe 2 ( Greece ), Asia 1 ( the Middle East , Iran and Pakistan ) and Asia 2 ( China , Kazakhstan , Tajikistan and Uzbekistan ). [ citation needed ]Ticks are both "environmental reservoir" and vector for the virus, carrying it from wild animals to domestic animals and humans. Tick species identified as infected with the virus include Argas reflexus , Hyalomma anatolicum , Hyalomma detritum , Hyalomma marginatum marginatum and Rhipicephalus sanguineus . [ citation needed ] At least 31 different species of ticks from the genera Haemaphysalis and Hyalomma in southeastern Iran have been found to carry the virus. Wild animals and small mammals, particularly European hare , Middle-African hedgehogs and multimammate rats are the "amplifying hosts" of the virus. Birds are generally resistant to CCHF, with the exception of ostriches . Domestic animals like sheep, goats and cattle can develop high titers of virus in their blood, but tend not to fall ill. The "sporadic infection" of humans is usually caused by a Hyalomma tick bite. Animals can transmit the virus to humans, but this would usually be as part of a disease cluster . When clusters of illness occur, it is typically after people treat, butcher or eat infected livestock, particularly ruminants and ostriches . Outbreaks have occurred in abattoirs and other places where workers have been exposed to infected human or animal blood and fomites [ citation needed ] Humans can infect humans and outbreaks also occur in clinical facilities through infected blood and unclean medical instruments. Where mammalian tick infection is common, agricultural regulations require de-ticking farm animals before transportation or delivery for slaughter. Personal tick avoidance measures are recommended, such as use of insect repellents, adequate clothing, and body inspection for adherent ticks. [ citation needed ] When feverish patients with evidence of bleeding require resuscitation or intensive care , body substance isolation precautions should be taken. [ citation needed ] Since the 1970s, several vaccine trials around the world against CCHF have been terminated due to high toxicity. As of March 2011 [ update ] , the only available and probably somewhat efficacious CCHF vaccine has been an inactivated antigen preparation then used in Bulgaria. No publication in the scientific literature related to this vaccine exists, which a Turkish virologist called suspicious both because antiquated technology and mouse brain were used to manufacture it. More vaccines are under development, but the sporadic nature of the disease, even in endemic countries, suggests that large trials of vaccine efficacy will be difficult to perform. Finding volunteers may prove challenging, given growing anti-vaccination sentiment and resistance of populations to vaccination against contagious diseases. The number of people to be vaccinated, and the length of time they would have to be followed to confirm protection would have to be carefully defined. Alternatively, many scientists appear to believe that treatment of CCHF with ribavirin is more practical than prevention, but some recently conducted clinical trials appear to counter assumptions of drug efficacy. In 2011, a Turkish research team led by Erciyes University successfully developed the first non-toxic preventive vaccine, which passed clinical trials. As of 2012, the vaccine was pending approval by the US FDA. Since the Ebola epidemic, the WHO jumpstarted a "Blueprint for Research and Development preparedness" on emerging pathogens with epidemic potential, against which there are no medical treatments. CCHF was the top priority on the initial list from December 2015, and is second as of January 2017. Since the 1970s, several vaccine trials around the world against CCHF have been terminated due to high toxicity. As of March 2011 [ update ] , the only available and probably somewhat efficacious CCHF vaccine has been an inactivated antigen preparation then used in Bulgaria. No publication in the scientific literature related to this vaccine exists, which a Turkish virologist called suspicious both because antiquated technology and mouse brain were used to manufacture it. More vaccines are under development, but the sporadic nature of the disease, even in endemic countries, suggests that large trials of vaccine efficacy will be difficult to perform. Finding volunteers may prove challenging, given growing anti-vaccination sentiment and resistance of populations to vaccination against contagious diseases. The number of people to be vaccinated, and the length of time they would have to be followed to confirm protection would have to be carefully defined. Alternatively, many scientists appear to believe that treatment of CCHF with ribavirin is more practical than prevention, but some recently conducted clinical trials appear to counter assumptions of drug efficacy. In 2011, a Turkish research team led by Erciyes University successfully developed the first non-toxic preventive vaccine, which passed clinical trials. As of 2012, the vaccine was pending approval by the US FDA. Since the Ebola epidemic, the WHO jumpstarted a "Blueprint for Research and Development preparedness" on emerging pathogens with epidemic potential, against which there are no medical treatments. CCHF was the top priority on the initial list from December 2015, and is second as of January 2017. Treatment is mostly supportive . Ribavirin has shown some efficacy in vitro and has been used by mouth during outbreaks, [ citation needed ] but there is uncertain evidence to support its use, and this medication can cause serious side effects including hemolytic anemia and liver damage. As of 2011 [ update ] the use of Immunoglobulin preparations has remained unproven and antibody engineering, which raised hopes for monoclonal antibody therapy, has remained in its infancy. CCHF occurs most frequently among agricultural workers, following the bite of an infected tick, and to a lesser extent among slaughterhouse workers exposed to the blood and tissues of infected livestock, and medical personnel through contact with the body fluids of infected persons. As of 2013 [ update ] the northern limit of CCHF has been 50 degrees northern latitude, north of which the Hyalomma ticks have not been found. Per a WHO map from 2008, Hyalomma ticks occurred south of this latitude across all of the Eurasian continent and Africa, sparing only the islands of Sri Lanka , Indonesia and Japan . Serological or virological evidence of CCHF was widespread in Asia, Eastern Europe, the Middle East (except Israel, Lebanon and Jordan), central Africa, Western Africa, South Africa and Madagascar. In 2008, more than 50 cases/year were reported from only 4 countries: Turkey, Iran, Russia and Uzbekistan. 5-49 cases/year were present in South Africa, Central Asia including Pakistan and Afghanistan (but sparing Turkmenistan), in the Middle East only the UAE and the Balkan countries limited to Romania, Bulgaria, Serbia, Montenegro and Albania. In Russia, the disease is limited to Southern and North Caucasian Federal Districts , but climate change may cause it to spread into more northerly areas. A 2014 map by the CDC shows endemic areas (in red) largely unchanged in Africa and the Middle East, but different for the Balkan, including all countries of the former Yugoslavia, and also Greece, but no longer Romania. India 's Northwestern regions of Rajasthan and Gujarat saw their first cases. From 1995 to 2013, 228 cases of CCHF were reported in the Republic of Kosovo, with a case-fatality rate of 25.5%. Between 2002–2008 the Ministry of Health of Turkey reported 3,128 CCHF cases, with a 5% death rate. [ citation needed ] In July 2005, authorities reported 41 cases of CCHF in central Turkey's Yozgat Province , with one death. [ clarification needed ] As of August 2008, a total of 50 deaths were reported for the year thus far in various cities in Turkey due to CCHF. [ clarification needed ] In 2003, 38 people were infected with CCHF in Mauritania , including 35 residents of Nouakchott. In September 2010, an outbreak was reported in Pakistan's Khyber Pakhtunkhwa province. Poor diagnosis and record keeping caused the extent of the outbreak to be uncertain, though some reports indicated over 100 cases, with a case-fatality rate above 10%. [ citation needed ] In January 2011, the first human cases of CCHF in India was reported in Sanand , Gujarat, India, with 4 reported deaths, which included the index patient , treating physician and nurse. As of May 2012 [ update ] , 71 people were reported to have contracted the disease in Iran, resulting in 8 fatalities. [ citation needed ] In October 2012, a British man died from the disease at the Royal Free Hospital in London. He had earlier been admitted to Gartnavel General Hospital in Glasgow , after returning on a flight from Kabul in Afghanistan . In July 2013, seven people died of CCHF in the Karyana village of Babra , Gujarat, India. In August 2013, a farmer from Agago , Uganda was treated at Kalongo Hospital for a confirmed CCHF infection. The deaths of three other individuals in the northern region were suspected to have been caused by the virus. Another unrelated CCHF patient was admitted to Mulago Hospital on the same day. The Ministry of Health announced on the 19th that the outbreak was under control, but the second patient, a 27-year-old woman from Nansana , died on the 21st. She is believed to have contracted the virus from her husband, who returned to Kampala after being treated for CCHF in Juba , South Sudan. In June 2014, cases were diagnosed in Kazakhstan. Ten people, including an ambulance crew, were admitted on to hospital in southern Kazakhstan with suspected CCHF. [ citation needed ] In July 2014 an 8th person was found to be infected with CCHF at Hayatabad Medical Complex (HMC), Pakistan. The eight patients, including a nurse and 6 Afghan nationals, died between April and July 2014. As of 2015 [ update ] , sporadic confirmed cases have been reported from Bhuj , Amreli , Sanand , Idar and Vadnagar in Gujarat, India. In November 2014, a doctor and a labourer in north Gujarat tested positive for the disease. In the following weeks, three more people died from CCHF. In March 2015, one more person died of CCHF in Gujarat. As of 2015, among livestock, CCHF was recognized as "widespread" in India, only 4 years after the first human case had been diagnosed. In August 2016, the first local case of CCHF in Western Europe occurred in Western Spain. A 62-year-old man, who had been bitten by a tick in Spain died on August 25, having infected a nurse. The tick bite occurred in the province of Ávila , 300 km away from the province of Cáceres , where CCHF viral RNA from ticks was amplified in 2010. As of July 2017 [ update ] it was unclear what specific ecology led to the Spanish cases. In August 2016, a number of Pakistani news sources raised concerns regarding the disease. Between January and October 2016, CCHF outbreaks in Pakistan were reported with highest numbers of cases and deaths during August 2016, just before the festival of Eid-al-Adha (held on September 13–15 in 2016). It was hypothesized that the festival could play an important part as people could come into contact with domestic or imported animals potentially infected with CCHF virus. The Pakistani NIH showed there was no correlation, and that CCHF cases have coincided with the peak tick proliferation during the preceding 8–10 years. In 2017, the General Directorate of Public Health in Turkey published official records of infections and casualties involving CCHF between 2008 and 2017. Cases declined form 1,318 in 2009 to 343 in 2017 alongside a lowered mortality rate. Cases are concentrated in rural areas of the Southern Black Sea Region , Central Anatolia Region , and Eastern Anatolia Region during early summer months. On February 2, 2020, an outbreak was reported in Mali involving fourteen cases and seven deaths, days before the COVID-19 pandemic in Africa . In May 2020, a single case was reported in Mauritania. In 2022, an outbreak occurred in Iraq . Between 1 January and 22 May, 212 cases of CCHF were reported to the WHO. Of the 212 cases, 115 were suspected and 97 laboratory confirmed. Twenty seven deaths were recorded, of which 13 were in laboratory confirmed cases. In July 2023, there was a single confirmed fatality of tick-borne CCHF in North Macedonia . As of 2013 [ update ] the northern limit of CCHF has been 50 degrees northern latitude, north of which the Hyalomma ticks have not been found. Per a WHO map from 2008, Hyalomma ticks occurred south of this latitude across all of the Eurasian continent and Africa, sparing only the islands of Sri Lanka , Indonesia and Japan . Serological or virological evidence of CCHF was widespread in Asia, Eastern Europe, the Middle East (except Israel, Lebanon and Jordan), central Africa, Western Africa, South Africa and Madagascar. In 2008, more than 50 cases/year were reported from only 4 countries: Turkey, Iran, Russia and Uzbekistan. 5-49 cases/year were present in South Africa, Central Asia including Pakistan and Afghanistan (but sparing Turkmenistan), in the Middle East only the UAE and the Balkan countries limited to Romania, Bulgaria, Serbia, Montenegro and Albania. In Russia, the disease is limited to Southern and North Caucasian Federal Districts , but climate change may cause it to spread into more northerly areas. A 2014 map by the CDC shows endemic areas (in red) largely unchanged in Africa and the Middle East, but different for the Balkan, including all countries of the former Yugoslavia, and also Greece, but no longer Romania. India 's Northwestern regions of Rajasthan and Gujarat saw their first cases. From 1995 to 2013, 228 cases of CCHF were reported in the Republic of Kosovo, with a case-fatality rate of 25.5%. Between 2002–2008 the Ministry of Health of Turkey reported 3,128 CCHF cases, with a 5% death rate. [ citation needed ] In July 2005, authorities reported 41 cases of CCHF in central Turkey's Yozgat Province , with one death. [ clarification needed ] As of August 2008, a total of 50 deaths were reported for the year thus far in various cities in Turkey due to CCHF. [ clarification needed ] In 2003, 38 people were infected with CCHF in Mauritania , including 35 residents of Nouakchott. In September 2010, an outbreak was reported in Pakistan's Khyber Pakhtunkhwa province. Poor diagnosis and record keeping caused the extent of the outbreak to be uncertain, though some reports indicated over 100 cases, with a case-fatality rate above 10%. [ citation needed ] In January 2011, the first human cases of CCHF in India was reported in Sanand , Gujarat, India, with 4 reported deaths, which included the index patient , treating physician and nurse. As of May 2012 [ update ] , 71 people were reported to have contracted the disease in Iran, resulting in 8 fatalities. [ citation needed ] In October 2012, a British man died from the disease at the Royal Free Hospital in London. He had earlier been admitted to Gartnavel General Hospital in Glasgow , after returning on a flight from Kabul in Afghanistan . In July 2013, seven people died of CCHF in the Karyana village of Babra , Gujarat, India. In August 2013, a farmer from Agago , Uganda was treated at Kalongo Hospital for a confirmed CCHF infection. The deaths of three other individuals in the northern region were suspected to have been caused by the virus. Another unrelated CCHF patient was admitted to Mulago Hospital on the same day. The Ministry of Health announced on the 19th that the outbreak was under control, but the second patient, a 27-year-old woman from Nansana , died on the 21st. She is believed to have contracted the virus from her husband, who returned to Kampala after being treated for CCHF in Juba , South Sudan. In June 2014, cases were diagnosed in Kazakhstan. Ten people, including an ambulance crew, were admitted on to hospital in southern Kazakhstan with suspected CCHF. [ citation needed ] In July 2014 an 8th person was found to be infected with CCHF at Hayatabad Medical Complex (HMC), Pakistan. The eight patients, including a nurse and 6 Afghan nationals, died between April and July 2014. As of 2015 [ update ] , sporadic confirmed cases have been reported from Bhuj , Amreli , Sanand , Idar and Vadnagar in Gujarat, India. In November 2014, a doctor and a labourer in north Gujarat tested positive for the disease. In the following weeks, three more people died from CCHF. In March 2015, one more person died of CCHF in Gujarat. As of 2015, among livestock, CCHF was recognized as "widespread" in India, only 4 years after the first human case had been diagnosed. In August 2016, the first local case of CCHF in Western Europe occurred in Western Spain. A 62-year-old man, who had been bitten by a tick in Spain died on August 25, having infected a nurse. The tick bite occurred in the province of Ávila , 300 km away from the province of Cáceres , where CCHF viral RNA from ticks was amplified in 2010. As of July 2017 [ update ] it was unclear what specific ecology led to the Spanish cases. In August 2016, a number of Pakistani news sources raised concerns regarding the disease. Between January and October 2016, CCHF outbreaks in Pakistan were reported with highest numbers of cases and deaths during August 2016, just before the festival of Eid-al-Adha (held on September 13–15 in 2016). It was hypothesized that the festival could play an important part as people could come into contact with domestic or imported animals potentially infected with CCHF virus. The Pakistani NIH showed there was no correlation, and that CCHF cases have coincided with the peak tick proliferation during the preceding 8–10 years. In 2017, the General Directorate of Public Health in Turkey published official records of infections and casualties involving CCHF between 2008 and 2017. Cases declined form 1,318 in 2009 to 343 in 2017 alongside a lowered mortality rate. Cases are concentrated in rural areas of the Southern Black Sea Region , Central Anatolia Region , and Eastern Anatolia Region during early summer months. On February 2, 2020, an outbreak was reported in Mali involving fourteen cases and seven deaths, days before the COVID-19 pandemic in Africa . In May 2020, a single case was reported in Mauritania. In 2022, an outbreak occurred in Iraq . Between 1 January and 22 May, 212 cases of CCHF were reported to the WHO. Of the 212 cases, 115 were suspected and 97 laboratory confirmed. Twenty seven deaths were recorded, of which 13 were in laboratory confirmed cases. In July 2023, there was a single confirmed fatality of tick-borne CCHF in North Macedonia . In ancient Celtic settlements in the Upper Danube area in Germany, the CCHF virus was detected in archaeological blood samples, indicating that it was endemic at the time. The virus may have evolved around 1500–1100 BC. It is thought that changing climate and agricultural practices around this time could be behind its evolution. In the 12th century a case of a hemorrhagic disease reported from what is now Tajikistan may have been the first known case of Crimean–Congo hemorrhagic fever. [ citation needed ] In 1944, roughly 200 Soviet military agricultural workers were infected by Crimean hemorrhagic fever (CHF), leading to experiments showing a tick-borne viral etiology. In February 1967, virologists John P. Woodall , David Simpson, Ghislaine Courtois and others published initial reports on a virus they called the Congo virus. In 1956, the Congo virus had first been isolated by physician Ghislaine Courtois, head of the Provincial Medical Laboratory, Stanleyville , in the Belgian Congo . Strain V3010, isolated by Courtois, was sent to the Rockefeller Foundation Virus Laboratory (RFVL) in New York City and found to be identical to another strain from Uganda , but to no other named virus at that time. [ citation needed ] In June 1967, Soviet virologist Mikhail Chumakov registered an isolate from a fatal case that occurred in Samarkand in the Catalogue of Arthropod-borne Viruses. In 1969, the Russian strain, which Chumakov had sent to the RFVL, was found to be antigenically indistinguishable from the Congo virus. In 1973, the International Committee on Taxonomy of Viruses adopted Crimean–Congo hemorrhagic fever virus as the official name. These reports include records of the occurrence of the virus or antibodies to the virus from Greece, Portugal, South Africa, Madagascar (the first isolation from there), the Maghreb , Dubai , Saudi Arabia , Kuwait and Iraq.

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Acute hemorrhagic fever syndrome

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Pulmonary edema

Pulmonary edema ( British English : oedema), also known as pulmonary congestion , is excessive fluid accumulation in the tissue or air spaces (usually alveoli ) of the lungs . This leads to impaired gas exchange , most often leading to dyspnea which can progress to hypoxemia and respiratory failure . Pulmonary edema has multiple causes and is traditionally classified as cardiogenic (caused by the heart) or noncardiogenic (all other types not caused by the heart). Various laboratory tests ( CBC , troponin , BNP , etc.) and imaging studies ( chest x-ray , CT scan , ultrasound ) are often used to diagnose and classify the cause of pulmonary edema. Treatment is focused on three aspects: improving respiratory function, treating the underlying cause, and preventing further damage and allow full recovery to the lung. Pulmonary edema can cause permanent organ damage, and when sudden (acute), can lead to respiratory failure or cardiac arrest due to hypoxia . The term edema is from the Greek οἴδημα ( oidēma , "swelling"), from οἰδέω ( oidéō , "(I) swell"). The amount of fluid in the lungs is governed by multiple forces and is visualized using the Starling equation . There are two hydrostatic pressures and two oncotic (protein) pressures that determine the fluid movement within the lung air spaces ( alveoli ). Of the forces that explain fluid movement, only the pulmonary wedge pressure is obtainable via pulmonary artery catheterization . Due to the complication rate associated with pulmonary artery catheterization, other imaging modalities and diagnostic methods have become more popular. Imbalance in any of these forces can cause fluid movement (or lack of movement) causing a buildup of fluid where it should not normally be. Although rarely clinically measured, these forces allow us to classify, and subsequently treat the underlying cause of pulmonary edema.Pulmonary edema has a multitude of causes, and is typically classified as cardiogenic or noncardiogenic. Cardiogenic pulmonary edema is caused by increased hydrostatic pressure causing increased fluid in the pulmonary interstitium and alveoli . Noncardiogenic causes are associated with the oncotic pressure as discussed above causing malfunctioning barriers in the lungs (increased microvascular permeability ). Cardiogenic pulmonary edema is typically caused by either volume overload or impaired left ventricular function. As a result, pulmonary pressures rises from the normal average of 15 mmHg. As the pulmonary pressure rises, these pressures overwhelm the barriers and fluid enters the alveoli when the pressure is above 25 mmHg. Depending whether the cause is acute or chronic determines how fast pulmonary edema develops and the severity of symptoms. Some of the common causes of cardiogenic pulmonary edema include: A particularly severe type of cardiogenic pulmonary edema is flash pulmonary edema (FPE). Flash pulmonary edema is a clinical syndrome of acute heart failure that begins suddenly and accelerates rapidly. Frequently the most noticeable abnormality is edema of the lungs. Nevertheless it is a cardiovascular disease not a pulmonary disease. It is also known by other appellations including sympathetic crashing acute pulmonary edema (SCAPE). It is often associated with severe hypertension Typically, patients with the syndrome of flash pulmonary edema do not have chest pain.  Treatment of FPE should include reducing systemic vascular resistance with nitroglycerin, ensuring adequate oxygenation with non-invasive ventilation, and decrease of pulmonary circulation pressures while FPE stays. Recurrence of FPE is thought to be associated with hypertension and may signify renal artery stenosis . Prevention of recurrence is based on managing or preventing hypertension, coronary artery disease , renovascular hypertension , and heart failure. Noncardiogenic pulmonary edema is caused by increased microvascular permeability (increased oncotic pressure ) leading to increased fluid transfer into the alveolar spaces. The pulmonary artery wedge pressure is typically normal as opposed to cardiogenic pulmonary edema where the elevated pressure is causing the fluid transfer. There are multiple causes of noncardiogenic edema with multiple subtypes within each cause. Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Although ARDS can present with pulmonary edema (fluid accumulation), it is a distinct clinical syndrome that is not synonymous with pulmonary edema. Acute lung injury may cause pulmonary edema directly through injury to the vasculature and parenchyma of the lung, causes include: Some causes of pulmonary edema are less well characterized and arguably represent specific instances of the broader classifications above.Cardiogenic pulmonary edema is typically caused by either volume overload or impaired left ventricular function. As a result, pulmonary pressures rises from the normal average of 15 mmHg. As the pulmonary pressure rises, these pressures overwhelm the barriers and fluid enters the alveoli when the pressure is above 25 mmHg. Depending whether the cause is acute or chronic determines how fast pulmonary edema develops and the severity of symptoms. Some of the common causes of cardiogenic pulmonary edema include: A particularly severe type of cardiogenic pulmonary edema is flash pulmonary edema (FPE). Flash pulmonary edema is a clinical syndrome of acute heart failure that begins suddenly and accelerates rapidly. Frequently the most noticeable abnormality is edema of the lungs. Nevertheless it is a cardiovascular disease not a pulmonary disease. It is also known by other appellations including sympathetic crashing acute pulmonary edema (SCAPE). It is often associated with severe hypertension Typically, patients with the syndrome of flash pulmonary edema do not have chest pain.  Treatment of FPE should include reducing systemic vascular resistance with nitroglycerin, ensuring adequate oxygenation with non-invasive ventilation, and decrease of pulmonary circulation pressures while FPE stays. Recurrence of FPE is thought to be associated with hypertension and may signify renal artery stenosis . Prevention of recurrence is based on managing or preventing hypertension, coronary artery disease , renovascular hypertension , and heart failure.A particularly severe type of cardiogenic pulmonary edema is flash pulmonary edema (FPE). Flash pulmonary edema is a clinical syndrome of acute heart failure that begins suddenly and accelerates rapidly. Frequently the most noticeable abnormality is edema of the lungs. Nevertheless it is a cardiovascular disease not a pulmonary disease. It is also known by other appellations including sympathetic crashing acute pulmonary edema (SCAPE). It is often associated with severe hypertension Typically, patients with the syndrome of flash pulmonary edema do not have chest pain.  Treatment of FPE should include reducing systemic vascular resistance with nitroglycerin, ensuring adequate oxygenation with non-invasive ventilation, and decrease of pulmonary circulation pressures while FPE stays. Recurrence of FPE is thought to be associated with hypertension and may signify renal artery stenosis . Prevention of recurrence is based on managing or preventing hypertension, coronary artery disease , renovascular hypertension , and heart failure.Noncardiogenic pulmonary edema is caused by increased microvascular permeability (increased oncotic pressure ) leading to increased fluid transfer into the alveolar spaces. The pulmonary artery wedge pressure is typically normal as opposed to cardiogenic pulmonary edema where the elevated pressure is causing the fluid transfer. There are multiple causes of noncardiogenic edema with multiple subtypes within each cause. Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Although ARDS can present with pulmonary edema (fluid accumulation), it is a distinct clinical syndrome that is not synonymous with pulmonary edema. Acute lung injury may cause pulmonary edema directly through injury to the vasculature and parenchyma of the lung, causes include: Some causes of pulmonary edema are less well characterized and arguably represent specific instances of the broader classifications above.Acute lung injury may cause pulmonary edema directly through injury to the vasculature and parenchyma of the lung, causes include:Some causes of pulmonary edema are less well characterized and arguably represent specific instances of the broader classifications above.The most common symptom of pulmonary edema is dyspnea and may include other symptoms relating to inadequate oxygen ( hypoxia ) such as fast breathing ( tachypnea ), tachycardia and cyanosis . Other common symptoms include coughing up blood (classically seen as pink or red, frothy sputum), excessive sweating , anxiety , and pale skin . Other signs include end-inspiratory crackles (crackling sounds heard at the end of a deep breath) on auscultation and the presence of a third heart sound . Shortness of breath can manifest as orthopnea (inability to breathe sufficiently when lying down flat due to breathlessness) and/or paroxysmal nocturnal dyspnea (episodes of severe sudden breathlessness at night). These are common presenting symptoms of chronic and cardiogenic pulmonary edema due to left ventricular failure. The development of pulmonary edema may be associated with symptoms and signs of "fluid overload" in the lungs; this is a non-specific term to describe the manifestations of right ventricular failure on the rest of the body. These symptoms may include peripheral edema (swelling of the legs, in general, of the "pitting" variety, wherein the skin is slow to return to normal when pressed upon due to fluid), raised jugular venous pressure and hepatomegaly , where the liver is excessively enlarged and may be tender or even pulsatile. Additional symptoms such as fever, low blood pressure, injuries or burns may be present and can help characterize the cause and subsequent treatment strategies.There is no single test for confirming that breathlessness is caused by pulmonary edema – there are many causes of shortness of breath ; but there are methods to suggest a high probability of an edema. Low oxygen saturation in blood and disturbed arterial blood gas readings support the proposed diagnosis by suggesting a pulmonary shunt . Blood tests are performed for electrolytes (sodium, potassium) and markers of renal function (creatinine, urea). Elevated creatine levels may suggest a cardiogenic cause of pulmonary edema. Liver enzymes , inflammatory markers (usually C-reactive protein ) and a complete blood count as well as coagulation studies (PT, aPTT) are also typically requested as further diagnosis. Elevated white blood cell count ( WBC ) may suggest a non-cardiogenic cause such as sepsis or infection. B-type natriuretic peptide (BNP) is available in many hospitals, sometimes even as a point-of-care test. Low levels of BNP (<100 pg/ml) suggest a cardiac cause is unlikely, and suggest noncardiogenic pulmonary edema. Chest X-ray has been used for many years to diagnose pulmonary edema due to its wide availability and relatively cheap cost. A chest X-ray will show fluid in the alveolar walls, Kerley B lines , increased vascular shadowing in a classical batwing peri- hilum pattern, upper lobe diversion (biased blood flow to the superior parts instead of inferior parts of the lung), and possibly pleural effusions . In contrast, patchy alveolar infiltrates are more typically associated with noncardiogenic edema. Lung ultrasounds , employed by a healthcare provider at the point of care, is also a useful tool to diagnose pulmonary edema; not only is it accurate, but it may quantify the degree of lung water, track changes over time, and differentiate between cardiogenic and non-cardiogenic edema. Lung ultrasound is recommended as the first-line method due to its wide availability, ability to be performed bedside, and wide diagnostic utility for other similar diseases. Especially in the case of cardiogenic pulmonary edema, urgent echocardiography may strengthen the diagnosis by demonstrating impaired left ventricular function, high central venous pressures and high pulmonary artery pressures leading to pulmonary edema.Low oxygen saturation in blood and disturbed arterial blood gas readings support the proposed diagnosis by suggesting a pulmonary shunt . Blood tests are performed for electrolytes (sodium, potassium) and markers of renal function (creatinine, urea). Elevated creatine levels may suggest a cardiogenic cause of pulmonary edema. Liver enzymes , inflammatory markers (usually C-reactive protein ) and a complete blood count as well as coagulation studies (PT, aPTT) are also typically requested as further diagnosis. Elevated white blood cell count ( WBC ) may suggest a non-cardiogenic cause such as sepsis or infection. B-type natriuretic peptide (BNP) is available in many hospitals, sometimes even as a point-of-care test. Low levels of BNP (<100 pg/ml) suggest a cardiac cause is unlikely, and suggest noncardiogenic pulmonary edema. Chest X-ray has been used for many years to diagnose pulmonary edema due to its wide availability and relatively cheap cost. A chest X-ray will show fluid in the alveolar walls, Kerley B lines , increased vascular shadowing in a classical batwing peri- hilum pattern, upper lobe diversion (biased blood flow to the superior parts instead of inferior parts of the lung), and possibly pleural effusions . In contrast, patchy alveolar infiltrates are more typically associated with noncardiogenic edema. Lung ultrasounds , employed by a healthcare provider at the point of care, is also a useful tool to diagnose pulmonary edema; not only is it accurate, but it may quantify the degree of lung water, track changes over time, and differentiate between cardiogenic and non-cardiogenic edema. Lung ultrasound is recommended as the first-line method due to its wide availability, ability to be performed bedside, and wide diagnostic utility for other similar diseases. Especially in the case of cardiogenic pulmonary edema, urgent echocardiography may strengthen the diagnosis by demonstrating impaired left ventricular function, high central venous pressures and high pulmonary artery pressures leading to pulmonary edema.In those with underlying heart or lung disease, effective control of congestive and respiratory symptoms can help prevent pulmonary edema. Dexamethasone is in widespread use for the prevention of high altitude pulmonary edema . Sildenafil is used as a preventive treatment for altitude-induced pulmonary edema and pulmonary hypertension. Sildenafil's mechanism of action is via phosphodiesterase inhibition which raises cGMP, resulting in pulmonary arterial vasodilation and inhibition of smooth muscle cell proliferation and indirectly fluid formation in the lungs. While this effect has only recently been discovered, sildenafil is already becoming an accepted treatment for this condition, in particular in situations where the standard treatment of rapid descent (acclimatization) has been delayed for some reason. The initial management of pulmonary edema, irrespective of the type or cause, is supporting vital functions while edema lasts. Hypoxia may require supplementary oxygen to balance blood oxygen levels, but if this is insufficient then again mechanical ventilation may be required to prevent complications caused by hypoxia. Therefore, if the level of consciousness is decreased it may be required to proceed to tracheal intubation and mechanical ventilation to prevent airway compromise. Treatment of the underlying cause is the next priority; pulmonary edema secondary to infection, for instance, would require the administration of appropriate antibiotics or antivirals . Acute cardiogenic pulmonary edema often responds rapidly to medical treatment. Positioning upright may relieve symptoms. A loop diuretic such as furosemide (or Lasix®) is administered, often together with morphine to reduce respiratory distress. Both diuretic and morphine may have vasodilator effects, but specific vasodilators may be used (particularly intravenous glyceryl trinitrate or ISDN ) provided the blood pressure is adequate. Continuous positive airway pressure and bilevel positive airway pressure (CPAP/BiPAP) has been demonstrated to reduce mortality and the need of mechanical ventilation in people with severe cardiogenic pulmonary edema. It is possible for cardiogenic pulmonary edema to occur together with cardiogenic shock , in which the cardiac output is insufficient to sustain an adequate blood pressure to the lungs. This can be treated with inotropic agents or by intra-aortic balloon pump , but this is regarded as temporary treatment while the underlying cause is addressed and the lungs recover. Acute cardiogenic pulmonary edema often responds rapidly to medical treatment. Positioning upright may relieve symptoms. A loop diuretic such as furosemide (or Lasix®) is administered, often together with morphine to reduce respiratory distress. Both diuretic and morphine may have vasodilator effects, but specific vasodilators may be used (particularly intravenous glyceryl trinitrate or ISDN ) provided the blood pressure is adequate. Continuous positive airway pressure and bilevel positive airway pressure (CPAP/BiPAP) has been demonstrated to reduce mortality and the need of mechanical ventilation in people with severe cardiogenic pulmonary edema. It is possible for cardiogenic pulmonary edema to occur together with cardiogenic shock , in which the cardiac output is insufficient to sustain an adequate blood pressure to the lungs. This can be treated with inotropic agents or by intra-aortic balloon pump , but this is regarded as temporary treatment while the underlying cause is addressed and the lungs recover. As pulmonary edema has a wide variety of causes and presentations, the outcome or prognosis is often disease-dependent and more accurately described in relation to the associated syndrome. It is a major health problem, with one large review stating an incidence of 7.6% with an associated in hospital mortality rate of 11.9%. Generally, pulmonary edema is associated with a poor prognosis with a 50% survival rate at one year, and 85% mortality at six years.

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Acute hemorrhagic fever syndrome

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Subarachnoid hemorrhage

Subarachnoid hemorrhage ( SAH ) is bleeding into the subarachnoid space —the area between the arachnoid membrane and the pia mater surrounding the brain . Symptoms may include a severe headache of rapid onset , vomiting, decreased level of consciousness , fever , weakness, numbness, and sometimes seizures . Neck stiffness or neck pain are also relatively common. In about a quarter of people a small bleed with resolving symptoms occurs within a month of a larger bleed. SAH may occur as a result of a head injury or spontaneously, usually from a ruptured cerebral aneurysm . Risk factors for spontaneous cases include high blood pressure , smoking, family history, alcoholism, and cocaine use. Generally, the diagnosis can be determined by a CT scan of the head if done within six hours of symptom onset. Occasionally, a lumbar puncture is also required. After confirmation further tests are usually performed to determine the underlying cause. Treatment is by prompt neurosurgery or endovascular coiling . Medications such as labetalol may be required to lower the blood pressure until repair can occur. Efforts to treat fevers are also recommended. Nimodipine , a calcium channel blocker , is frequently used to prevent vasospasm . The routine use of medications to prevent further seizures is of unclear benefit. Nearly half of people with a SAH due to an underlying aneurysm die within 30 days and about a third who survive have ongoing problems. Between ten and fifteen percent die before reaching a hospital. Spontaneous SAH occurs in about one per 10,000 people per year. Females are more commonly affected than males. While it becomes more common with age, about 50% of people present under 55 years old. It is a form of stroke and comprises about 5 percent of all strokes. Surgery for aneurysms was introduced in the 1930s. Since the 1990s many aneurysms are treated by a less invasive procedure called endovascular coiling , which is carried out through a large blood vessel. A true subarachnoid hemorrhage may be confused with a pseudosubarachnoid hemorrhage , an apparent increased attenuation on CT scans within the basal cisterns that mimics a true subarachnoid hemorrhage. This occurs in cases of severe cerebral edema , such as by cerebral hypoxia . It may also occur due to intrathecally administered contrast material , leakage of high-dose intravenous contrast material into the subarachnoid spaces , or in patients with cerebral venous sinus thrombosis , severe meningitis , leptomeningeal carcinomatosis , intracranial hypotension , cerebellar infarctions , or bilateral subdural hematomas . The classic symptom of subarachnoid hemorrhage is thunderclap headache (a headache described as "like being kicked in the head", or the "worst ever", developing over seconds to minutes). This headache often pulsates towards the occiput (the back of the head). About one-third of people have no symptoms apart from the characteristic headache, and about one in ten people who seek medical care with this symptom are later diagnosed with a subarachnoid hemorrhage. Vomiting may be present, and 1 in 14 have seizures . Confusion , decreased level of consciousness or coma may be present, as may neck stiffness and other signs of meningism . Neck stiffness usually presents six hours after initial onset of SAH. Isolated dilation of a pupil and loss of the pupillary light reflex may reflect brain herniation as a result of rising intracranial pressure (pressure inside the skull). Intraocular hemorrhage (bleeding into the eyeball) may occur in response to the raised pressure: subhyaloid hemorrhage (bleeding under the hyaloid membrane , which envelops the vitreous body of the eye) and vitreous hemorrhage may be visible on fundoscopy . This is known as Terson syndrome (occurring in 3–13 percent of cases) and is more common in more severe SAH. Oculomotor nerve abnormalities (affected eye looking downward and outward and inability to lift the eyelid on the same side ) or palsy (loss of movement) may indicate bleeding from the posterior communicating artery . Seizures are more common if the hemorrhage is from an aneurysm; it is otherwise difficult to predict the site and origin of the hemorrhage from the symptoms. SAH in a person known to have seizures is often diagnostic of a cerebral arteriovenous malformation . The combination of intracerebral hemorrhage and raised intracranial pressure (if present) leads to a "sympathetic surge", i.e. over-activation of the sympathetic system. This is thought to occur through two mechanisms, a direct effect on the medulla that leads to activation of the descending sympathetic nervous system and a local release of inflammatory mediators that circulate to the peripheral circulation where they activate the sympathetic system. As a consequence of the sympathetic surge there is a sudden increase in blood pressure ; mediated by increased contractility of the ventricle and increased vasoconstriction leading to increased systemic vascular resistance . The consequences of this sympathetic surge can be sudden, severe, and are frequently life-threatening. The high plasma concentrations of adrenaline also may cause cardiac arrhythmias (irregularities in the heart rate and rhythm), electrocardiographic changes (in 27 percent of cases) and cardiac arrest (in 3 percent of cases) may occur rapidly after the onset of hemorrhage. A further consequence of this process is neurogenic pulmonary edema , where a process of increased pressure within the pulmonary circulation causes leaking of fluid from the pulmonary capillaries into the air spaces, the alveoli , of the lung. Subarachnoid hemorrhage may also occur in people who have had a head injury. Symptoms may include headache, decreased level of consciousness and hemiparesis (weakness of one side of the body). SAH is a frequent occurrence in traumatic brain injury and carries a poor prognosis if it is associated with deterioration in the level of consciousness. While thunderclap headache is the characteristic symptom of subarachnoid hemorrhage, less than 10% of those with concerning symptoms have SAH on investigations. A number of other causes may need to be considered. Most cases of SAH are due to trauma such as a blow to the head. Traumatic SAH usually occurs near the site of a skull fracture or intracerebral contusion . It often happens in the setting of other forms of traumatic brain injury. In these cases prognosis is poorer; however, it is unclear if this is a direct result of the SAH or whether the presence of subarachnoid blood is simply an indicator of a more severe head injury. In 85 percent of spontaneous cases the cause is a cerebral aneurysm —a weakness in the wall of one of the arteries in the brain that becomes enlarged. They tend to be located in the circle of Willis and its branches. While most cases are due to bleeding from small aneurysms, larger aneurysms (which are less common) are more likely to rupture. Aspirin also appears to increase the risk. In 15–20 percent of cases of spontaneous SAH, no aneurysm is detected on the first angiogram . About half of these are attributed to non-aneurysmal perimesencephalic hemorrhage, in which the blood is limited to the subarachnoid spaces around the midbrain (i.e. mesencephalon). In these, the origin of the blood is uncertain. The remainder are due to other disorders affecting the blood vessels (such as cerebral arteriovenous malformations ), disorders of the blood vessels in the spinal cord , and bleeding into various tumors . Cocaine abuse and sickle cell anemia (usually in children) and, rarely, anticoagulant therapy, problems with blood clotting and pituitary apoplexy can also result in SAH. Dissection of the vertebral artery , usually caused by trauma, can lead to subarachnoid hemorrhage if the dissection involves the part of the vessel inside the skull. Cerebral vasospasm is one of the complications caused by subarachnoid hemorrhage. It usually happens from the third day after the aneurysm event, and reaches its peak on 5th to 7th day. There are several mechanisms proposed for this complication. Blood products released from subarachnoid hemorrhage stimulates the tyrosine kinase pathway causing the release of calcium ions from intracellular storage, resulting in smooth muscle contraction of cerebral arteries. Oxyhaemoglobin in cerebrospinal fluid (CSF) causes vasoconstriction by increasing free radicals , endothelin-1 , prostaglandin and reducing the level of nitric oxide and prostacyclin . Besides, the disturbances of autonomic nervous system innervating cerebral arteries is also thought to cause vasospasm. As only 10 percent of people admitted to the emergency department with a thunderclap headache are having an SAH, other possible causes are usually considered simultaneously, such as meningitis , migraine , and cerebral venous sinus thrombosis . Intracerebral hemorrhage , in which bleeding occurs within the brain itself, is twice as common as SAH and is often misdiagnosed as the latter. It is not unusual for SAH to be initially misdiagnosed as a migraine or tension headache , which can lead to a delay in obtaining a CT scan. In a 2004 study, this occurred in 12 percent of all cases and was more likely in people who had smaller hemorrhages and no impairment in their mental status. The delay in diagnosis led to a worse outcome. In some people, the headache resolves by itself, and no other symptoms are present. This type of headache is referred to as "sentinel headache", because it is presumed to result from a small leak (a "warning leak") from an aneurysm. A sentinel headache still warrants investigations with CT scan and lumbar puncture, as further bleeding may occur in the subsequent three weeks. The initial steps for evaluating a person with a suspected subarachnoid hemorrhage are obtaining a medical history and performing a physical examination . The diagnosis cannot be made on clinical grounds alone and in general medical imaging and possibly a lumbar puncture is required to confirm or exclude bleeding. The modality of choice is computed tomography (CT scan), without contrast , of the brain. This has a high sensitivity and will correctly identify 98.7% of cases within six hours of the onset of symptoms. A CT scan can rule out the diagnosis in someone with a normal neurological exam if done within six hours. Its efficacy declines thereafter, and magnetic resonance imaging (MRI) is more sensitive than CT after several days. After a subarachnoid hemorrhage is confirmed, its origin needs to be determined. If the bleeding is likely to have originated from an aneurysm (as determined by the CT scan appearance), the choice is between cerebral angiography (injecting radiocontrast through a catheter to the brain arteries) and CT angiography (visualizing blood vessels with radiocontrast on a CT scan) to identify aneurysms. Catheter angiography also offers the possibility of coiling an aneurysm (see below). In emergency department patients complaining of acute-onset headache without significant risk factors for SAH, evidence suggests that CT scanning of the head followed by CT angiography can reliably exclude SAH without the need for a lumbar puncture. The risk of missing an aneurysmal bleed as the cause of SAH with this approach is less than 1%. Lumbar puncture , in which cerebrospinal fluid (CSF) is removed from the subarachnoid space of the spinal canal using a hypodermic needle , shows evidence of bleeding in three percent of people in whom a non-contrast CT was found normal. A lumbar puncture or CT scan with contrast is therefore regarded as mandatory in people with suspected SAH when imaging is delayed to after six hours from the onset of symptoms and is negative. At least three tubes of CSF are collected. If an elevated number of red blood cells is present equally in all bottles, this indicates a subarachnoid hemorrhage. If the number of cells decreases per bottle, it is more likely that it is due to damage to a small blood vessel during the procedure (known as a "traumatic tap"). While there is no official cutoff for red blood cells in the CSF no documented cases have occurred at less than "a few hundred cells" per high-powered field. The CSF sample is also examined for xanthochromia —the yellow appearance of centrifugated fluid. This can be determined by spectrophotometry (measuring the absorption of particular wavelengths of light) or visual examination. It is unclear which method is superior. Xanthochromia remains a reliable ways to detect SAH several days after the onset of headache. An interval of at least 12 hours between the onset of the headache and lumbar puncture is required, as it takes several hours for the hemoglobin from the red blood cells to be metabolized into bilirubin . Electrocardiographic changes are relatively common in subarachnoid hemorrhage, occurring in 40–70 percent of cases. They may include QT prolongation , Q waves , cardiac dysrhythmias , and ST elevation that mimics a heart attack . Also one of the characteristic ECG changes that could be found in patients with subarachnoid hemorrhage, is the J waves or Osborn waves, which are positive deflections that occur at the junction between QRS complexes and ST segments , where the S point, also known as the J point, has a myocardial infarction-like elevation. J waves or Osborn waves, which represent an early repolarization and delayed depolarization of the heart ventricles, are thought to be caused by the high catecholamines surge released in patients with subarachnoid hemorrhage or brain damage, the issue that might lead to ventricular fibrillation and cardiac arrest in unmanaged patients. There are several grading scales available for SAH. The Glasgow Coma Scale (GCS) is ubiquitously used for assessing consciousness. Its three specialized scores are used to evaluate SAH; in each, a higher number is associated with a worse outcome. These scales have been derived by retrospectively matching characteristics of people with their outcomes. The first widely used scale for neurological condition following SAH was published by Botterell and Cannell in 1956 and referred to as the Botterell Grading Scale. This was modified by Hunt and Hess in 1968: The Fisher Grade classifies the appearance of subarachnoid hemorrhage on CT scan. This scale has been modified by Claassen and coworkers, reflecting the additive risk from SAH size and accompanying intraventricular hemorrhage (0 – none; 1 – minimal SAH w/o IVH; 2 – minimal SAH with IVH; 3 – thick SAH w/o IVH; 4 – thick SAH with IVH);. The World Federation of Neurosurgeons (WFNS) classification uses Glasgow coma score and focal neurological deficit to gauge severity of symptoms. A comprehensive classification scheme has been suggested by Ogilvy and Carter to predict outcome and gauge therapy. The system consists of five grades and it assigns one point for the presence or absence of each of five factors: age greater than 50; Hunt and Hess grade 4 or 5; Fisher scale 3 or 4; aneurysm size greater than 10 mm; and posterior circulation aneurysm 25 mm or more. The modality of choice is computed tomography (CT scan), without contrast , of the brain. This has a high sensitivity and will correctly identify 98.7% of cases within six hours of the onset of symptoms. A CT scan can rule out the diagnosis in someone with a normal neurological exam if done within six hours. Its efficacy declines thereafter, and magnetic resonance imaging (MRI) is more sensitive than CT after several days. After a subarachnoid hemorrhage is confirmed, its origin needs to be determined. If the bleeding is likely to have originated from an aneurysm (as determined by the CT scan appearance), the choice is between cerebral angiography (injecting radiocontrast through a catheter to the brain arteries) and CT angiography (visualizing blood vessels with radiocontrast on a CT scan) to identify aneurysms. Catheter angiography also offers the possibility of coiling an aneurysm (see below). In emergency department patients complaining of acute-onset headache without significant risk factors for SAH, evidence suggests that CT scanning of the head followed by CT angiography can reliably exclude SAH without the need for a lumbar puncture. The risk of missing an aneurysmal bleed as the cause of SAH with this approach is less than 1%. After a subarachnoid hemorrhage is confirmed, its origin needs to be determined. If the bleeding is likely to have originated from an aneurysm (as determined by the CT scan appearance), the choice is between cerebral angiography (injecting radiocontrast through a catheter to the brain arteries) and CT angiography (visualizing blood vessels with radiocontrast on a CT scan) to identify aneurysms. Catheter angiography also offers the possibility of coiling an aneurysm (see below). In emergency department patients complaining of acute-onset headache without significant risk factors for SAH, evidence suggests that CT scanning of the head followed by CT angiography can reliably exclude SAH without the need for a lumbar puncture. The risk of missing an aneurysmal bleed as the cause of SAH with this approach is less than 1%. Lumbar puncture , in which cerebrospinal fluid (CSF) is removed from the subarachnoid space of the spinal canal using a hypodermic needle , shows evidence of bleeding in three percent of people in whom a non-contrast CT was found normal. A lumbar puncture or CT scan with contrast is therefore regarded as mandatory in people with suspected SAH when imaging is delayed to after six hours from the onset of symptoms and is negative. At least three tubes of CSF are collected. If an elevated number of red blood cells is present equally in all bottles, this indicates a subarachnoid hemorrhage. If the number of cells decreases per bottle, it is more likely that it is due to damage to a small blood vessel during the procedure (known as a "traumatic tap"). While there is no official cutoff for red blood cells in the CSF no documented cases have occurred at less than "a few hundred cells" per high-powered field. The CSF sample is also examined for xanthochromia —the yellow appearance of centrifugated fluid. This can be determined by spectrophotometry (measuring the absorption of particular wavelengths of light) or visual examination. It is unclear which method is superior. Xanthochromia remains a reliable ways to detect SAH several days after the onset of headache. An interval of at least 12 hours between the onset of the headache and lumbar puncture is required, as it takes several hours for the hemoglobin from the red blood cells to be metabolized into bilirubin . Electrocardiographic changes are relatively common in subarachnoid hemorrhage, occurring in 40–70 percent of cases. They may include QT prolongation , Q waves , cardiac dysrhythmias , and ST elevation that mimics a heart attack . Also one of the characteristic ECG changes that could be found in patients with subarachnoid hemorrhage, is the J waves or Osborn waves, which are positive deflections that occur at the junction between QRS complexes and ST segments , where the S point, also known as the J point, has a myocardial infarction-like elevation. J waves or Osborn waves, which represent an early repolarization and delayed depolarization of the heart ventricles, are thought to be caused by the high catecholamines surge released in patients with subarachnoid hemorrhage or brain damage, the issue that might lead to ventricular fibrillation and cardiac arrest in unmanaged patients. There are several grading scales available for SAH. The Glasgow Coma Scale (GCS) is ubiquitously used for assessing consciousness. Its three specialized scores are used to evaluate SAH; in each, a higher number is associated with a worse outcome. These scales have been derived by retrospectively matching characteristics of people with their outcomes. The first widely used scale for neurological condition following SAH was published by Botterell and Cannell in 1956 and referred to as the Botterell Grading Scale. This was modified by Hunt and Hess in 1968: The Fisher Grade classifies the appearance of subarachnoid hemorrhage on CT scan. This scale has been modified by Claassen and coworkers, reflecting the additive risk from SAH size and accompanying intraventricular hemorrhage (0 – none; 1 – minimal SAH w/o IVH; 2 – minimal SAH with IVH; 3 – thick SAH w/o IVH; 4 – thick SAH with IVH);. The World Federation of Neurosurgeons (WFNS) classification uses Glasgow coma score and focal neurological deficit to gauge severity of symptoms. A comprehensive classification scheme has been suggested by Ogilvy and Carter to predict outcome and gauge therapy. The system consists of five grades and it assigns one point for the presence or absence of each of five factors: age greater than 50; Hunt and Hess grade 4 or 5; Fisher scale 3 or 4; aneurysm size greater than 10 mm; and posterior circulation aneurysm 25 mm or more. Screening for aneurysms is not performed on a population level; because they are relatively rare, it would not be cost-effective . However, if someone has two or more first-degree relatives who have had an aneurysmal subarachnoid hemorrhage, screening may be worthwhile. Autosomal dominant polycystic kidney disease (ADPKD), a hereditary kidney condition, is known to be associated with cerebral aneurysms in 8 percent of cases, but most such aneurysms are small and therefore unlikely to rupture. As a result, screening is only recommended in families with ADPKD where one family member has had a ruptured aneurysm. An aneurysm may be detected incidentally on brain imaging; this presents a conundrum, as all treatments for cerebral aneurysms are associated with potential complications. The International Study of Unruptured Intracranial Aneurysms (ISUIA) provided prognostic data both in people having previously had a subarachnoid hemorrhage and people who had aneurysms detected by other means. Those having previously had a SAH were more likely to bleed from other aneurysms. In contrast, those having never bled and had small aneurysms (smaller than 10 mm) were very unlikely to have a SAH and were likely to sustain harm from attempts to repair these aneurysms. On the basis of the ISUIA and other studies, it is now recommended that people are considered for preventive treatment only if they have a reasonable life expectancy and have aneurysms that are highly likely to rupture. Moreover, there is only limited evidence that endovascular treatment of unruptured aneurysms is actually beneficial. Management involves general measures to stabilize the person while also using specific investigations and treatments. These include the prevention of rebleeding by obliterating the bleeding source, prevention of a phenomenon known as vasospasm , and prevention and treatment of complications. Stabilizing the person is the first priority. Those with a depressed level of consciousness may need to be intubated and mechanically ventilated . Blood pressure, pulse , respiratory rate , and Glasgow Coma Scale are monitored frequently. Once the diagnosis is confirmed, admission to an intensive care unit may be preferable, especially since 15 percent may have further bleeding soon after admission. Nutrition is an early priority, mouth or nasogastric tube feeding being preferable over parenteral routes. In general, pain control is restricted to less-sedating agents such as codeine , as sedation may impact on the mental status and thus interfere with the ability to monitor the level of consciousness. Deep vein thrombosis is prevented with compression stockings , intermittent pneumatic compression of the calves , or both. A bladder catheter is usually inserted to monitor fluid balance. Benzodiazepines may be administered to help relieve distress. Antiemetic drugs should be given to awake persons. People with poor clinical grade on admission, acute neurologic deterioration, or progressive enlargement of ventricles on CT scan are, in general, indications for the placement of an external ventricular drain by a neurosurgeon. The external ventricular drain may be inserted at the bedside or in the operating room. In either case, strict aseptic technique must be maintained during insertion. In people with aneurysmal subarachnoid hemorrhage the EVD is used to remove cerebrospinal fluid , blood, and blood byproducts that increase intracranial pressure and may increase the risk for cerebral vasospasm . Efforts to keep a person's systolic blood pressure somewhere between 140 and 160 mmHg is generally recommended. Medications to achieve this may include labetalol or nicardipine . People whose CT scan shows a large hematoma , depressed level of consciousness, or focal neurologic signs may benefit from urgent surgical removal of the blood or occlusion of the bleeding site. The remainder are stabilized more extensively and undergo a transfemoral angiogram or CT angiogram later. It is hard to predict who will have a rebleed, yet it may happen at any time and carries a dismal prognosis. After the first 24 hours have passed, rebleeding risk remains around 40 percent over the subsequent four weeks, suggesting that interventions should be aimed at reducing this risk as soon as possible. Some predictors of early rebleeding are high systolic blood pressure, the presence of a hematoma in the brain or ventricles, poor Hunt-Hess grade (III-IV), aneurysms in the posterior circulation, and an aneurysm >10 mm in size. If a cerebral aneurysm is identified on angiography, two measures are available to reduce the risk of further bleeding from the same aneurysm: clipping and coiling . Clipping requires a craniotomy (opening of the skull) to locate the aneurysm, followed by the placement of clips around the neck of the aneurysm. Coiling is performed through the large blood vessels (endovascularly): a catheter is inserted into the femoral artery in the groin and advanced through the aorta to the arteries (both carotid arteries and both vertebral arteries ) that supply the brain. When the aneurysm has been located, platinum coils are deployed that cause a blood clot to form in the aneurysm, obliterating it. The decision as to which treatment is undertaken is typically made by a multidisciplinary team consisting of a neurosurgeon , neuroradiologist , and often other health professionals. In general, the decision between clipping and coiling is made on the basis of the location of the aneurysm, its size and the condition of the person. Aneurysms of the middle cerebral artery and its related vessels are hard to reach with angiography and tend to be amenable to clipping. Those of the basilar artery and posterior cerebral artery are hard to reach surgically and are more accessible for endovascular management. These approaches are based on general experience, and the only randomized controlled trial directly comparing the different modalities was performed in relatively well people with small (less than 10 mm) aneurysms of the anterior cerebral artery and anterior communicating artery (together the "anterior circulation"), who constitute about 20 percent of all people with aneurysmal SAH. This trial, the International Subarachnoid Aneurysm Trial (ISAT), showed that in this group the likelihood of death or being dependent on others for activities of daily living was reduced (7.4 percent absolute risk reduction , 23.5 percent relative risk reduction) if endovascular coiling was used as opposed to surgery. The main drawback of coiling is the possibility that the aneurysm will recur; this risk is extremely small in the surgical approach. In ISAT, 8.3 percent needed further treatment in the longer term. Hence, people who have undergone coiling are typically followed up for many years afterwards with angiography or other measures to ensure recurrence of aneurysms is identified early. Other trials have also found a higher rate of recurrence necessitating further treatments. Vasospasm , in which the blood vessels constrict and thus restrict blood flow , is a serious complication of SAH. It can cause ischemic brain injury (referred to as "delayed ischemia") and permanent brain damage due to lack of oxygen in parts of the brain. It can be fatal if severe. Delayed ischemia is characterized by new neurological symptoms, and can be confirmed by transcranial doppler or cerebral angiography. About one third of people admitted with subarachnoid hemorrhage will have delayed ischemia, and half of those have permanent damage as a result. It is possible to screen for the development of vasospasm with transcranial Doppler every 24–48 hours. A blood flow velocity of more than 120 centimeters per second is suggestive of vasospasm. The pathogenesis of cerebral vasospasm following subarachnoid hemorrhage is attributed to the higher levels of endothelin 1 , a potent vasoconstrictor, and the lower levels of endothelial NOS (eNOS), a potent vasodilator. Both of which are produced from a series of events that begin from the inflammatory reaction caused by the products released from erythrocytes' degradation. Following subarachnoid hemorrhage, different clotting factors and blood products are released into the surrounding perivascular spaces known as ( Virchow-Robin spaces ). The released clotting factors like; fibrinopeptides , thromboxane A2 and others lead to microthrombosis around near vessels that leads to extrinsic vasoconstriction of these vessels. Besides that extrinsic vasoconstriction, the erythrocytes' degradation products like; bilirubin and oxyhemoglobin lead to neuroinflammation that in turn increases the production of reactive oxygen species (ROS) which increases and decreases the production of endothelin 1 and endothelial NOS, respectively, the issue that yields in intrinsic vasoconstriction of the neighboring blood vessels and results in cerebral ischemia if left untreated. The use of calcium channel blockers , thought to be able to prevent the spasm of blood vessels by preventing calcium from entering smooth muscle cells, has been proposed for prevention. The calcium channel blocker nimodipine when taken by mouth improves outcome if given between the fourth and twenty-first day after the bleeding, even if it does not reduce the amount of vasospasm detected on angiography. It is the only Food and Drug Administration (FDA)-approved drug for treating cerebral vasospasm. In traumatic subarachnoid hemorrhage, nimodipine does not affect long-term outcome, and is not recommended. Other calcium channel blockers and magnesium sulfate have been studied, but are not presently recommended; neither is there any evidence that shows benefit if nimodipine is given intravenously. Nimodipine is readily authorized in the form of tablets and solution for infusion for the prevention and treatment of complications due to vasospasm following subarachnoid hemorrhage. Another sustained formulation of nimodipine administered via an external ventricular drain (EVD), called EG-1962, is also available. In contrast to the tablets and solution formulations of Nimodipine which require an administration every 4hrs for a total of 21 days, the sustained formulation, EG-1962, needs to be administered once directly into the ventricles. The CSF concentrations from EG-1962, however, were at least 2 orders of magnitude higher than those with oral nimodipine. These results supported a phase 3 study that demonstrated a favorable safety profile for EG-1962 but yielded inconclusive efficacy results due to notable differences in clinical outcome based on baseline disease severity. Some older studies have suggested that statin therapy might reduce vasospasm, but a subsequent meta-analysis including further trials did not demonstrate benefit on either vasospasm or outcomes. While corticosteroids with mineralocorticoid activity may help prevent vasospasm their use does not appear to change outcomes. A protocol referred to as "triple H" is often used as a measure to treat vasospasm when it causes symptoms; this is the use of intravenous fluids to achieve a state of hypertension (high blood pressure), hypervolemia (excess fluid in the circulation), and hemodilution (mild dilution of the blood). Evidence for this approach is inconclusive; no randomized controlled trials have been undertaken to demonstrate its effect. If the symptoms of delayed ischemia do not improve with medical treatment, angiography may be attempted to identify the sites of vasospasms and administer vasodilator medication (drugs that relax the blood vessel wall) directly into the artery. Angioplasty (opening the constricted area with a balloon) may also be performed. Hydrocephalus (obstruction of the flow of cerebrospinal fluid) may complicate SAH in both the short and long term. It is detected on CT scanning, on which there is enlargement of the lateral ventricles . If the level of consciousness is decreased, drainage of the excess fluid is performed by therapeutic lumbar puncture, extraventricular drain (a temporary device inserted into one of the ventricles), or occasionally a permanent shunt . Relief of hydrocephalus can lead to an enormous improvement in a person's condition. Fluctuations in blood pressure and electrolyte imbalance , as well as pneumonia and cardiac decompensation occur in about half the hospitalized persons with SAH and may worsen prognosis. Seizures occur during the hospital stay in about a third of cases. People have often been treated with preventative antiepileptic medications . This is controversial and not based on good evidence . In some studies, use of these medications was associated with a worse prognosis; although it is unclear whether this might be because the drugs themselves actually cause harm, or because they are used more often in persons with a poorer prognosis. There is a possibility of a gastric hemorrhage due to stress ulcers. Efforts to keep a person's systolic blood pressure somewhere between 140 and 160 mmHg is generally recommended. Medications to achieve this may include labetalol or nicardipine . People whose CT scan shows a large hematoma , depressed level of consciousness, or focal neurologic signs may benefit from urgent surgical removal of the blood or occlusion of the bleeding site. The remainder are stabilized more extensively and undergo a transfemoral angiogram or CT angiogram later. It is hard to predict who will have a rebleed, yet it may happen at any time and carries a dismal prognosis. After the first 24 hours have passed, rebleeding risk remains around 40 percent over the subsequent four weeks, suggesting that interventions should be aimed at reducing this risk as soon as possible. Some predictors of early rebleeding are high systolic blood pressure, the presence of a hematoma in the brain or ventricles, poor Hunt-Hess grade (III-IV), aneurysms in the posterior circulation, and an aneurysm >10 mm in size. If a cerebral aneurysm is identified on angiography, two measures are available to reduce the risk of further bleeding from the same aneurysm: clipping and coiling . Clipping requires a craniotomy (opening of the skull) to locate the aneurysm, followed by the placement of clips around the neck of the aneurysm. Coiling is performed through the large blood vessels (endovascularly): a catheter is inserted into the femoral artery in the groin and advanced through the aorta to the arteries (both carotid arteries and both vertebral arteries ) that supply the brain. When the aneurysm has been located, platinum coils are deployed that cause a blood clot to form in the aneurysm, obliterating it. The decision as to which treatment is undertaken is typically made by a multidisciplinary team consisting of a neurosurgeon , neuroradiologist , and often other health professionals. In general, the decision between clipping and coiling is made on the basis of the location of the aneurysm, its size and the condition of the person. Aneurysms of the middle cerebral artery and its related vessels are hard to reach with angiography and tend to be amenable to clipping. Those of the basilar artery and posterior cerebral artery are hard to reach surgically and are more accessible for endovascular management. These approaches are based on general experience, and the only randomized controlled trial directly comparing the different modalities was performed in relatively well people with small (less than 10 mm) aneurysms of the anterior cerebral artery and anterior communicating artery (together the "anterior circulation"), who constitute about 20 percent of all people with aneurysmal SAH. This trial, the International Subarachnoid Aneurysm Trial (ISAT), showed that in this group the likelihood of death or being dependent on others for activities of daily living was reduced (7.4 percent absolute risk reduction , 23.5 percent relative risk reduction) if endovascular coiling was used as opposed to surgery. The main drawback of coiling is the possibility that the aneurysm will recur; this risk is extremely small in the surgical approach. In ISAT, 8.3 percent needed further treatment in the longer term. Hence, people who have undergone coiling are typically followed up for many years afterwards with angiography or other measures to ensure recurrence of aneurysms is identified early. Other trials have also found a higher rate of recurrence necessitating further treatments. Vasospasm , in which the blood vessels constrict and thus restrict blood flow , is a serious complication of SAH. It can cause ischemic brain injury (referred to as "delayed ischemia") and permanent brain damage due to lack of oxygen in parts of the brain. It can be fatal if severe. Delayed ischemia is characterized by new neurological symptoms, and can be confirmed by transcranial doppler or cerebral angiography. About one third of people admitted with subarachnoid hemorrhage will have delayed ischemia, and half of those have permanent damage as a result. It is possible to screen for the development of vasospasm with transcranial Doppler every 24–48 hours. A blood flow velocity of more than 120 centimeters per second is suggestive of vasospasm. The pathogenesis of cerebral vasospasm following subarachnoid hemorrhage is attributed to the higher levels of endothelin 1 , a potent vasoconstrictor, and the lower levels of endothelial NOS (eNOS), a potent vasodilator. Both of which are produced from a series of events that begin from the inflammatory reaction caused by the products released from erythrocytes' degradation. Following subarachnoid hemorrhage, different clotting factors and blood products are released into the surrounding perivascular spaces known as ( Virchow-Robin spaces ). The released clotting factors like; fibrinopeptides , thromboxane A2 and others lead to microthrombosis around near vessels that leads to extrinsic vasoconstriction of these vessels. Besides that extrinsic vasoconstriction, the erythrocytes' degradation products like; bilirubin and oxyhemoglobin lead to neuroinflammation that in turn increases the production of reactive oxygen species (ROS) which increases and decreases the production of endothelin 1 and endothelial NOS, respectively, the issue that yields in intrinsic vasoconstriction of the neighboring blood vessels and results in cerebral ischemia if left untreated. The use of calcium channel blockers , thought to be able to prevent the spasm of blood vessels by preventing calcium from entering smooth muscle cells, has been proposed for prevention. The calcium channel blocker nimodipine when taken by mouth improves outcome if given between the fourth and twenty-first day after the bleeding, even if it does not reduce the amount of vasospasm detected on angiography. It is the only Food and Drug Administration (FDA)-approved drug for treating cerebral vasospasm. In traumatic subarachnoid hemorrhage, nimodipine does not affect long-term outcome, and is not recommended. Other calcium channel blockers and magnesium sulfate have been studied, but are not presently recommended; neither is there any evidence that shows benefit if nimodipine is given intravenously. Nimodipine is readily authorized in the form of tablets and solution for infusion for the prevention and treatment of complications due to vasospasm following subarachnoid hemorrhage. Another sustained formulation of nimodipine administered via an external ventricular drain (EVD), called EG-1962, is also available. In contrast to the tablets and solution formulations of Nimodipine which require an administration every 4hrs for a total of 21 days, the sustained formulation, EG-1962, needs to be administered once directly into the ventricles. The CSF concentrations from EG-1962, however, were at least 2 orders of magnitude higher than those with oral nimodipine. These results supported a phase 3 study that demonstrated a favorable safety profile for EG-1962 but yielded inconclusive efficacy results due to notable differences in clinical outcome based on baseline disease severity. Some older studies have suggested that statin therapy might reduce vasospasm, but a subsequent meta-analysis including further trials did not demonstrate benefit on either vasospasm or outcomes. While corticosteroids with mineralocorticoid activity may help prevent vasospasm their use does not appear to change outcomes. A protocol referred to as "triple H" is often used as a measure to treat vasospasm when it causes symptoms; this is the use of intravenous fluids to achieve a state of hypertension (high blood pressure), hypervolemia (excess fluid in the circulation), and hemodilution (mild dilution of the blood). Evidence for this approach is inconclusive; no randomized controlled trials have been undertaken to demonstrate its effect. If the symptoms of delayed ischemia do not improve with medical treatment, angiography may be attempted to identify the sites of vasospasms and administer vasodilator medication (drugs that relax the blood vessel wall) directly into the artery. Angioplasty (opening the constricted area with a balloon) may also be performed. Hydrocephalus (obstruction of the flow of cerebrospinal fluid) may complicate SAH in both the short and long term. It is detected on CT scanning, on which there is enlargement of the lateral ventricles . If the level of consciousness is decreased, drainage of the excess fluid is performed by therapeutic lumbar puncture, extraventricular drain (a temporary device inserted into one of the ventricles), or occasionally a permanent shunt . Relief of hydrocephalus can lead to an enormous improvement in a person's condition. Fluctuations in blood pressure and electrolyte imbalance , as well as pneumonia and cardiac decompensation occur in about half the hospitalized persons with SAH and may worsen prognosis. Seizures occur during the hospital stay in about a third of cases. People have often been treated with preventative antiepileptic medications . This is controversial and not based on good evidence . In some studies, use of these medications was associated with a worse prognosis; although it is unclear whether this might be because the drugs themselves actually cause harm, or because they are used more often in persons with a poorer prognosis. There is a possibility of a gastric hemorrhage due to stress ulcers. SAH is often associated with a poor outcome. The death rate ( mortality ) for SAH is between 40 and 50 percent, but trends for survival are improving. Of those that survive hospitalization, more than a quarter have significant restrictions in their lifestyle, and less than a fifth have no residual symptoms whatsoever. Delay in diagnosis of minor SAH (mistaking the sudden headache for migraine) contributes to poor outcome. Factors found on admission that are associated with poorer outcome include poorer neurological grade; systolic hypertension ; a previous diagnosis of heart attack or SAH; liver disease ; more blood and larger aneurysm on the initial CT scan; location of an aneurysm in the posterior circulation ; and higher age. Factors that carry a worse prognosis during the hospital stay include occurrence of delayed ischemia resulting from vasospasm , development of intracerebral hematoma , or intraventricular hemorrhage (bleeding into the ventricles of the brain) and presence of fever on the eighth day of admission. So-called "angiogram-negative subarachnoid hemorrhage", SAH that does not show an aneurysm with four-vessel angiography, carries a better prognosis than SAH with aneurysm, but it is still associated with a risk of ischemia, rebleeding, and hydrocephalus . Perimesencephalic SAH (bleeding around the mesencephalon in the brain), however, has a very low rate of rebleeding or delayed ischemia , and the prognosis of this subtype is excellent. The prognosis of head trauma is thought to be influenced in part by the location and amount of subarachnoid bleeding. It is difficult to isolate the effects of SAH from those of other aspects of traumatic brain injury; it is unknown whether the presence of subarachnoid blood actually worsens the prognosis or whether it is merely a sign that a significant trauma has occurred. People with moderate and severe traumatic brain injury who have SAH when admitted to a hospital have as much as twice the risk of dying as those who do not. They also have a higher risk of severe disability and persistent vegetative state , and traumatic SAH has been correlated with other markers of poor outcome such as post traumatic epilepsy , hydrocephalus, and longer stays in the intensive care unit. More than 90 percent of people with traumatic subarachnoid bleeding and a Glasgow Coma Score over 12 have a good outcome. There is also modest evidence that genetic factors influence the prognosis in SAH. For example, having two copies of ApoE4 (a variant of the gene encoding apolipoprotein E that also plays a role in Alzheimer's disease ) seems to increase risk for delayed ischemia and a worse outcome. The occurrence of hyperglycemia (high blood sugars) after an episode of SAH confers a higher risk of poor outcome. Neurocognitive symptoms, such as fatigue , mood disturbances, and other related symptoms, are common sequelae . Even in those who have made good neurological recovery, anxiety, depression, posttraumatic stress disorder , and cognitive impairment are common; 46 percent of people who have had a subarachnoid hemorrhage have cognitive impairment that affects their quality of life. Over 60 percent report frequent headaches. Aneurysmal subarachnoid hemorrhage may lead to damage of the hypothalamus and the pituitary gland , two areas of the brain that play a central role in hormonal regulation and production. More than a quarter of people with a previous SAH may develop hypopituitarism (deficiencies in one or more of the hypothalamic–pituitary hormones such as growth hormone , luteinizing hormone , or follicle-stimulating hormone ). SAH is also associated with SIADH and cerebral salt wasting , and is the most common cause of the latter.SAH is often associated with a poor outcome. The death rate ( mortality ) for SAH is between 40 and 50 percent, but trends for survival are improving. Of those that survive hospitalization, more than a quarter have significant restrictions in their lifestyle, and less than a fifth have no residual symptoms whatsoever. Delay in diagnosis of minor SAH (mistaking the sudden headache for migraine) contributes to poor outcome. Factors found on admission that are associated with poorer outcome include poorer neurological grade; systolic hypertension ; a previous diagnosis of heart attack or SAH; liver disease ; more blood and larger aneurysm on the initial CT scan; location of an aneurysm in the posterior circulation ; and higher age. Factors that carry a worse prognosis during the hospital stay include occurrence of delayed ischemia resulting from vasospasm , development of intracerebral hematoma , or intraventricular hemorrhage (bleeding into the ventricles of the brain) and presence of fever on the eighth day of admission. So-called "angiogram-negative subarachnoid hemorrhage", SAH that does not show an aneurysm with four-vessel angiography, carries a better prognosis than SAH with aneurysm, but it is still associated with a risk of ischemia, rebleeding, and hydrocephalus . Perimesencephalic SAH (bleeding around the mesencephalon in the brain), however, has a very low rate of rebleeding or delayed ischemia , and the prognosis of this subtype is excellent. The prognosis of head trauma is thought to be influenced in part by the location and amount of subarachnoid bleeding. It is difficult to isolate the effects of SAH from those of other aspects of traumatic brain injury; it is unknown whether the presence of subarachnoid blood actually worsens the prognosis or whether it is merely a sign that a significant trauma has occurred. People with moderate and severe traumatic brain injury who have SAH when admitted to a hospital have as much as twice the risk of dying as those who do not. They also have a higher risk of severe disability and persistent vegetative state , and traumatic SAH has been correlated with other markers of poor outcome such as post traumatic epilepsy , hydrocephalus, and longer stays in the intensive care unit. More than 90 percent of people with traumatic subarachnoid bleeding and a Glasgow Coma Score over 12 have a good outcome. There is also modest evidence that genetic factors influence the prognosis in SAH. For example, having two copies of ApoE4 (a variant of the gene encoding apolipoprotein E that also plays a role in Alzheimer's disease ) seems to increase risk for delayed ischemia and a worse outcome. The occurrence of hyperglycemia (high blood sugars) after an episode of SAH confers a higher risk of poor outcome. Neurocognitive symptoms, such as fatigue , mood disturbances, and other related symptoms, are common sequelae . Even in those who have made good neurological recovery, anxiety, depression, posttraumatic stress disorder , and cognitive impairment are common; 46 percent of people who have had a subarachnoid hemorrhage have cognitive impairment that affects their quality of life. Over 60 percent report frequent headaches. Aneurysmal subarachnoid hemorrhage may lead to damage of the hypothalamus and the pituitary gland , two areas of the brain that play a central role in hormonal regulation and production. More than a quarter of people with a previous SAH may develop hypopituitarism (deficiencies in one or more of the hypothalamic–pituitary hormones such as growth hormone , luteinizing hormone , or follicle-stimulating hormone ). SAH is also associated with SIADH and cerebral salt wasting , and is the most common cause of the latter.According to a review of 51 studies from 21 countries, the average incidence of subarachnoid hemorrhage is 9.1 per 100,000 annually. Studies from Japan and Finland show higher rates in those countries (22.7 and 19.7, respectively), for reasons that are not entirely understood. South and Central America, in contrast, have a rate of 4.2 per 100,000 on average. Although the group of people at risk for SAH is younger than the population usually affected by stroke, the risk still increases with age. Young people are much less likely than middle-age people (risk ratio 0.1, or 10 percent) to have a subarachnoid hemorrhage. The risk continues to rise with age and is 60 percent higher in the very elderly (over 85) than in those between 45 and 55. Risk of SAH is about 25 percent higher in women over 55 compared to men the same age, probably reflecting the hormonal changes that result from the menopause , such as a decrease in estrogen levels. Genetics may play a role in a person's disposition to SAH; risk is increased three- to fivefold in first-degree relatives of people having had a subarachnoid hemorrhage. But lifestyle factors are more important in determining overall risk. These risk factors are smoking , hypertension (high blood pressure), and excessive alcohol consumption . Having smoked in the past confers a doubled risk of SAH compared to those who have never smoked. Some protection of uncertain significance is conferred by caucasian ethnicity , hormone replacement therapy , and diabetes mellitus . There is likely an inverse relationship between total serum cholesterol and the risk of non-traumatic SAH, though confirmation of this association is hindered by a lack of studies. Approximately 4 percent of aneurysmal bleeds occur after sexual intercourse and 10 percent of people with SAH are bending over or lifting heavy objects at the onset of their symptoms. Overall, about 1 percent of all people have one or more cerebral aneurysms. Most of these are small and unlikely to rupture. While the clinical picture of subarachnoid hemorrhage may have been recognized by Hippocrates , the existence of cerebral aneurysms and the fact that they could rupture was not established until the 18th century. The associated symptoms were described in more detail in 1886 by Edinburgh physician Dr Byrom Bramwell . In 1924, London neurologist Sir Charles P. Symonds (1890–1978) gave a complete account of all major symptoms of subarachnoid hemorrhage, and he coined the term "spontaneous subarachnoid hemorrhage". Symonds also described the use of lumbar puncture and xanthochromia in diagnosis. The first surgical intervention was performed by Norman Dott, who was a pupil of Harvey Cushing then working in Edinburgh. He introduced the wrapping of aneurysms in the 1930s, and was an early pioneer in the use of angiograms. American neurosurgeon Dr Walter Dandy , working in Baltimore , was the first to introduce clips in 1938. Microsurgery was applied to aneurysm treatment in 1972 in order to further improve outcomes. The 1980s saw the introduction of triple H therapy as a treatment for delayed ischemia due to vasospasm , and trials with nimodipine in an attempt to prevent this complication. In 1983, the Russian neurosurgeon Zubkov and colleagues reported the first use of transluminal balloon angioplasty for vasospasm after aneurysmal SAH. The Italian neurosurgeon Dr Guido Guglielmi introduced his endovascular coil treatment in 1991.

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Acute hemorrhagic fever syndrome

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Myalgia

Myalgia is the medical term for muscle pain . Myalgia is a symptom of many diseases . The most common cause of acute myalgia is the overuse of a muscle or group of muscles ; another likely cause is viral infection , especially when there has been no trauma . Long-lasting myalgia can be caused by metabolic myopathy , some nutritional deficiencies , chronic fatigue syndrome , fibromyalgia , and amplified musculoskeletal pain syndrome .The most common causes of myalgia are overuse , injury , and strain . Myalgia might also be caused by allergies, diseases, medications, or as a response to a vaccination . Dehydration at times results in muscle pain as well, especially for people involved in extensive physical activities such as workout . Muscle pain is also a common symptom in a variety of diseases, including infectious diseases, such as influenza, muscle abscesses, Lyme disease, malaria, trichinosis or poliomyelitis; autoimmune diseases, such as celiac disease, systemic lupus erythematosus, Sjögren's syndrome or polymyositis; gastrointestinal diseases , such as non-celiac gluten sensitivity (which can also occur without digestive symptoms) and inflammatory bowel disease (including Crohn's disease and ulcerative colitis). The most common causes are: [ citation needed ] Injury or trauma, including sprains, hematoma Overuse: using a muscle too much, too often, including protecting a separate injury Chronic tension Muscle pain occurs with: Overuse of a muscle is using it too much, too soon or too often. One example is repetitive strain injury . See also: The most common causes of myalgia by injury are: sprains and strains . Sudden cessation of high-dose corticosteroids , opioids , barbiturates , benzodiazepines , caffeine , or alcohol can induce myalgia. [ citation needed ]Overuse of a muscle is using it too much, too soon or too often. One example is repetitive strain injury . See also: The most common causes of myalgia by injury are: sprains and strains . The most common causes of myalgia by injury are: sprains and strains . Sudden cessation of high-dose corticosteroids , opioids , barbiturates , benzodiazepines , caffeine , or alcohol can induce myalgia. [ citation needed ]When the cause of myalgia is unknown, it should be treated symptomatically. Common treatments include heat , rest, paracetamol , NSAIDs , massage , cryotherapy and muscle relaxants .

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Acute hemorrhagic fever syndrome

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Leptospirosis

Leptospirosis is a blood infection caused by the bacteria Leptospira that can infect humans, dogs, rodents and many other wild and domesticated animals. Signs and symptoms can range from none to mild ( headaches , muscle pains , and fevers ) to severe ( bleeding in the lungs or meningitis ). Weil's disease ( / ˈ v aɪ l z / VILES ), the acute, severe form of leptospirosis, causes the infected individual to become jaundiced (skin and eyes become yellow), develop kidney failure , and bleed. Bleeding from the lungs associated with leptospirosis is known as severe pulmonary haemorrhage syndrome . More than ten genetic types of Leptospira cause disease in humans. Both wild and domestic animals can spread the disease, most commonly rodents. The bacteria are spread to humans through animal urine or feces , or water or soil contaminated with animal urine and feces, coming into contact with the eyes, mouth, nose or breaks in the skin. In developing countries, the disease occurs most commonly in pest control, farmers and low-income people who live in areas with poor sanitation. In developed countries, it occurs during heavy downpours and is a risk to pest controllers, sewage workers and those involved in outdoor activities in warm and wet areas. Diagnosis is typically by testing for antibodies against the bacteria or finding bacterial DNA in the blood. Efforts to prevent the disease include protective equipment to block contact when working with potentially infected animals, washing after contact, and reducing rodents in areas where people live and work. The antibiotic doxycycline is effective in preventing leptospirosis infection. Human vaccines are of limited usefulness; vaccines for other animals are more widely available. Treatment when infected is with antibiotics such as doxycycline, penicillin , or ceftriaxone . The overall risk of death is 5–10%. However, when the lungs are involved, the risk of death increases to the range of 50–70%. It is estimated that one million severe cases of leptospirosis in humans occur every year, causing about 58,900 deaths. The disease is most common in tropical areas of the world but may occur anywhere. Outbreaks may arise after heavy rainfall. The disease was first described by physician Adolf Weil in 1886 in Germany. Infected animals may have no, mild or severe symptoms. These may vary by the type of animal. In some animals Leptospira live in the reproductive tract, leading to transmission during mating. The symptoms of leptospirosis usually appear one to two weeks after infection, but the incubation period can be as long as a month. The illness is biphasic in a majority of symptomatic cases. Symptoms of the first phase (acute or leptospiremic phase) last five to seven days. In the second phase (immune phase), the symptoms resolve as antibodies against the bacteria are produced. Additional symptoms develop in the second phase. The phases of illness may not be distinct, especially in patients with severe illness. 90% of those infected experience mild symptoms while 10% experience severe leptospirosis. Leptospiral infection in humans causes a range of symptoms , though some infected persons may have none. The disease begins suddenly with fever accompanied by chills, intense headache, severe muscle aches and abdominal pain. A headache brought on by leptospirosis causes throbbing pain and is characteristically located at the head's bilateral temporal or frontal regions. The person could also have pain behind the eyes and a sensitivity to light . Muscle pain usually involves the calf muscle and the lower back. The most characteristic feature of leptospirosis is the conjunctival suffusion ( conjunctivitis without exudate ) which is rarely found in other febrile illnesses. Other characteristic findings on the eye include subconjunctival bleeding and jaundice . A rash is rarely found in leptospirosis. When one is found alternative diagnoses such as dengue fever and chikungunya fever should be considered. Dry cough is observed in 20–57% of people with leptospirosis. Thus, this clinical feature can mislead a doctor to diagnose the disease as a respiratory illness. Additionally, gastrointestinal symptoms such as nausea , vomiting, abdominal pain, and diarrhoea frequently occur. Vomiting and diarrhea may contribute to dehydration . The abdominal pain can be due to acalculous cholecystitis or inflammation of the pancreas . Rarely, the lymph nodes , liver , and spleen may be enlarged and palpable. There will be a resolution of symptoms for one to three days. The immune phase starts after this and can last from four to 30 days and can be anything from brain to kidney complications. The hallmark of the second phase is inflammation of the membranes covering the brain . Signs and symptoms of meningitis include severe headache and neck stiffness. Kidney involvement is associated with reduced or absent urine output. The classic form of severe leptospirosis, known as Weil's disease, is characterised by liver damage (causing jaundice), kidney failure , and bleeding, which happens in 5–10% of those infected. Lung and brain damage can also occur. For those with signs of inflammation of membranes covering the brain and the brain itself , altered level of consciousness can happen. A variety of neurological problems such as paralysis of half of the body , complete inflammation of a whole horizontal section of spinal cord , and muscle weakness due to immune damage of the nerves supplying the muscles are the complications. Signs of bleeding such as non-traumatic bruises at 1 mm (0.039 in) , non-traumatic bruises more than 1 cm (0.39 in) , nose bleeding , blackish stools due to bleeding in the stomach , vomiting blood and bleeding from the lungs can also be found. Prolongation of prothrombin time in coagulation testing is associated with severe bleeding manifestation. However, low platelet count is not associated with severe bleeding. Pulmonary haemorrhage is alveolar haemorrhage (bleeding into the alveoli of the lungs) leading to massive coughing up of blood , and causing acute respiratory distress syndrome , where the risk of death is more than 50%. Rarely, inflammation of the heart muscles , inflammation of membranes covering the heart , abnormalities in the heart's natural pacemaker and abnormal heart rhythms may occur. Leptospirosis is caused by spirochaete bacteria that belong to the genus Leptospira , which are aerobic , right-handed helical , and 6–20 micrometers long. Like Gram-negative bacteria, Leptospira have an outer membrane studded with lipopolysaccharide (LPS) on the surface, an inner membrane and a layer of peptidoglycan cell wall. However, unlike Gram-negative bacteria, the peptidoglycan layer in Leptospira lies closer to the inner than the outer membrane. This results in a fluid outer membrane loosely associated with the cell wall. In addition, Leptospira have a flagellum located in the periplasm , associated with corkscrew style movement. Chemoreceptors at the poles of the bacteria sense various substrates and change the direction of its movement. The bacteria are traditionally visualised using dark-field microscopy without staining. A total of 66 species of Leptospira has been identified. Based on their genomic sequence, they are divided into two clades and four subclades: P1, P2, S1, and S2. The 19 members of the P1 subclade include the 8 species that can cause severe disease in humans: L. alexanderi , L. borgpetersenii , L. interrogans , L. kirschneri , L. mayottensis , L. noguchii , L. santarosai , and L. weilii . The P2 clade comprises 21 species that may cause mild disease in humans. The remaining 26 species comprise the S1 and S2 subclades, which include "saprophytes" known to consume decaying matter ( saprotrophic nutrition ). Pathogenic Leptospira do not multiply in the environment. Leptospira require high humidity for survival but can remain alive in environments such as stagnant water or contaminated soil. The bacterium can be killed by temperatures of 50 °C (122 °F) and can be inactivated by 70% ethanol , 1% sodium hypochlorite , formaldehyde , detergents and acids. Leptospira are also classified based on their serovar . The diverse sugar composition of the lipopolysaccharide on the surface of the bacteria is responsible for the antigenic difference between serovars. About 300 pathogenic serovars of Leptospira are recognised. Antigenically related serovars (belonging to the same serogroup) may belong to different species because of horizontal gene transfer of LPS biosynthetic genes between different species. Currently, the cross agglutination absorption test and DNA-DNA hybridisation are used to classify Leptospira species, but are time-consuming. Therefore, total genomic sequencing could potentially replace these two methods as the new gold standard of classifying Leptospira species. The bacteria can be found in ponds, rivers, puddles, sewers, agricultural fields and moist soil. Pathogenic Leptospira have been found in the form of aquatic biofilms , which may aid survival in the environment. The number of cases of leptospirosis is directly related to the amount of rainfall, making the disease seasonal in temperate climates and year-round in tropical climates. The risk of contracting leptospirosis depends upon the risk of disease carriage in the community and the frequency of exposure. In rural areas, farming and animal husbandry are the major risk factors for contracting leptospirosis. Poor housing and inadequate sanitation also increase the risk of infection. In tropical and semi-tropical areas, the disease often becomes widespread after heavy rains or after flooding. Leptospira are found mostly in mammals. However, reptiles and cold-blooded animals such as frogs, snakes, turtles, and toads have been shown to have the infection. Whether there are reservoirs of human infection is unknown. Rats, mice, and moles are important primary hosts , but other mammals including dogs, deer, rabbits, hedgehogs, cows, sheep, swine, raccoons, opossums, and skunks can also carry the disease. In Africa, a number of wildlife hosts have been identified as carriers, including the banded mongoose , Egyptian fox , Rusa deer , and shrews . There are various mechanisms whereby animals can infect each other. Dogs may lick the urine of an infected animal off the grass or soil , or drink from an infected puddle. House-bound domestic dogs have contracted leptospirosis, apparently from licking the urine of infected mice in the house. Leptospirosis can also be transmitted via the semen of infected animals. The duration of bacteria being consistently present in animal urine may persist for years. Humans are the accidental host of Leptospira . Humans become infected through contact with water or moist soil that contains urine & feces from infected animals. The bacteria enter through cuts, abrasions, ingestion of contaminated food, or contact with mucous membrane of the body (e.g. mouth, nose, and eyes). Occupations at risk of contracting leptospirosis include farmers, fishermen, garbage collectors and sewage workers. The disease is also related to adventure tourism and recreational activities. It is common among water-sports enthusiasts in specific areas, including triathlons , water rafting , canoeing and swimming, as prolonged immersion in water promotes the entry of the bacteria. However, Leptospira are unlikely to penetrate intact skin. The disease is not known to spread between humans, and bacterial dissemination in recovery period is extremely rare in humans. Once humans are infected, bacterial shedding from the kidneys usually persists for up to 60 days. Rarely, leptospirosis can be transmitted through an organ transplant. Infection through the placenta during pregnancy is also possible. It can cause miscarriage and infection in infants . Leptospirosis transmission through eating raw meat of wildlife animals have also been reported (e.g. psychiatric patients with allotriophagy). Leptospirosis is caused by spirochaete bacteria that belong to the genus Leptospira , which are aerobic , right-handed helical , and 6–20 micrometers long. Like Gram-negative bacteria, Leptospira have an outer membrane studded with lipopolysaccharide (LPS) on the surface, an inner membrane and a layer of peptidoglycan cell wall. However, unlike Gram-negative bacteria, the peptidoglycan layer in Leptospira lies closer to the inner than the outer membrane. This results in a fluid outer membrane loosely associated with the cell wall. In addition, Leptospira have a flagellum located in the periplasm , associated with corkscrew style movement. Chemoreceptors at the poles of the bacteria sense various substrates and change the direction of its movement. The bacteria are traditionally visualised using dark-field microscopy without staining. A total of 66 species of Leptospira has been identified. Based on their genomic sequence, they are divided into two clades and four subclades: P1, P2, S1, and S2. The 19 members of the P1 subclade include the 8 species that can cause severe disease in humans: L. alexanderi , L. borgpetersenii , L. interrogans , L. kirschneri , L. mayottensis , L. noguchii , L. santarosai , and L. weilii . The P2 clade comprises 21 species that may cause mild disease in humans. The remaining 26 species comprise the S1 and S2 subclades, which include "saprophytes" known to consume decaying matter ( saprotrophic nutrition ). Pathogenic Leptospira do not multiply in the environment. Leptospira require high humidity for survival but can remain alive in environments such as stagnant water or contaminated soil. The bacterium can be killed by temperatures of 50 °C (122 °F) and can be inactivated by 70% ethanol , 1% sodium hypochlorite , formaldehyde , detergents and acids. Leptospira are also classified based on their serovar . The diverse sugar composition of the lipopolysaccharide on the surface of the bacteria is responsible for the antigenic difference between serovars. About 300 pathogenic serovars of Leptospira are recognised. Antigenically related serovars (belonging to the same serogroup) may belong to different species because of horizontal gene transfer of LPS biosynthetic genes between different species. Currently, the cross agglutination absorption test and DNA-DNA hybridisation are used to classify Leptospira species, but are time-consuming. Therefore, total genomic sequencing could potentially replace these two methods as the new gold standard of classifying Leptospira species. The bacteria can be found in ponds, rivers, puddles, sewers, agricultural fields and moist soil. Pathogenic Leptospira have been found in the form of aquatic biofilms , which may aid survival in the environment. The number of cases of leptospirosis is directly related to the amount of rainfall, making the disease seasonal in temperate climates and year-round in tropical climates. The risk of contracting leptospirosis depends upon the risk of disease carriage in the community and the frequency of exposure. In rural areas, farming and animal husbandry are the major risk factors for contracting leptospirosis. Poor housing and inadequate sanitation also increase the risk of infection. In tropical and semi-tropical areas, the disease often becomes widespread after heavy rains or after flooding. Leptospira are found mostly in mammals. However, reptiles and cold-blooded animals such as frogs, snakes, turtles, and toads have been shown to have the infection. Whether there are reservoirs of human infection is unknown. Rats, mice, and moles are important primary hosts , but other mammals including dogs, deer, rabbits, hedgehogs, cows, sheep, swine, raccoons, opossums, and skunks can also carry the disease. In Africa, a number of wildlife hosts have been identified as carriers, including the banded mongoose , Egyptian fox , Rusa deer , and shrews . There are various mechanisms whereby animals can infect each other. Dogs may lick the urine of an infected animal off the grass or soil , or drink from an infected puddle. House-bound domestic dogs have contracted leptospirosis, apparently from licking the urine of infected mice in the house. Leptospirosis can also be transmitted via the semen of infected animals. The duration of bacteria being consistently present in animal urine may persist for years. Humans are the accidental host of Leptospira . Humans become infected through contact with water or moist soil that contains urine & feces from infected animals. The bacteria enter through cuts, abrasions, ingestion of contaminated food, or contact with mucous membrane of the body (e.g. mouth, nose, and eyes). Occupations at risk of contracting leptospirosis include farmers, fishermen, garbage collectors and sewage workers. The disease is also related to adventure tourism and recreational activities. It is common among water-sports enthusiasts in specific areas, including triathlons , water rafting , canoeing and swimming, as prolonged immersion in water promotes the entry of the bacteria. However, Leptospira are unlikely to penetrate intact skin. The disease is not known to spread between humans, and bacterial dissemination in recovery period is extremely rare in humans. Once humans are infected, bacterial shedding from the kidneys usually persists for up to 60 days. Rarely, leptospirosis can be transmitted through an organ transplant. Infection through the placenta during pregnancy is also possible. It can cause miscarriage and infection in infants . Leptospirosis transmission through eating raw meat of wildlife animals have also been reported (e.g. psychiatric patients with allotriophagy). When animals ingest the bacteria, they circulate in the bloodstream, then lodge themselves into the kidneys through the glomerular or peritubular capillaries . The bacteria then pass into the lumens of the renal tubules and colonise the brush border and proximal convoluted tubule . This causes the continuous shedding of bacteria in the urine without the animal experiencing significant ill effects. This relationship between the animal and the bacteria is known as a commensal relationship , and the animal is known as a reservoir host . Humans are the accidental host of Leptospira . The pathogenesis of leptospirosis remains poorly understood despite research efforts. The bacteria enter the human body through either breaches in the skin or the mucous membrane, then into the bloodstream. The bacteria later attach to the endothelial cells of the blood vessels and extracellular matrix (complex network of proteins and carbohydrates present between cells). The bacteria use their flagella for moving between cell layers. They bind to cells such as fibroblasts , macrophages , endothelial cells, and kidney epithelial cells. They also bind to several human proteins such as complement proteins, thrombin , fibrinogen , and plasminogen using surface leptospiral immunoglobulin-like (Lig) proteins such as LigB and LipL32, whose genes are found in all pathogenic species. Through the innate immune system , endothelial cells of the capillaries in the human body are activated by the presence of these bacteria. The endothelial cells produce cytokines and antimicrobial peptides against the bacteria. These products regulate the coagulation cascade and movements of white blood cells. Macrophages presented in humans are able to engulf Leptospira . However, Leptospira are able to reside and proliferate in the cytoplasmic matrix after being ingested by macrophages. Those with severe leptospirosis can experience a high level of cytokines such as interleukin 6 , tumor necrosis factor alpha (TNF-α), and interleukin 10 . The high level of cytokines causes sepsis -like symptoms which is life-threatening instead of helping to fight against the infection. Those who have a high risk of sepsis during a leptospirosis infection are found to have the HLA-DQ6 genotype , possibly due to superantigen activation, which damages bodily organs. Leptospira LPS only activates toll-like receptor 2 (TLR2) in monocytes in humans. The lipid A molecule of the bacteria is not recognised by human TLR4 receptors. Therefore, the lack of Leptospira recognition by TLR4 receptors probably contributes to the leptospirosis disease process in humans. Although there are various mechanisms in the human body to fight against the bacteria, Leptospira is well adapted to such an inflammatory condition created by it. In the bloodstream, it can activate host plasminogen to become plasmin that breaks down extracellular matrix, degrades fibrin clots and complemental proteins ( C3b and C5 ) to avoid opsonisation . It can also recruit complement regulators such as Factor H , C4b -binding protein, factor H-like binding protein, and vitronectin to prevent the activation of membrane attack complex on its surface. It also secretes proteases to degrade complement proteins such as C3 . It can bind to thrombin that decreases the fibrin formation. Reduced fibrin formation increases the risk of bleeding. Leptospira also secretes sphingomyelinase and haemolysin that target red blood cells. Leptospira spreads rapidly to all organs through the bloodstream. They mainly affect the liver. They invade spaces between hepatocytes , causing apoptosis. The damaged hepatocytes and hepatocyte intercellular junctions cause leakage of bile into the bloodstream, causing elevated levels of bilirubin , resulting in jaundice. Congested liver sinusoids and perisinusoidal spaces have been reported. Meanwhile, in the lungs, petechiae or frank bleeding can be found at the alveolar septum and spaces between alveoli. Leptospira secretes toxins that cause mild to severe kidney failure or interstitial nephritis . The kidney failure can recover completely or lead to atrophy and fibrosis . Rarely, inflammation of the heart muscles, coronary arteries, and aorta are found. For those who are infected, a complete blood count may show a high white cell count and a low platelet count. When a low haemoglobin count is present together with a low white cell count and thrombocytopenia , bone marrow suppression should be considered. Erythrocyte sedimentation rate and C-reactive protein may also be elevated. The kidneys are commonly involved in leptospirosis. Blood urea and creatinine levels will be elevated. Leptospirosis increases potassium excretion in urine, which leads to a low potassium level and a low sodium level in the blood. Urinalysis may reveal the presence of protein , white blood cells , and microscopic haematuria . Because the bacteria settle in the kidneys, urine cultures will be positive for leptospirosis starting after the second week of illness until 30 days of infection. For those with liver involvement, transaminases and direct bilirubin are elevated in liver function tests . The Icterohaemorrhagiae serogroup is associated with jaundice and elevated bilirubin levels. Hemolytic anemia contributes to jaundice. A feature of leptospirosis is acute haemolytic anaemia and conjugated hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase deficiency . Abnormal serum amylase and lipase levels (associated with pancreatitis) are found in those who are admitted to hospital due to leptospirosis. Impaired kidney function with creatinine clearance less than 50 ml/min is associated with elevated pancreatic enzymes. For those with severe headache who show signs of meningitis, a lumbar puncture can be attempted. If infected, cerebrospinal fluid (CSF) examination shows lymphocytic predominance with a cell count of about 500/mm 3 , protein between 50 and 100 mg/ml and normal glucose levels. These findings are consistent with aseptic meningitis . Rapid detection of Leptospira can be done by quantifying the IgM antibodies using an enzyme-linked immunosorbent assay (ELISA) . Typically, L. biflexa antigen is used to detect the IgM antibodies. This test can quickly determine the diagnosis and help in early treatment. However, the test specificity depends upon the type of antigen used and the presence of antibodies from previous infections. The presence of other diseases such as Epstein–Barr virus infection, viral hepatitis , and cytomegalovirus infection can cause false-positive results. Other rapid screening tests have been developed such as dipsticks, latex and slide agglutination tests. The microscopic agglutination test (MAT) is the reference test for the diagnosis of leptospirosis. MAT is a test where serial dilutions of patient sera are mixed with different serovars of Leptospira . The mixture is then examined under a dark field microscope to look for agglutination . The highest dilution where 50% agglutination occurs is the result. MAT titres of 1:100 to 1:800 are diagnostic of leptospirosis. A fourfold or greater rise in titre of two sera taken at symptoms' onset and three to 10 days of disease onset confirms the diagnosis. During the acute phase of the disease, MAT is not specific in detecting a serotype of Leptospira because of cross-reactivity between the serovars. In the convalescent phase, MAT is more specific in detecting the serovar types. MAT requires a panel of live antigens and requires laborious work. Leptospiral DNA can be amplified by using polymerase chain reaction (PCR) from serum, urine, aqueous humour , CSF, and autopsy specimens. It detects the presence of bacteria faster than MAT during the first few days of infection without waiting for the appearance of antibodies. As PCR detects the presence of leptospiral DNA in the blood it is useful even when the bacteria is killed by antibiotics. In those who have lung involvement, a chest X-ray may demonstrate diffuse alveolar opacities. In 1982, the World Health Organization (WHO) proposed the Faine's criteria for the diagnosis of leptospirosis. It consists of three parts: A (clinical findings), B (epidemiological factors), and C (lab findings and bacteriological data). Since the original Faine's criteria only included culture and MAT in part C, which is difficult and complex to perform, the modified Faine's criteria were proposed in 2004 to include ELISA and slide agglutination tests which are easier to perform. In 2012, modified Faine's criteria (with amendment) was proposed to include shortness of breath and coughing up blood in the diagnosis. In 2013, India recommended modified Faine's criteria in the diagnosis of leptospirosis. For those who are infected, a complete blood count may show a high white cell count and a low platelet count. When a low haemoglobin count is present together with a low white cell count and thrombocytopenia , bone marrow suppression should be considered. Erythrocyte sedimentation rate and C-reactive protein may also be elevated. The kidneys are commonly involved in leptospirosis. Blood urea and creatinine levels will be elevated. Leptospirosis increases potassium excretion in urine, which leads to a low potassium level and a low sodium level in the blood. Urinalysis may reveal the presence of protein , white blood cells , and microscopic haematuria . Because the bacteria settle in the kidneys, urine cultures will be positive for leptospirosis starting after the second week of illness until 30 days of infection. For those with liver involvement, transaminases and direct bilirubin are elevated in liver function tests . The Icterohaemorrhagiae serogroup is associated with jaundice and elevated bilirubin levels. Hemolytic anemia contributes to jaundice. A feature of leptospirosis is acute haemolytic anaemia and conjugated hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase deficiency . Abnormal serum amylase and lipase levels (associated with pancreatitis) are found in those who are admitted to hospital due to leptospirosis. Impaired kidney function with creatinine clearance less than 50 ml/min is associated with elevated pancreatic enzymes. For those with severe headache who show signs of meningitis, a lumbar puncture can be attempted. If infected, cerebrospinal fluid (CSF) examination shows lymphocytic predominance with a cell count of about 500/mm 3 , protein between 50 and 100 mg/ml and normal glucose levels. These findings are consistent with aseptic meningitis . Rapid detection of Leptospira can be done by quantifying the IgM antibodies using an enzyme-linked immunosorbent assay (ELISA) . Typically, L. biflexa antigen is used to detect the IgM antibodies. This test can quickly determine the diagnosis and help in early treatment. However, the test specificity depends upon the type of antigen used and the presence of antibodies from previous infections. The presence of other diseases such as Epstein–Barr virus infection, viral hepatitis , and cytomegalovirus infection can cause false-positive results. Other rapid screening tests have been developed such as dipsticks, latex and slide agglutination tests. The microscopic agglutination test (MAT) is the reference test for the diagnosis of leptospirosis. MAT is a test where serial dilutions of patient sera are mixed with different serovars of Leptospira . The mixture is then examined under a dark field microscope to look for agglutination . The highest dilution where 50% agglutination occurs is the result. MAT titres of 1:100 to 1:800 are diagnostic of leptospirosis. A fourfold or greater rise in titre of two sera taken at symptoms' onset and three to 10 days of disease onset confirms the diagnosis. During the acute phase of the disease, MAT is not specific in detecting a serotype of Leptospira because of cross-reactivity between the serovars. In the convalescent phase, MAT is more specific in detecting the serovar types. MAT requires a panel of live antigens and requires laborious work. Leptospiral DNA can be amplified by using polymerase chain reaction (PCR) from serum, urine, aqueous humour , CSF, and autopsy specimens. It detects the presence of bacteria faster than MAT during the first few days of infection without waiting for the appearance of antibodies. As PCR detects the presence of leptospiral DNA in the blood it is useful even when the bacteria is killed by antibiotics. Rapid detection of Leptospira can be done by quantifying the IgM antibodies using an enzyme-linked immunosorbent assay (ELISA) . Typically, L. biflexa antigen is used to detect the IgM antibodies. This test can quickly determine the diagnosis and help in early treatment. However, the test specificity depends upon the type of antigen used and the presence of antibodies from previous infections. The presence of other diseases such as Epstein–Barr virus infection, viral hepatitis , and cytomegalovirus infection can cause false-positive results. Other rapid screening tests have been developed such as dipsticks, latex and slide agglutination tests. The microscopic agglutination test (MAT) is the reference test for the diagnosis of leptospirosis. MAT is a test where serial dilutions of patient sera are mixed with different serovars of Leptospira . The mixture is then examined under a dark field microscope to look for agglutination . The highest dilution where 50% agglutination occurs is the result. MAT titres of 1:100 to 1:800 are diagnostic of leptospirosis. A fourfold or greater rise in titre of two sera taken at symptoms' onset and three to 10 days of disease onset confirms the diagnosis. During the acute phase of the disease, MAT is not specific in detecting a serotype of Leptospira because of cross-reactivity between the serovars. In the convalescent phase, MAT is more specific in detecting the serovar types. MAT requires a panel of live antigens and requires laborious work. Leptospiral DNA can be amplified by using polymerase chain reaction (PCR) from serum, urine, aqueous humour , CSF, and autopsy specimens. It detects the presence of bacteria faster than MAT during the first few days of infection without waiting for the appearance of antibodies. As PCR detects the presence of leptospiral DNA in the blood it is useful even when the bacteria is killed by antibiotics. In those who have lung involvement, a chest X-ray may demonstrate diffuse alveolar opacities. In 1982, the World Health Organization (WHO) proposed the Faine's criteria for the diagnosis of leptospirosis. It consists of three parts: A (clinical findings), B (epidemiological factors), and C (lab findings and bacteriological data). Since the original Faine's criteria only included culture and MAT in part C, which is difficult and complex to perform, the modified Faine's criteria were proposed in 2004 to include ELISA and slide agglutination tests which are easier to perform. In 2012, modified Faine's criteria (with amendment) was proposed to include shortness of breath and coughing up blood in the diagnosis. In 2013, India recommended modified Faine's criteria in the diagnosis of leptospirosis. Rates of leptospirosis can be reduced by improving housing, infrastructure, and sanitation standards. Rodent abatement efforts and flood mitigation projects can also help to prevent it. Proper use of personal protective equipment (PPE) by people who have a high risk of occupational exposure can prevent leptospirosis infections in most cases. There is no human vaccine suitable for worldwide use. Only a few countries such as Cuba, Japan, France, and China have approved the use of inactivated vaccines with limited protective effects. Side effects such as nausea, injection site redness and swelling have been reported after the vaccine was injected. Since the immunity induced by one Leptospira serovar is only protective against that specific one, trivalent vaccines have been developed. However, they do not confer long-lasting immunity to humans or animals. Vaccines for other animals are more widely available. Doxycycline is given once a week as a prophylaxis and is effective in reducing the rate of leptospirosis infections amongst high-risk individuals in flood-prone areas. In one study, it reduced the number of leptospirosis cases in military personnel undergoing exercises in the jungles. In another study, it reduced the number of symptomatic cases after exposure to leptospirosis under heavy rainfall in endemic areas. The prevention of leptospirosis from the environmental sources like contaminated waterways, soil, sewers, and agricultural fields, is disinfection used by effective microorganisms , which is mixed with bokashi mudballs for the infected waterways & sewers.Most leptospiral cases resolve spontaneously. Early initiation of antibiotics may prevent the progression to severe disease. Therefore, in resource-limited settings, antibiotics can be started once leptospirosis is suspected after history taking and examination. For mild leptospirosis, antibiotic recommendations such as doxycycline, azithromycin , ampicillin and amoxicillin were based solely on in vitro testing. In 2001, the WHO recommended oral doxycycline (2 mg/kg up to 100 mg every 12 hours) for five to seven days for those with mild leptospirosis. Tetracycline , ampicillin, and amoxicillin can also be used in such cases. However, in areas where both rickettsia and leptospirosis are endemic, azithromycin and doxycycline are the drugs of choice. It should be noted doxycycline is not used in cases where the patient suffers from liver damage as it has been linked to hepatotoxicity. Based on a 1988 study, intravenous (IV) benzylpenicillin (also known as penicillin G) is recommended for the treatment of severe leptospirosis. Intravenous benzylpenicillin (30 mg/kg up to 1.2 g every six hours) is used for five to seven days. Amoxicillin, ampicillin, and erythromycin may also be used for severe cases. Ceftriaxone (1 g IV every 24 hours for seven days) is also effective for severe leptospirosis. Cefotaxime (1 g IV every six hours for seven days) and doxycycline (200 mg initially followed by 100 mg IV every 12 hours for seven days) are equally effective as benzylpenicillin (1.5 million units IV every six hours for seven days). Therefore, there is no evidence on differences in death reduction when benzylpenicillin is compared with ceftriaxone or cefotaxime. Another study conducted in 2007 also showed no difference in efficacy between doxycycline (200 mg initially followed by 100 mg orally every 12 hours for seven days) or azithromycin (2 g on day one followed by 1 g daily for two more days) for suspected leptospirosis. There was no difference in the resolution of fever and azithromycin is better tolerated than doxycycline. Outpatients are given doxycycline or azithromycin. Doxycycline can shorten the duration of leptospirosis by two days, improve symptoms, and prevent the shedding of organisms in their urine. Azithromycin and amoxicillin are given to pregnant women and children. Rarely, a Jarisch–Herxheimer reaction can develop in the first few hours after antibiotic administration. However, according to a meta-analysis done in 2012, the benefit of antibiotics in the treatment of leptospirosis was unclear although the use of antibiotics may reduce the duration of illness by two to four days. Another meta-analysis done in 2013 reached a similar conclusion. For those with severe leptospirosis, including potassium wasting with high kidney output dysfunction, intravenous hydration and potassium supplements can prevent dehydration and hypokalemia . When acute kidney failure occurs, early initiation of haemodialysis or peritoneal dialysis can help to improve survival. For those with respiratory failure, tracheal intubation with low tidal volume improves survival rates. Corticosteroids have been proposed to suppress inflammation in leptospirosis because Leptospira infection can induce the release of chemical signals which promote inflammation of blood vessels in the lungs. However, there is insufficient evidence to determine whether the use of corticosteroids is beneficial. The overall risk of death for leptospirosis is 5–10%. For those with jaundice, the case fatality can increase up to 15%. For those infected who present with confusion and neurological signs, there is a high risk of death. Other factors that increase the risk of death include reduced urine output, age more than 36 years, and respiratory failure. With proper care, most of those infected will recover completely. Those with acute kidney failure may develop persistent mild kidney impairment after they recover. In those with severe lung involvement, the risk of death is 50–70%. Thirty percent of people with acute leptospirosis complained of long-lasting symptoms characterised by weakness, muscle pain, and headaches. Eye problems can occur in 10% of those who recovered from leptospirosis in the range from two weeks to a few years post-infection. Most commonly, eye complications can occur at six months after the infection. This is due to the immune privilege of the eye which protects it from immunological damage during the initial phase of leptospiral infection. These complications can range from mild anterior uveitis to severe panuveitis (which involves all three vascular layers of the eye). The uveitis is more commonly happen in young to middle-aged males and those working in agricultural farming. In up to 80% of those infected, Leptospira DNA can be found in the aqueous humour of the eye. Eye problems usually have a good prognosis following treatment or they are self-limiting. In anterior uveitis, only topical steroids and mydriatics (an agent that causes dilation of the pupil) are needed while in panuveitis, it requires periocular corticosteroids. Leptospiral uveitis is characterised by hypopyon , rapidly maturing cataract , free floating vitreous membranes, disc hyperemia and retinal vasculitis . Eye problems can occur in 10% of those who recovered from leptospirosis in the range from two weeks to a few years post-infection. Most commonly, eye complications can occur at six months after the infection. This is due to the immune privilege of the eye which protects it from immunological damage during the initial phase of leptospiral infection. These complications can range from mild anterior uveitis to severe panuveitis (which involves all three vascular layers of the eye). The uveitis is more commonly happen in young to middle-aged males and those working in agricultural farming. In up to 80% of those infected, Leptospira DNA can be found in the aqueous humour of the eye. Eye problems usually have a good prognosis following treatment or they are self-limiting. In anterior uveitis, only topical steroids and mydriatics (an agent that causes dilation of the pupil) are needed while in panuveitis, it requires periocular corticosteroids. Leptospiral uveitis is characterised by hypopyon , rapidly maturing cataract , free floating vitreous membranes, disc hyperemia and retinal vasculitis . It is estimated that one million severe cases of leptospirosis occur annually, with 58,900 deaths. Severe cases account for 5–15% of all leptospirosis cases. Leptospirosis is found in both urban and rural areas in tropical , subtropical , and temperate regions. The global health burden for leptospirosis can be measured by disability-adjusted life year (DALY). The score is 42 per 100,000 people per year, which is more than other diseases such as rabies and filariasis . The disease is observed persistently in parts of Asia, Oceania, the Caribbean, Latin America and Africa. Antarctica is the only place not affected by leptospirosis. In the United States, there were 100 to 150 leptospirosis cases annually. In 1994, leptospirosis ceased to be a notifiable disease in the United States except in 36 states/territories where it is prevalent such as Hawaii, Texas, California, and Puerto Rico. About 50% of the reported cases occurred in Puerto Rico. In January 2013, leptospirosis was reinstated as a nationally notifiable disease in the United States. Research on epidemiology of leptospirosis in high-risk groups and risk factors is limited in India. The global rates of leptospirosis have been underestimated because most affected countries lack notification or notification is not mandatory. Distinguishing clinical signs of leptospirosis from other diseases and lack of laboratory diagnostic services are other problems. The socioeconomic status of many of the world's population is closely tied to malnutrition; subsequent lack of micronutrients may lead to increased risk of infection and death due to leptospirosis infection. Micronutrients such as iron , calcium , and magnesium represent important areas for future research. The disease was first described by Adolf Weil in 1886 when he reported an "acute infectious disease with enlargement of spleen, jaundice, and nephritis ." Before Weil's description, the disease was known as "rice field jaundice " in ancient Chinese text, "autumn fever", "seven-day fever", and " nanukayami fever" in Japan; in Europe and Australia, the disease was associated with certain occupations and given names such as "cane-cutter's disease", "swine-herd's disease", and " Schlammfieber " (mud fever). It has been known historically as "black jaundice", or "dairy farm fever" in New Zealand. Leptospirosis was postulated as the cause of an epidemic among Native Americans along the coast of what is now New England during 1616–1619. The disease was most likely brought to the New World by Europeans. Leptospira was first observed in 1907 in a post mortem kidney tissue slice by Arthur Stimson using silver deposition staining technique. He called the organism Spirocheta interrogans because the bacteria resembled a question mark. In 1908, a Japanese research group led by Ryukichi Inada and Yutaka Ito first identified this bacterium as the causative agent of leptospirosis and noted its presence in rats in 1916. Japanese coal mine workers frequently contracted leptospirosis. In Japan, the organism was named Spirocheta icterohaemorrhagiae . The Japanese group also experimented with the first leptospiral immunisation studies in guinea pigs. They demonstrated that by injecting the infected guinea pigs with sera from convalescent humans or goats, passive immunity could be provided to the guinea pigs. In 1917, the Japanese group discovered rats as the carriers of leptospirosis. Unaware of the Japanese group's work, two German groups independently and almost simultaneously published their first demonstration of transmitting leptospiral infection in guinea pigs in October 1915. They named the organism Spirochaeta nodosa and Spirochaeta Icterogenes respectively. Leptospirosis was subsequently recognised as a disease of all mammalian species. In 1933, Dutch workers reported the isolation of Leptospira canicola which specifically infects dogs. In 1940, the strain that specifically infects cattle was first reported in Russia. In 1942, soldiers at Fort Bragg , North Carolina , were recorded to have an infectious disease which caused a rash over their shinbones . This disease was later known to be caused by leptospirosis. By the 1950s, the number of serovars that infected various mammals had expanded significantly. In the 1980s, leptospirosis was recognised as a veterinary disease of major economic importance. In 1982, there were about 200 serovars of Leptospira available for classification. The International Committee on Systematic Bacteriology 's subcommittee on taxonomy of Leptospira proposed classifying these serovars into two big groups: L. interrogans containing pathogenic serovars and L. biflexa containing saprophytic serovars. In 1979, the leptospiral family of Leptospiraceae was proposed. In the same year, Leptospira illini was reclassified as the new genus Leptonema . In 2002, "Lepthangamushi syndrome" was coined to describe a series of overlapping symptoms of leptospirosis with Hantavirus hemorrhagic fever with renal syndrome , and scrub typhus caused by Orientia tsutsugamushi . In 2005, Leptospira parva was classified as Turneriella . With DNA-DNA hybridisation technology, L. interrogans was divided into seven species. More Leptospira species have been discovered since then. The WHO established the Leptospirosis Burden Epidemiology Reference Group (LERG) to review the latest disease epidemiological data of leptospirosis, formulate a disease transmission model, and identify gaps in knowledge and research. The first meeting was convened in 2009. In 2011, LERG estimated that the global yearly rate of leptospirosis is five to 14 cases per 100,000 population. Infected animals can have no, mild, or severe symptoms; the presenting symptoms may vary by the type of animal. In some animals the bacteria live in the reproductive tract, leading to transmission during mating. Animals also present with similar clinical features when compared to humans. Clinical signs can appear in 5–15 days in dogs. The incubation period can be prolonged in cats. Leptospirosis can cause abortions after 2–12 weeks in cattle, and 1–4 weeks of infection in pigs. The illness tends to be milder in reservoir hosts. The most commonly affected organs are the kidneys, liver, and reproductive system, but other organs can be affected. In dogs, the acute clinical signs include fever, loss of appetite , shivering, muscle pain, weakness, and urinary symptoms. Vomiting, diarrhea, and abdominal pain may also present. Petechiae and ecchymoses may be seen on mucous membranes. Bleeding from the lungs may also be seen in dogs. In chronic presentations, the affected dog may have no symptoms. In animals that have died of leptospirosis, their kidneys may be swollen with grey and white spots, mottling , or scarring. Their liver may be enlarged with areas of cell death . Petechiae and ecchymoses may be found in various organs. Inflammation of the blood vessels , inflammation of the heart, meningeal layers covering the brain and spinal cord, and uveitis are also possible. Equine recurrent uveitis (ERU) is the most common disease associated with Leptospira infection in horses in North America and may lead to blindness. ERU is an autoimmune disease involving antibodies against Leptospira proteins LruA and LruB cross-reacting with eye proteins. Live Leptospira can be recovered from the aqueous or vitreous fluid of many horses with Leptospira -associated ERU. Risk of death or disability in infected animals varies depending upon the species and age of the animals. In adult pigs and cattle, reproductive signs are the most common signs of leptospirosis. Up to 40% of cows may have a spontaneous abortion. Younger animals usually develop more severe disease. About 80% of dogs can survive with treatment, but the survival rate is reduced if the lungs are involved. ELISA and microscopic agglutination tests are most commonly used to diagnose leptospirosis in animals. The bacteria can be detected in blood, urine, and milk or liver, kidney, or other tissue samples by using immunofluorescence or immunohistochemical or polymerase chain reaction techniques. Silver staining or immunogold silver staining is used to detect Leptospira in tissue sections. The organisms stain poorly with Gram stain . Dark-field microscopy can be used to detect Leptospira in body fluids, but it is neither sensitive nor specific in detecting the organism. A positive culture for leptospirosis is definitive, but the availability is limited, and culture results can take 13–26 weeks for a result, limiting its utility. Paired acute and convalescent samples are preferred for serological diagnosis of leptospirosis in animals. A positive serological sample from an aborted fetus is also diagnostic of leptospirosis. Various antibiotics such as doxycycline, penicillins, dihydrostreptomycin , and streptomycin have been used to treat leptospirosis in animals. Fluid therapy, blood transfusion, and respiratory support may be required in severe disease. For horses with ERU, the primary treatment is with anti-inflammatory drugs. Leptospirosis vaccines are available for animals such as pigs, dogs, cattle, sheep, and goats. Vaccines for cattle usually contain Leptospira serovar Hardjo and Pomona, for dogs, the vaccines usually contain serovar Icterohaemorrhagiae and Canicola. Vaccines containing multiple serovars do not work for cattle as well as vaccines containing a single serovar, yet the multivalent vaccines continue to be sold. Isolation of infected animals and prophylactic antibiotics are also effective in preventing leptospirosis transmission between animals. Environmental control and sanitation also reduce transmission rates.

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Acute hemorrhagic fever syndrome

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Typhoid fever

Among untreated acute cases, 10% will shed bacteria for three months after initial onset of symptoms, and 2–5% will become chronic typhoid carriers. 99j Typhoid fever , also known simply as typhoid , is a disease caused by Salmonella enterica serotype Typhi bacteria, also called Salmonella typhi . Symptoms vary from mild to severe, and usually begin six to 30 days after exposure. Often there is a gradual onset of a high fever over several days. This is commonly accompanied by weakness, abdominal pain , constipation , headaches , and mild vomiting. Some people develop a skin rash with rose colored spots . In severe cases, people may experience confusion. Without treatment, symptoms may last weeks or months. Diarrhea may be severe, but is uncommon. Other people may carry it without being affected, but are still contagious. Typhoid fever is a type of enteric fever, along with paratyphoid fever . Salmonella enterica Typhi is believed to infect and replicate only within humans. Typhoid is caused by the bacterium Salmonella enterica subsp. enterica serovar Typhi growing in the intestines , Peyer's patches , mesenteric lymph nodes , spleen , liver , gallbladder , bone marrow and blood . Typhoid is spread by eating or drinking food or water contaminated with the feces of an infected person. Risk factors include limited access to clean drinking water and poor sanitation . Those who have not yet been exposed to it and ingest contaminated drinking water or food are most at risk for developing symptoms. Only humans can be infected; there are no known animal reservoirs. Salmonella Typhi which causes typhoid fever is different than the other Salmonella bacteria that usually cause salmonellosis , a common type of food poisoning. Diagnosis is performed by culturing and identifying S. enterica typhi from patient samples or detecting an immune response to the pathogen from blood samples . Recently, new advances in large-scale data collection and analysis have allowed researchers to develop better diagnostics, such as detecting changing abundances of small molecules in the blood that may specifically indicate typhoid fever. Diagnostic tools in regions where typhoid is most prevalent are quite limited in their accuracy and specificity, and the time required for a proper diagnosis, the increasing spread of antibiotic resistance , and the cost of testing are also hardships for under-resourced healthcare systems. A typhoid vaccine can prevent about 40% to 90% of cases during the first two years. The vaccine may have some effect for up to seven years. For those at high risk or people traveling to areas where it is common, vaccination is recommended. Other efforts to prevent it include providing clean drinking water , good sanitation , and handwashing . Until an infection is confirmed as cleared, the infected person should not prepare food for others. Typhoid is treated with antibiotics such as azithromycin , fluoroquinolones , or third-generation cephalosporins . Resistance to these antibiotics has been developing, which has made treatment more difficult. In 2015, 12.5 million new typhoid cases were reported. The disease is most common in India. Children are most commonly affected. Typhoid decreased in the developed world in the 1940s as a result of improved sanitation and the use of antibiotics. Every year about 400 cases are reported in the U.S. and an estimated 6,000 people have typhoid. In 2015, it resulted in about 149,000 deaths worldwide – down from 181,000 in 1990. Without treatment, the risk of death may be as high as 20%. With treatment, it is between 1% and 4%. Typhus is a different disease, caused by unrelated species of bacteria. Owing to their similar symptoms, they were not recognized as distinct diseases until the 1800s. "Typhoid" means "resembling typhus". Classically, the progression of untreated typhoid fever has three distinct stages, each lasting about a week. Over the course of these stages, the patient becomes exhausted and emaciated. The Gram-negative bacterium that causes typhoid fever is Salmonella enterica subsp. enterica serovar Typhi. Based on MLST subtyping scheme, the two main sequence types of the S. Typhi are ST1 and ST2, which are widespread globally. Global phylogeographical analysis showed dominance of a haplotype 58 (H58), which probably originated in India during the late 1980s and is now spreading through the world with multi-drug resistance . A more detailed genotyping scheme was reported in 2016 and is now being used widely. This scheme reclassified the nomenclature of H58 to genotype 4.3.1. Unlike other strains of Salmonella , no animal carriers of typhoid are known. Humans are the only known carriers of the bacterium. S. enterica subsp. enterica serovar Typhi is spread by the fecal-oral route from people who are infected and from asymptomatic carriers of the bacterium. An asymptomatic human carrier is someone who is still excreting typhoid bacteria in stool a year after the acute stage of the infection. The Gram-negative bacterium that causes typhoid fever is Salmonella enterica subsp. enterica serovar Typhi. Based on MLST subtyping scheme, the two main sequence types of the S. Typhi are ST1 and ST2, which are widespread globally. Global phylogeographical analysis showed dominance of a haplotype 58 (H58), which probably originated in India during the late 1980s and is now spreading through the world with multi-drug resistance . A more detailed genotyping scheme was reported in 2016 and is now being used widely. This scheme reclassified the nomenclature of H58 to genotype 4.3.1. Unlike other strains of Salmonella , no animal carriers of typhoid are known. Humans are the only known carriers of the bacterium. S. enterica subsp. enterica serovar Typhi is spread by the fecal-oral route from people who are infected and from asymptomatic carriers of the bacterium. An asymptomatic human carrier is someone who is still excreting typhoid bacteria in stool a year after the acute stage of the infection. Diagnosis is made by any blood , bone marrow , or stool cultures and with the Widal test (demonstration of antibodies against Salmonella antigens O-somatic and H-flagellar ). In epidemics and less wealthy countries, after excluding malaria , dysentery , or pneumonia , a therapeutic trial time with chloramphenicol is generally undertaken while awaiting the results of the Widal test and blood and stool cultures. The Widal test is used to identify specific antibodies in the serum of people with typhoid by using antigen-antibody interactions. In this test, the serum is mixed with a dead bacterial suspension of salmonella with specific antigens. If the patient's serum contains antibodies against those antigens, they get attached to them, forming clumps. If clumping does not occur, the test is negative. The Widal test is time-consuming and prone to significant false positives. It may also be falsely negative in recently infected people. But unlike the Typhidot test, the Widal test quantifies the specimen with titres . Rapid diagnostic tests such as Tubex, Typhidot, and Test-It have shown moderate diagnostic accuracy. Typhidot is based on the presence of specific IgM and IgG antibodies to a specific 50 Kd OMP antigen. This test is carried out on a cellulose nitrate membrane where a specific S. typhi outer membrane protein is attached as fixed test lines. It separately identifies IgM and IgG antibodies. IgM shows recent infection; IgG signifies remote infection. [ citation needed ] The sample pad of this kit contains colloidal gold-anti-human IgG or gold-anti-human IgM. If the sample contains IgG and IgM antibodies against those antigens, they will react and turn red. The typhidot test becomes positive within 2–3 days of infection. [ citation needed ] Two colored bands indicate a positive test. A single control band indicates a negative test. A single first fixed line or no band at all indicates an invalid test. Typhidot's biggest limitation is that it is not quantitative, just positive or negative. The Tubex test contains two types of particles: brown magnetic particles coated with antigen and blue indicator particles coated with O9 antibody. During the test, if antibodies are present in the serum, they will attach to the brown magnetic particles and settle at the base, while the blue indicator particles remain in the solution, producing a blue color, which means the test is positive. [ citation needed ] If the serum does not have an antibody in it, the blue particles attach to the brown particles and settle at the bottom, producing a colorless solution, which means the test is negative. The Widal test is used to identify specific antibodies in the serum of people with typhoid by using antigen-antibody interactions. In this test, the serum is mixed with a dead bacterial suspension of salmonella with specific antigens. If the patient's serum contains antibodies against those antigens, they get attached to them, forming clumps. If clumping does not occur, the test is negative. The Widal test is time-consuming and prone to significant false positives. It may also be falsely negative in recently infected people. But unlike the Typhidot test, the Widal test quantifies the specimen with titres . Rapid diagnostic tests such as Tubex, Typhidot, and Test-It have shown moderate diagnostic accuracy. Typhidot is based on the presence of specific IgM and IgG antibodies to a specific 50 Kd OMP antigen. This test is carried out on a cellulose nitrate membrane where a specific S. typhi outer membrane protein is attached as fixed test lines. It separately identifies IgM and IgG antibodies. IgM shows recent infection; IgG signifies remote infection. [ citation needed ] The sample pad of this kit contains colloidal gold-anti-human IgG or gold-anti-human IgM. If the sample contains IgG and IgM antibodies against those antigens, they will react and turn red. The typhidot test becomes positive within 2–3 days of infection. [ citation needed ] Two colored bands indicate a positive test. A single control band indicates a negative test. A single first fixed line or no band at all indicates an invalid test. Typhidot's biggest limitation is that it is not quantitative, just positive or negative. The Tubex test contains two types of particles: brown magnetic particles coated with antigen and blue indicator particles coated with O9 antibody. During the test, if antibodies are present in the serum, they will attach to the brown magnetic particles and settle at the base, while the blue indicator particles remain in the solution, producing a blue color, which means the test is positive. [ citation needed ] If the serum does not have an antibody in it, the blue particles attach to the brown particles and settle at the bottom, producing a colorless solution, which means the test is negative. Typhidot is based on the presence of specific IgM and IgG antibodies to a specific 50 Kd OMP antigen. This test is carried out on a cellulose nitrate membrane where a specific S. typhi outer membrane protein is attached as fixed test lines. It separately identifies IgM and IgG antibodies. IgM shows recent infection; IgG signifies remote infection. [ citation needed ] The sample pad of this kit contains colloidal gold-anti-human IgG or gold-anti-human IgM. If the sample contains IgG and IgM antibodies against those antigens, they will react and turn red. The typhidot test becomes positive within 2–3 days of infection. [ citation needed ] Two colored bands indicate a positive test. A single control band indicates a negative test. A single first fixed line or no band at all indicates an invalid test. Typhidot's biggest limitation is that it is not quantitative, just positive or negative. The Tubex test contains two types of particles: brown magnetic particles coated with antigen and blue indicator particles coated with O9 antibody. During the test, if antibodies are present in the serum, they will attach to the brown magnetic particles and settle at the base, while the blue indicator particles remain in the solution, producing a blue color, which means the test is positive. [ citation needed ] If the serum does not have an antibody in it, the blue particles attach to the brown particles and settle at the bottom, producing a colorless solution, which means the test is negative. Sanitation and hygiene are important to prevent typhoid. It can spread only in environments where human feces can come into contact with food or drinking water. Careful food preparation and washing of hands are crucial to prevent typhoid. Industrialization contributed greatly to the elimination of typhoid fever, as it eliminated the public-health hazards associated with having horse manure in public streets, which led to a large number of flies, which are vectors of many pathogens, including Salmonella spp. According to statistics from the U.S. Centers for Disease Control and Prevention , the chlorination of drinking water has led to dramatic decreases in the transmission of typhoid fever. Two typhoid vaccines are licensed for use for the prevention of typhoid: the live, oral Ty21a vaccine (sold as Vivotif by Crucell Switzerland AG) and the injectable typhoid polysaccharide vaccine (sold as Typhim Vi by Sanofi Pasteur and Typherix by GlaxoSmithKline ). Both are efficacious and recommended for travelers to areas where typhoid is endemic. Boosters are recommended every five years for the oral vaccine and every two years for the injectable form. An older, killed whole-cell vaccine is still used in countries where the newer preparations are not available, but this vaccine is no longer recommended for use because it has more side effects (mainly pain and inflammation at the site of the injection). To help decrease rates of typhoid fever in developing nations , the World Health Organization (WHO) endorsed the use of a vaccination program starting in 1999. Vaccination has proven effective at controlling outbreaks in high-incidence areas and is also very cost-effective: prices are normally less than US$1 per dose. Because the price is low, poverty-stricken communities are more willing to take advantage of the vaccinations. Although vaccination programs for typhoid have proven effective, they alone cannot eliminate typhoid fever. Combining vaccines with public-health efforts is the only proven way to control this disease. Since the 1990s, the WHO has recommended two typhoid fever vaccines. The ViPS vaccine is given by injection, and the Ty21a by capsules. Only people over age two are recommended to be vaccinated with the ViPS vaccine, and it requires a revaccination after 2–3 years, with a 55%–72% efficacy. The Ty21a vaccine is recommended for people five and older, lasting 5–7 years with 51%–67% efficacy. The two vaccines have proved safe and effective for epidemic disease control in multiple regions. A version of the vaccine combined with a hepatitis A vaccine is also available. Results of a phase 3 trial of typhoid conjugate vaccine (TCV) in December 2019 reported 81% fewer cases among children. Two typhoid vaccines are licensed for use for the prevention of typhoid: the live, oral Ty21a vaccine (sold as Vivotif by Crucell Switzerland AG) and the injectable typhoid polysaccharide vaccine (sold as Typhim Vi by Sanofi Pasteur and Typherix by GlaxoSmithKline ). Both are efficacious and recommended for travelers to areas where typhoid is endemic. Boosters are recommended every five years for the oral vaccine and every two years for the injectable form. An older, killed whole-cell vaccine is still used in countries where the newer preparations are not available, but this vaccine is no longer recommended for use because it has more side effects (mainly pain and inflammation at the site of the injection). To help decrease rates of typhoid fever in developing nations , the World Health Organization (WHO) endorsed the use of a vaccination program starting in 1999. Vaccination has proven effective at controlling outbreaks in high-incidence areas and is also very cost-effective: prices are normally less than US$1 per dose. Because the price is low, poverty-stricken communities are more willing to take advantage of the vaccinations. Although vaccination programs for typhoid have proven effective, they alone cannot eliminate typhoid fever. Combining vaccines with public-health efforts is the only proven way to control this disease. Since the 1990s, the WHO has recommended two typhoid fever vaccines. The ViPS vaccine is given by injection, and the Ty21a by capsules. Only people over age two are recommended to be vaccinated with the ViPS vaccine, and it requires a revaccination after 2–3 years, with a 55%–72% efficacy. The Ty21a vaccine is recommended for people five and older, lasting 5–7 years with 51%–67% efficacy. The two vaccines have proved safe and effective for epidemic disease control in multiple regions. A version of the vaccine combined with a hepatitis A vaccine is also available. Results of a phase 3 trial of typhoid conjugate vaccine (TCV) in December 2019 reported 81% fewer cases among children. The rediscovery of oral rehydration therapy in the 1960s provided a simple way to prevent many of the deaths of diarrheal diseases in general. Where resistance is uncommon, the treatment of choice is a fluoroquinolone such as ciprofloxacin . Otherwise, a third-generation cephalosporin such as ceftriaxone or cefotaxime is the first choice. Cefixime is a suitable oral alternative. Properly treated, typhoid fever is not fatal in most cases. Antibiotics such as ampicillin , chloramphenicol, trimethoprim-sulfamethoxazole , amoxicillin , and ciprofloxacin have been commonly used to treat it. Treatment with antibiotics reduces the case-fatality rate to about 1%. Without treatment, some patients develop sustained fever, bradycardia, hepatosplenomegaly, abdominal symptoms, and occasionally pneumonia. In white-skinned patients, pink spots, which fade on pressure, appear on the skin of the trunk in up to 20% of cases. In the third week, untreated cases may develop gastrointestinal and cerebral complications, which may prove fatal in 10%–20% of cases. The highest case fatality rates are reported in children under 4. Around 2%–5% of those who contract typhoid fever become chronic carriers, as bacteria persist in the biliary tract after symptoms have resolved. Surgery is usually indicated if intestinal perforation occurs. One study found a 30-day mortality rate of 9% (8/88), and surgical site infections at 67% (59/88), with the disease burden borne predominantly by low-resource countries. For surgical treatment, most surgeons prefer simple closure of the perforation with drainage of the peritoneum . Small-bowel resection is indicated for patients with multiple perforations. If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should be resected. Cholecystectomy is sometimes successful, especially in patients with gallstones , but is not always successful in eradicating the carrier state because of persisting hepatic infection. As resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and streptomycin is now common, these agents are no longer used as first–line treatment of typhoid fever. Typhoid resistant to these agents is known as multidrug-resistant typhoid. Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and Southeast Asia . Many centres are shifting from ciprofloxacin to ceftriaxone as the first line for treating suspected typhoid originating in South America, India, Pakistan, Bangladesh, Thailand, or Vietnam. Also, it has been suggested that azithromycin is better at treating resistant typhoid than both fluoroquinolone drugs and ceftriaxone. Azithromycin can be taken by mouth and is less expensive than ceftriaxone, which is given by injection. A separate problem exists with laboratory testing for reduced susceptibility to ciprofloxacin; current recommendations are that isolates should be tested simultaneously against ciprofloxacin (CIP) and against nalidixic acid (NAL), that isolates sensitive to both CIP and NAL should be reported as "sensitive to ciprofloxacin", and that isolates sensitive to CIP but not to NAL should be reported as "reduced sensitivity to ciprofloxacin". But an analysis of 271 isolates found that around 18% of isolates with a reduced susceptibility to fluoroquinolones , the class which CIP belongs ( MIC 0.125–1.0 mg/L), would not be detected by this method. The rediscovery of oral rehydration therapy in the 1960s provided a simple way to prevent many of the deaths of diarrheal diseases in general. Where resistance is uncommon, the treatment of choice is a fluoroquinolone such as ciprofloxacin . Otherwise, a third-generation cephalosporin such as ceftriaxone or cefotaxime is the first choice. Cefixime is a suitable oral alternative. Properly treated, typhoid fever is not fatal in most cases. Antibiotics such as ampicillin , chloramphenicol, trimethoprim-sulfamethoxazole , amoxicillin , and ciprofloxacin have been commonly used to treat it. Treatment with antibiotics reduces the case-fatality rate to about 1%. Without treatment, some patients develop sustained fever, bradycardia, hepatosplenomegaly, abdominal symptoms, and occasionally pneumonia. In white-skinned patients, pink spots, which fade on pressure, appear on the skin of the trunk in up to 20% of cases. In the third week, untreated cases may develop gastrointestinal and cerebral complications, which may prove fatal in 10%–20% of cases. The highest case fatality rates are reported in children under 4. Around 2%–5% of those who contract typhoid fever become chronic carriers, as bacteria persist in the biliary tract after symptoms have resolved. Surgery is usually indicated if intestinal perforation occurs. One study found a 30-day mortality rate of 9% (8/88), and surgical site infections at 67% (59/88), with the disease burden borne predominantly by low-resource countries. For surgical treatment, most surgeons prefer simple closure of the perforation with drainage of the peritoneum . Small-bowel resection is indicated for patients with multiple perforations. If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should be resected. Cholecystectomy is sometimes successful, especially in patients with gallstones , but is not always successful in eradicating the carrier state because of persisting hepatic infection. As resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and streptomycin is now common, these agents are no longer used as first–line treatment of typhoid fever. Typhoid resistant to these agents is known as multidrug-resistant typhoid. Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and Southeast Asia . Many centres are shifting from ciprofloxacin to ceftriaxone as the first line for treating suspected typhoid originating in South America, India, Pakistan, Bangladesh, Thailand, or Vietnam. Also, it has been suggested that azithromycin is better at treating resistant typhoid than both fluoroquinolone drugs and ceftriaxone. Azithromycin can be taken by mouth and is less expensive than ceftriaxone, which is given by injection. A separate problem exists with laboratory testing for reduced susceptibility to ciprofloxacin; current recommendations are that isolates should be tested simultaneously against ciprofloxacin (CIP) and against nalidixic acid (NAL), that isolates sensitive to both CIP and NAL should be reported as "sensitive to ciprofloxacin", and that isolates sensitive to CIP but not to NAL should be reported as "reduced sensitivity to ciprofloxacin". But an analysis of 271 isolates found that around 18% of isolates with a reduced susceptibility to fluoroquinolones , the class which CIP belongs ( MIC 0.125–1.0 mg/L), would not be detected by this method. In 2000, typhoid fever caused an estimated 21.7 million illnesses and 217,000 deaths. It occurs most often in children and young adults between 5 and 19 years old. In 2013, it resulted in about 161,000 deaths – down from 181,000 in 1990. Infants, children, and adolescents in south-central and Southeast Asia have the highest rates of typhoid. Outbreaks are also often reported in sub-Saharan Africa and Southeast Asia. In 2000, more than 90% of morbidity and mortality due to typhoid fever occurred in Asia. In the U.S., about 400 cases occur each year, 75% of which are acquired while traveling internationally. Before the antibiotic era, the case fatality rate of typhoid fever was 10%–20%. Today, with prompt treatment, it is less than 1%, but 3%–5% of people who are infected develop a chronic infection in the gall bladder. Since S. enterica subsp. enterica serovar Typhi is human-restricted, these chronic carriers become the crucial reservoir, which can persist for decades for further spread of the disease, further complicating its identification and treatment. Lately, the study of S. enterica subsp. enterica serovar Typhi associated with a large outbreak and a carrier at the genome level provides new insight into the pathogenesis of the pathogen. In industrialized nations, water sanitation and food handling improvements have reduced the number of typhoid cases. Third world nations have the highest rates. These areas lack access to clean water, proper sanitation systems, and proper health-care facilities. In these areas, such access to basic public-health needs is not expected in the near future. In 2004–2005 an outbreak in the Democratic Republic of Congo resulted in more than 42,000 cases and 214 deaths. Since November 2016, Pakistan has had an outbreak of extensively drug-resistant (XDR) typhoid fever. In Europe, a report based on data for 2017 retrieved from The European Surveillance System (TESSy) on the distribution of confirmed typhoid and paratyphoid fever cases found that 22 EU/EEA countries reported a total of 1,098 cases, 90.9% of which were travel-related, mainly acquired during travel to South Asia . The plague of Athens , during the Peloponnesian War , was most likely an outbreak of typhoid fever. During the war, Athenians retreated into a walled-in city to escape attack from the Spartans . This massive influx of humans into a concentrated space overwhelmed the water supply and waste infrastructure, likely leading to unsanitary conditions as fresh water became harder to obtain and waste became more difficult to collect and remove beyond the city walls. In 2006, examining the remains for a mass burial site from Athens from around the time of the plague (~430 B.C.) revealed that fragments of DNA similar to modern day S. Typhi DNA were detected, whereas Yersinia pestis (plague), Rickettsia prowazekii (typhus), Mycobacterium tuberculosis , cowpox virus , and Bartonella henselae were not detected in any of the remains tested. It is possible that the Roman emperor Augustus Caesar had either a liver abscess or typhoid fever, and survived by using ice baths and cold compresses as a means of treatment for his fever. There is a statue of the Greek physician, Antonius Musa , who treated his fever. [ citation needed ] The French doctors Pierre-Fidele Bretonneau and Pierre-Charles-Alexandre Louis are credited with describing typhoid fever as a specific disease, unique from typhus . Both doctors performed autopsies on individuals who died in Paris due to fever – and indicated that many had lesions on the Peyer's patches which correlated with distinct symptoms before death. British medics were skeptical of the differentiation between typhoid and typhus because both were endemic to Britain at that time. However, in France only typhoid was present circulating in the population. Pierre-Charlles-Alexandre Louis also performed case studies and statistical analysis to demonstrate that typhoid was contagious – and that persons who already had the disease seemed to be protected. Afterward, several American doctors confirmed these findings, and then Sir William Jenner convinced any remaining skeptics that typhoid is a specific disease recognizable by lesions in the Peyer's patches by examining sixty-six autopsies from fever patients and concluding that the symptoms of headaches, diarrhea, rash spots, and abdominal pain were present only in patients who were found to have intestinal lesions after death; these observations solidified the association of the disease with the intestinal tract and gave the first clue to the route of transmission. In 1847 William Budd learned of an epidemic of typhoid fever in Clifton, and identified that all 13 of 34 residents who had contracted the disease drew their drinking water from the same well. Notably, this observation was two years prior to John Snow first publishing an early version of his theory that contaminated water was the central conduit for transmitting cholera . Budd later became health officer of Bristol and ensured a clean water supply, and documented further evidence of typhoid as a water-borne illness throughout his career. Polish scientist Tadeusz Browicz described a short bacillus in the organs and feces of typhoid victims in 1874. Browicz was able to isolate and grow the bacilli but did not go as far as to insinuate or prove that they caused the disease. In April 1880, three months prior to Eberth's publication, Edwin Klebs described short and filamentous bacilli in the Peyer's patches in typhoid victims. The bacterium's role in disease was speculated but not confirmed. In 1880, Karl Joseph Eberth described a bacillus that he suspected was the cause of typhoid. Eberth is given credit for discovering the bacterium definitively by successfully isolating the same bacterium from 18 of 40 typhoid victims and failing to discover the bacterium present in any "control" victims of other diseases. In 1884, pathologist Georg Theodor August Gaffky (1850–1918) confirmed Eberth's findings. Gaffky isolated the same bacterium as Eberth from the spleen of a typhoid victim, and was able to grow the bacterium on solid media. The organism was given names such as Eberth's bacillus, Eberthella Typhi, and Gaffky-Eberth bacillus. Today, the bacillus that causes typhoid fever goes by the scientific name Salmonella enterica serovar Typhi. Most developed countries had declining rates of typhoid fever throughout the first half of the 20th century due to vaccinations and advances in public sanitation and hygiene. In 1893 attempts were made to chlorinate the water supply in Hamburg , Germany and in 1897 Maidstone , England, was the first town to have its entire water supply chlorinated. In 1905, following an outbreak of typhoid fever, the City of Lincoln, England , instituted permanent water chlorination. The first permanent disinfection of drinking water in the US was made in 1908 to the Jersey City, New Jersey , water supply. Credit for the decision to build the chlorination system has been given to John L. Leal . The chlorination facility was designed by George W. Fuller . Outbreaks in traveling military groups led to the creation of the Lyster bag in 1915; a bag with a faucet which can be hung from a tree or pole, filled with water, and comes with a chlorination tablet to drop into the water. The Lyster bag was essential for the survival of American soldiers in the Vietnam War . There were several occurrences of milk delivery men spreading typhoid fever throughout the communities they served. Although typhoid is not spread through milk itself, there were several examples of milk distributors in many locations watering their milk down with contaminated water, or cleaning the glass bottles the milk was placed in with contaminated water. Boston had two such cases around the turn of the 20th century. In 1899 there were 24 cases of typhoid traced to a single milkman, whose wife had died of typhoid fever a week before the outbreak. In 1908, J.J. Fallon, who was also a milkman, died of typhoid fever. Following his death and confirmation of the typhoid fever diagnosis, the city conducted an investigation of typhoid symptoms and cases along his route and found evidence of a significant outbreak. A month after the outbreak was first reported, the Boston Globe published a short statement declaring the outbreak over, stating "[a]t Jamaica Plain there is a slight increase, the total being 272 cases. Throughout the city there is a total of 348 cases." There was at least one death reported during this outbreak: Mrs. Sophia S. Engstrom, aged 46. Typhoid continued to ravage the Jamaica Plain neighborhood in particular throughout 1908, and several more people were reported dead due to typhoid fever, although these cases were not explicitly linked to the outbreak. The Jamaica Plain neighborhood at that time was home to many working-class and poor immigrants, mostly from Ireland . The most notorious carrier of typhoid fever, but by no means the most destructive, was Mary Mallon , known as Typhoid Mary. Although other cases of human-to-human spread of typhoid were known at the time, the concept of an asymptomatic carrier, who was able to transmit disease, had only been hypothesized and not yet identified or proven. Mary Mallon became the first known example of an asymptomatic carrier of an infectious disease, making typhoid fever the first known disease being transmissible through asymptomatic hosts. The cases and deaths caused by Mallon were mainly upper-class families in New York City. At the time of Mallon's tenure as a personal cook for upper-class families, New York City reported 3,000 to 4,500 cases of typhoid fever annually. In the summer of 1906 two daughters of a wealthy family and maids working in their home became ill with typhoid fever. After investigating their home water sources and ruling out water contamination, the family hired civil engineer George Soper to conduct an investigation of the possible source of typhoid fever in the home. Soper described himself as an "epidemic fighter". His investigation ruled out many sources of food, and led him to question if the cook the family hired just prior to their household outbreak, Mallon, was the source. Since she had already left and begun employment elsewhere, he proceeded to track her down in order to obtain a stool sample. When he was able to finally meet Mallon in person he described her by saying "Mary had a good figure and might have been called athletic had she not been a little too heavy." In recounts of Soper's pursuit of Mallon, his only remorse appears to be that he was not given enough credit for his relentless pursuit and publication of her personal identifying information, stating that the media "rob[s] me of whatever credit belongs to the discovery of the first typhoid fever carrier to be found in America." Ultimately, 51 cases and 3 deaths were suspected to be caused by Mallon. In 1924 the city of Portland, Oregon , experienced an outbreak of typhoid fever, consisting of 26 cases and 5 deaths, all deaths due to intestinal hemorrhage . All cases were concluded to be due to a single milk farm worker, who was shedding large amounts of the typhoid pathogen in his urine. Misidentification of the disease, due to inaccurate Widal test results, delayed identification of the carrier and proper treatment. Ultimately, it took four samplings of different secretions from all of the dairy workers in order to successfully identify the carrier. Upon discovery, the dairy worker was forcibly quarantined for seven weeks, and regular samples were taken, most of the time the stool samples yielding no typhoid and often the urine yielding the pathogen. The carrier was reported as being 72 years old and appearing in excellent health with no symptoms. Pharmaceutical treatment decreased the amount of bacteria secreted, however, the infection was never fully cleared from the urine, and the carrier was released "under orders never again to engage in the handling of foods for human consumption." At the time of release, the authors noted "for more than fifty years he has earned his living chiefly by milking cows and knows little of other forms of labor, it must be expected that the closest surveillance will be necessary to make certain that he does not again engage in this occupation." Overall, in the early 20th century the medical profession began to identify carriers of the disease, and evidence of transmission independent of water contamination. In a 1933 American Medical Association publication, physicians' treatment of asymptomatic carriers is best summarized by the opening line "Carriers of typhoid bacilli are a menace". Within the same publication, the first official estimate of typhoid carriers is given: 2 to 5% of all typhoid patients, and distinguished between temporary carriers and chronic carriers. The authors further estimate that there are four to five chronic female carriers to every one male carrier, although offered no data to explain this assertion of a gender difference in the rate of typhoid carriers. As far as treatment, the authors suggest: "When recognized, carriers must be instructed as to the disposal of excreta as well as to the importance of personal cleanliness. They should be forbidden to handle food or drink intended for others, and their movements and whereabouts must be reported to the public health officers". Today, typhoid carriers exist all over the world, but the highest incidence of asymptomatic infection is likely to occur in South/Southeast Asian and Sub-Saharan countries. The Los Angeles County department of public health tracks typhoid carriers and reports the number of carriers identified within the county yearly; between 2006 and 2016 0–4 new cases of typhoid carriers were identified per year. Cases of typhoid fever must be reported within one working day from identification. As of 2018, chronic typhoid carriers must sign a "Carrier Agreement" and are required to test for typhoid shedding twice yearly, ideally every 6 months. Carriers may be released from their agreements upon fulfilling "release" requirements, based on completion of a personalized treatment plan designed with medical professionals. Fecal or gallbladder carrier release requirements: 6 consecutive negative feces and urine specimens submitted at 1-month or greater intervals beginning at least 7 days after completion of therapy. Urinary or kidney carrier release requirements: 6 consecutive negative urine specimens submitted at 1-month or greater intervals beginning at least 7 days after completion of therapy. Due to the nature of asymptomatic cases, many questions remain about how individuals are able to tolerate infection for long periods of time, how to identify such cases, and efficient options for treatment. Researchers are currently working to understand asymptomatic infection with Salmonella species by studying infections in laboratory animals, which will ultimately lead to improved prevention and treatment options for typhoid carriers. In 2002, John Gunn described the ability of Salmonella sp. to form biofilms on gallstones in mice, providing a model for studying carriage in the gallbladder. Denise Monack and Stanley Falkow described a mouse model of asymptomatic intestinal and systemic infection in 2004, and Monack went on to demonstrate that a sub-population of superspreaders are responsible for the majority of transmission to new hosts, following the 80/20 rule of disease transmission, and that the intestinal microbiota likely plays a role in transmission. Monack 's mouse model allows long-term carriage of salmonella in mesenteric lymph nodes , spleen and liver . British bacteriologist Almroth Edward Wright first developed an effective typhoid vaccine at the Army Medical School in Netley , Hampshire . It was introduced in 1896 and used successfully by the British during the Second Boer War in South Africa. At that time, typhoid often killed more soldiers at war than were lost due to enemy combat. Wright further developed his vaccine at a newly opened research department at St Mary's Hospital Medical School in London from 1902, where he established a method for measuring protective substances ( opsonin ) in human blood. Wright's version of the typhoid vaccine was produced by growing the bacterium at body temperature in broth, then heating the bacteria to 60 °C to "heat inactivate" the pathogen, killing it, while keeping the surface antigens intact. The heat-killed bacteria was then injected into a patient. To show evidence of the vaccine's efficacy, Wright then collected serum samples from patients several weeks post-vaccination, and tested their serum's ability to agglutinate live typhoid bacteria. A "positive" result was represented by clumping of bacteria, indicating that the body was producing anti-serum (now called antibodies ) against the pathogen. Citing the example of the Second Boer War, during which many soldiers died from easily preventable diseases, Wright convinced the British Army that 10 million vaccine doses should be produced for the troops being sent to the Western Front , thereby saving up to half a million lives during World War I . The British Army was the only combatant at the outbreak of the war to have its troops fully immunized against the bacterium. For the first time, their casualties due to combat exceeded those from disease. In 1909, Frederick F. Russell , a U.S. Army physician, adopted Wright's typhoid vaccine for use with the Army, and two years later, his vaccination program became the first in which an entire army was immunized. It eliminated typhoid as a significant cause of morbidity and mortality in the U.S. military. Typhoid vaccination for members of the American military became mandatory in 1911. Before the vaccine, the rate of typhoid fever in the military was 14,000 or greater per 100,000 soldiers. By World War I, the rate of typhoid in American soldiers was 37 per 100,000. During the second world war, the United States army authorized the use of a trivalent vaccine – containing heat-inactivated Typhoid, Paratyphi A and Paratyphi B pathogens. In 1934, discovery of the Vi capsular antigen by Arthur Felix and Miss S. R. Margaret Pitt enabled development of the safer Vi Antigen vaccine – which is widely in use today. Arthur Felix and Margaret Pitt also isolated the strain Ty2, which became the parent strain of Ty21a , the strain used as a live-attenuated vaccine for typhoid fever today. Chloramphenicol was isolated from Streptomyces by David Gotlieb during the 1940s. In 1948 American army doctors tested its efficacy in treating typhoid patients in Kuala Lumpur , Malaysia. Individuals who received a full course of treatment cleared the infection, whereas patients given a lower dose had a relapse. Asymptomatic carriers continued to shed bacilli despite chloramphenicol treatment – only ill patients were improved with chloramphenicol. Resistance to chloramphenicol became frequent in Southeast Asia by the 1950s, and today chloramphenicol is only used as a last resort due to the high prevalence of resistance. The plague of Athens , during the Peloponnesian War , was most likely an outbreak of typhoid fever. During the war, Athenians retreated into a walled-in city to escape attack from the Spartans . This massive influx of humans into a concentrated space overwhelmed the water supply and waste infrastructure, likely leading to unsanitary conditions as fresh water became harder to obtain and waste became more difficult to collect and remove beyond the city walls. In 2006, examining the remains for a mass burial site from Athens from around the time of the plague (~430 B.C.) revealed that fragments of DNA similar to modern day S. Typhi DNA were detected, whereas Yersinia pestis (plague), Rickettsia prowazekii (typhus), Mycobacterium tuberculosis , cowpox virus , and Bartonella henselae were not detected in any of the remains tested. It is possible that the Roman emperor Augustus Caesar had either a liver abscess or typhoid fever, and survived by using ice baths and cold compresses as a means of treatment for his fever. There is a statue of the Greek physician, Antonius Musa , who treated his fever. [ citation needed ]The French doctors Pierre-Fidele Bretonneau and Pierre-Charles-Alexandre Louis are credited with describing typhoid fever as a specific disease, unique from typhus . Both doctors performed autopsies on individuals who died in Paris due to fever – and indicated that many had lesions on the Peyer's patches which correlated with distinct symptoms before death. British medics were skeptical of the differentiation between typhoid and typhus because both were endemic to Britain at that time. However, in France only typhoid was present circulating in the population. Pierre-Charlles-Alexandre Louis also performed case studies and statistical analysis to demonstrate that typhoid was contagious – and that persons who already had the disease seemed to be protected. Afterward, several American doctors confirmed these findings, and then Sir William Jenner convinced any remaining skeptics that typhoid is a specific disease recognizable by lesions in the Peyer's patches by examining sixty-six autopsies from fever patients and concluding that the symptoms of headaches, diarrhea, rash spots, and abdominal pain were present only in patients who were found to have intestinal lesions after death; these observations solidified the association of the disease with the intestinal tract and gave the first clue to the route of transmission. In 1847 William Budd learned of an epidemic of typhoid fever in Clifton, and identified that all 13 of 34 residents who had contracted the disease drew their drinking water from the same well. Notably, this observation was two years prior to John Snow first publishing an early version of his theory that contaminated water was the central conduit for transmitting cholera . Budd later became health officer of Bristol and ensured a clean water supply, and documented further evidence of typhoid as a water-borne illness throughout his career. Polish scientist Tadeusz Browicz described a short bacillus in the organs and feces of typhoid victims in 1874. Browicz was able to isolate and grow the bacilli but did not go as far as to insinuate or prove that they caused the disease. In April 1880, three months prior to Eberth's publication, Edwin Klebs described short and filamentous bacilli in the Peyer's patches in typhoid victims. The bacterium's role in disease was speculated but not confirmed. In 1880, Karl Joseph Eberth described a bacillus that he suspected was the cause of typhoid. Eberth is given credit for discovering the bacterium definitively by successfully isolating the same bacterium from 18 of 40 typhoid victims and failing to discover the bacterium present in any "control" victims of other diseases. In 1884, pathologist Georg Theodor August Gaffky (1850–1918) confirmed Eberth's findings. Gaffky isolated the same bacterium as Eberth from the spleen of a typhoid victim, and was able to grow the bacterium on solid media. The organism was given names such as Eberth's bacillus, Eberthella Typhi, and Gaffky-Eberth bacillus. Today, the bacillus that causes typhoid fever goes by the scientific name Salmonella enterica serovar Typhi. Most developed countries had declining rates of typhoid fever throughout the first half of the 20th century due to vaccinations and advances in public sanitation and hygiene. In 1893 attempts were made to chlorinate the water supply in Hamburg , Germany and in 1897 Maidstone , England, was the first town to have its entire water supply chlorinated. In 1905, following an outbreak of typhoid fever, the City of Lincoln, England , instituted permanent water chlorination. The first permanent disinfection of drinking water in the US was made in 1908 to the Jersey City, New Jersey , water supply. Credit for the decision to build the chlorination system has been given to John L. Leal . The chlorination facility was designed by George W. Fuller . Outbreaks in traveling military groups led to the creation of the Lyster bag in 1915; a bag with a faucet which can be hung from a tree or pole, filled with water, and comes with a chlorination tablet to drop into the water. The Lyster bag was essential for the survival of American soldiers in the Vietnam War . There were several occurrences of milk delivery men spreading typhoid fever throughout the communities they served. Although typhoid is not spread through milk itself, there were several examples of milk distributors in many locations watering their milk down with contaminated water, or cleaning the glass bottles the milk was placed in with contaminated water. Boston had two such cases around the turn of the 20th century. In 1899 there were 24 cases of typhoid traced to a single milkman, whose wife had died of typhoid fever a week before the outbreak. In 1908, J.J. Fallon, who was also a milkman, died of typhoid fever. Following his death and confirmation of the typhoid fever diagnosis, the city conducted an investigation of typhoid symptoms and cases along his route and found evidence of a significant outbreak. A month after the outbreak was first reported, the Boston Globe published a short statement declaring the outbreak over, stating "[a]t Jamaica Plain there is a slight increase, the total being 272 cases. Throughout the city there is a total of 348 cases." There was at least one death reported during this outbreak: Mrs. Sophia S. Engstrom, aged 46. Typhoid continued to ravage the Jamaica Plain neighborhood in particular throughout 1908, and several more people were reported dead due to typhoid fever, although these cases were not explicitly linked to the outbreak. The Jamaica Plain neighborhood at that time was home to many working-class and poor immigrants, mostly from Ireland . The most notorious carrier of typhoid fever, but by no means the most destructive, was Mary Mallon , known as Typhoid Mary. Although other cases of human-to-human spread of typhoid were known at the time, the concept of an asymptomatic carrier, who was able to transmit disease, had only been hypothesized and not yet identified or proven. Mary Mallon became the first known example of an asymptomatic carrier of an infectious disease, making typhoid fever the first known disease being transmissible through asymptomatic hosts. The cases and deaths caused by Mallon were mainly upper-class families in New York City. At the time of Mallon's tenure as a personal cook for upper-class families, New York City reported 3,000 to 4,500 cases of typhoid fever annually. In the summer of 1906 two daughters of a wealthy family and maids working in their home became ill with typhoid fever. After investigating their home water sources and ruling out water contamination, the family hired civil engineer George Soper to conduct an investigation of the possible source of typhoid fever in the home. Soper described himself as an "epidemic fighter". His investigation ruled out many sources of food, and led him to question if the cook the family hired just prior to their household outbreak, Mallon, was the source. Since she had already left and begun employment elsewhere, he proceeded to track her down in order to obtain a stool sample. When he was able to finally meet Mallon in person he described her by saying "Mary had a good figure and might have been called athletic had she not been a little too heavy." In recounts of Soper's pursuit of Mallon, his only remorse appears to be that he was not given enough credit for his relentless pursuit and publication of her personal identifying information, stating that the media "rob[s] me of whatever credit belongs to the discovery of the first typhoid fever carrier to be found in America." Ultimately, 51 cases and 3 deaths were suspected to be caused by Mallon. In 1924 the city of Portland, Oregon , experienced an outbreak of typhoid fever, consisting of 26 cases and 5 deaths, all deaths due to intestinal hemorrhage . All cases were concluded to be due to a single milk farm worker, who was shedding large amounts of the typhoid pathogen in his urine. Misidentification of the disease, due to inaccurate Widal test results, delayed identification of the carrier and proper treatment. Ultimately, it took four samplings of different secretions from all of the dairy workers in order to successfully identify the carrier. Upon discovery, the dairy worker was forcibly quarantined for seven weeks, and regular samples were taken, most of the time the stool samples yielding no typhoid and often the urine yielding the pathogen. The carrier was reported as being 72 years old and appearing in excellent health with no symptoms. Pharmaceutical treatment decreased the amount of bacteria secreted, however, the infection was never fully cleared from the urine, and the carrier was released "under orders never again to engage in the handling of foods for human consumption." At the time of release, the authors noted "for more than fifty years he has earned his living chiefly by milking cows and knows little of other forms of labor, it must be expected that the closest surveillance will be necessary to make certain that he does not again engage in this occupation." Overall, in the early 20th century the medical profession began to identify carriers of the disease, and evidence of transmission independent of water contamination. In a 1933 American Medical Association publication, physicians' treatment of asymptomatic carriers is best summarized by the opening line "Carriers of typhoid bacilli are a menace". Within the same publication, the first official estimate of typhoid carriers is given: 2 to 5% of all typhoid patients, and distinguished between temporary carriers and chronic carriers. The authors further estimate that there are four to five chronic female carriers to every one male carrier, although offered no data to explain this assertion of a gender difference in the rate of typhoid carriers. As far as treatment, the authors suggest: "When recognized, carriers must be instructed as to the disposal of excreta as well as to the importance of personal cleanliness. They should be forbidden to handle food or drink intended for others, and their movements and whereabouts must be reported to the public health officers". Today, typhoid carriers exist all over the world, but the highest incidence of asymptomatic infection is likely to occur in South/Southeast Asian and Sub-Saharan countries. The Los Angeles County department of public health tracks typhoid carriers and reports the number of carriers identified within the county yearly; between 2006 and 2016 0–4 new cases of typhoid carriers were identified per year. Cases of typhoid fever must be reported within one working day from identification. As of 2018, chronic typhoid carriers must sign a "Carrier Agreement" and are required to test for typhoid shedding twice yearly, ideally every 6 months. Carriers may be released from their agreements upon fulfilling "release" requirements, based on completion of a personalized treatment plan designed with medical professionals. Fecal or gallbladder carrier release requirements: 6 consecutive negative feces and urine specimens submitted at 1-month or greater intervals beginning at least 7 days after completion of therapy. Urinary or kidney carrier release requirements: 6 consecutive negative urine specimens submitted at 1-month or greater intervals beginning at least 7 days after completion of therapy. Due to the nature of asymptomatic cases, many questions remain about how individuals are able to tolerate infection for long periods of time, how to identify such cases, and efficient options for treatment. Researchers are currently working to understand asymptomatic infection with Salmonella species by studying infections in laboratory animals, which will ultimately lead to improved prevention and treatment options for typhoid carriers. In 2002, John Gunn described the ability of Salmonella sp. to form biofilms on gallstones in mice, providing a model for studying carriage in the gallbladder. Denise Monack and Stanley Falkow described a mouse model of asymptomatic intestinal and systemic infection in 2004, and Monack went on to demonstrate that a sub-population of superspreaders are responsible for the majority of transmission to new hosts, following the 80/20 rule of disease transmission, and that the intestinal microbiota likely plays a role in transmission. Monack 's mouse model allows long-term carriage of salmonella in mesenteric lymph nodes , spleen and liver . British bacteriologist Almroth Edward Wright first developed an effective typhoid vaccine at the Army Medical School in Netley , Hampshire . It was introduced in 1896 and used successfully by the British during the Second Boer War in South Africa. At that time, typhoid often killed more soldiers at war than were lost due to enemy combat. Wright further developed his vaccine at a newly opened research department at St Mary's Hospital Medical School in London from 1902, where he established a method for measuring protective substances ( opsonin ) in human blood. Wright's version of the typhoid vaccine was produced by growing the bacterium at body temperature in broth, then heating the bacteria to 60 °C to "heat inactivate" the pathogen, killing it, while keeping the surface antigens intact. The heat-killed bacteria was then injected into a patient. To show evidence of the vaccine's efficacy, Wright then collected serum samples from patients several weeks post-vaccination, and tested their serum's ability to agglutinate live typhoid bacteria. A "positive" result was represented by clumping of bacteria, indicating that the body was producing anti-serum (now called antibodies ) against the pathogen. Citing the example of the Second Boer War, during which many soldiers died from easily preventable diseases, Wright convinced the British Army that 10 million vaccine doses should be produced for the troops being sent to the Western Front , thereby saving up to half a million lives during World War I . The British Army was the only combatant at the outbreak of the war to have its troops fully immunized against the bacterium. For the first time, their casualties due to combat exceeded those from disease. In 1909, Frederick F. Russell , a U.S. Army physician, adopted Wright's typhoid vaccine for use with the Army, and two years later, his vaccination program became the first in which an entire army was immunized. It eliminated typhoid as a significant cause of morbidity and mortality in the U.S. military. Typhoid vaccination for members of the American military became mandatory in 1911. Before the vaccine, the rate of typhoid fever in the military was 14,000 or greater per 100,000 soldiers. By World War I, the rate of typhoid in American soldiers was 37 per 100,000. During the second world war, the United States army authorized the use of a trivalent vaccine – containing heat-inactivated Typhoid, Paratyphi A and Paratyphi B pathogens. In 1934, discovery of the Vi capsular antigen by Arthur Felix and Miss S. R. Margaret Pitt enabled development of the safer Vi Antigen vaccine – which is widely in use today. Arthur Felix and Margaret Pitt also isolated the strain Ty2, which became the parent strain of Ty21a , the strain used as a live-attenuated vaccine for typhoid fever today. Chloramphenicol was isolated from Streptomyces by David Gotlieb during the 1940s. In 1948 American army doctors tested its efficacy in treating typhoid patients in Kuala Lumpur , Malaysia. Individuals who received a full course of treatment cleared the infection, whereas patients given a lower dose had a relapse. Asymptomatic carriers continued to shed bacilli despite chloramphenicol treatment – only ill patients were improved with chloramphenicol. Resistance to chloramphenicol became frequent in Southeast Asia by the 1950s, and today chloramphenicol is only used as a last resort due to the high prevalence of resistance. The disease has been referred to by various names, often associated with symptoms, such as gastric fever, enteric fever, abdominal typhus, infantile remittant fever, slow fever, nervous fever, pythogenic fever, drain fever, and low fever.

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Acute hemorrhagic fever syndrome

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Takotsubo cardiomyopathy

Takotsubo cardiomyopathy or takotsubo syndrome (TTS), also known as stress cardiomyopathy , is a type of non- ischemic cardiomyopathy in which there is a sudden temporary weakening of the muscular portion of the heart . It usually appears after a significant stressor, either physical or emotional; when caused by the latter, the condition is sometimes called broken heart syndrome . Examples of physical stressors that can cause TTS are sepsis, shock, subarachnoid hemorrhage, and pheochromocytoma . Emotional stressors include bereavement, divorce, or the loss of a job. Reviews suggest that of patients diagnosed with the condition, about 70–80% recently experienced a major stressor, including 41–50% with a physical stressor and 26–30% with an emotional stressor. TTS can also appear in patients who have not experienced major stressors. The pathophysiology is not well understood, but a sudden massive surge of catecholamines such as adrenaline and norepinephrine from extreme stress or a tumor secreting these chemicals is thought to play a central role. Excess catecholamines, when released directly by nerves that stimulate cardiac muscle cells, have a toxic effect and can lead to decreased cardiac muscular function or "stunning". Further, this adrenaline surge triggers the arteries to tighten , thereby raising blood pressure and placing more stress on the heart, and may lead to spasm of the coronary arteries that supply blood to the heart muscle. This impairs the arteries from delivering adequate blood flow and oxygen to the heart muscle. Together, these events can lead to congestive heart failure and decrease the heart's output of blood with each squeeze. Takotsubo cardiomyopathy occurs worldwide. The condition is thought to be responsible for 2% of all acute coronary syndrome cases presenting to hospitals. Although TTS has generally been considered a self-limiting disease, spontaneously resolving over the course of days to weeks, contemporary observations show that "a subset of TTS patients may present with symptoms arising from its complications, e.g. heart failure, pulmonary edema, stroke, cardiogenic shock, or cardiac arrest". This does not imply that rates of shock/death of TTS are comparable to those of acute coronary syndrome (ACS), but that patients with acute complications may co-occur with TTS. These cases of shock and death have been associated with the occurrence of TTS secondary to an inciting physical stressor such as hemorrhage , brain injury sepsis , pulmonary embolism or severe COPD . It occurs more commonly in postmenopausal women. The name "takotsubo" comes from the Japanese word takotsubo "octopus trap", because the left ventricle of the heart takes on a shape resembling an octopus trap when affected by this condition. A study published in the Journal of the American Heart Association in October 2021 found a steady annual increase in takotsubo cardiomyopathy among both women and men from 2006 to 2017, with the sharpest increases among women 50 and older. The typical presentation of takotsubo cardiomyopathy is chest pain with or without shortness of breath and associated electrocardiogram (ECG) changes mimicking a myocardial infarction of the anterior wall . During the course of evaluation of the patient, a bulging out of the left ventricular apex with a hypercontractile base of the left ventricle is often noted. It is the hallmark bulging-out of the apex of the heart with preserved function of the base that earned the syndrome its name takotsubo "octopus trap" , in Japan , where it was first described. Stress is the main factor in takotsubo cardiomyopathy, with more than 85% of cases set in motion by either a physically or emotionally stressful event that prefaces the start of symptoms. Examples of emotional stressors include grief from the death of a loved one, fear of public speaking, arguing with a spouse, relationship disagreements, betrayal, and financial problems. Acute asthma , surgery, subarachnoid hemorrhage , chemotherapy , and stroke are examples of physical stressors. In a few cases, the stress may be a happy event, such as a wedding, winning a jackpot, a sporting triumph, or a birthday. Although there have been documented cases of TTS without a triggering stressor, it is widely recognized that TTS is preceded by a stressful or emotional event. Case series looking at large groups of patients report that some patients develop takotsubo cardiomyopathy after experiencing emotional stress. Some patients have a preceding clinical stressor (such as a brain injury, asthma attack or exacerbation of a chronic illness) and research has indicated that this type of stress may even occur more often than emotionally stressful triggers. Roughly one-third of patients have no preceding stressful event. A 2009 large case series from Europe found that takotsubo cardiomyopathy was slightly more frequent during the winter season. This may be related to two possible/suspected pathophysiological causes: coronary spasms of microvessels, which are more prevalent in cold weather, and viral infections – such as Parvovirus B19 – which occur more frequently during the winter. Women, specifically postmenopausal women, are at greatest risk of developing TTS. This has led some researchers to theorize about the possible protective effects of estrogen in preventing TTS. It is currently being investigated if certain genetic traits associated with catecholamine receptors found on cardiac muscle cells play a role in the development of TTS. There is limited evidence tying TTS directly to a specific genetic expression or mutation, however there is currently a widely held hypothesis supporting the idea of the interaction between environmental factors and the interplay of genetic predisposition leading to the susceptibility to microvascular alterations that contribute to the TTS disease process. Certain endocrine diseases including pheochromocytoma and thyrotoxicosis have been identified as potential risk factors for TTS. The relationship between thyroid function and stress cardiomyopathy is marked by a dual phenotype, where both impending primary hyperthyroidism and a high set point of thyroid homeostasis (encoding type 2 allostatic load ) are common phenomena. A multi-centre observation study found normal thyroid function to be the exception rather than the rule in TTS. Especially hyperthyroidism is highly prevalent in takotsubo cardiomyopathy, and it seems to predict a poor prognosis in terms of complications and mortality. This observation was confirmed by results of the international GEIST registry, which demonstrated that thyrotoxicosis is associated with significantly increased fatality, whereas hypothyroidism indicates a better survial. Although there have been documented cases of TTS without a triggering stressor, it is widely recognized that TTS is preceded by a stressful or emotional event. Case series looking at large groups of patients report that some patients develop takotsubo cardiomyopathy after experiencing emotional stress. Some patients have a preceding clinical stressor (such as a brain injury, asthma attack or exacerbation of a chronic illness) and research has indicated that this type of stress may even occur more often than emotionally stressful triggers. Roughly one-third of patients have no preceding stressful event. A 2009 large case series from Europe found that takotsubo cardiomyopathy was slightly more frequent during the winter season. This may be related to two possible/suspected pathophysiological causes: coronary spasms of microvessels, which are more prevalent in cold weather, and viral infections – such as Parvovirus B19 – which occur more frequently during the winter. Women, specifically postmenopausal women, are at greatest risk of developing TTS. This has led some researchers to theorize about the possible protective effects of estrogen in preventing TTS. It is currently being investigated if certain genetic traits associated with catecholamine receptors found on cardiac muscle cells play a role in the development of TTS. There is limited evidence tying TTS directly to a specific genetic expression or mutation, however there is currently a widely held hypothesis supporting the idea of the interaction between environmental factors and the interplay of genetic predisposition leading to the susceptibility to microvascular alterations that contribute to the TTS disease process. Certain endocrine diseases including pheochromocytoma and thyrotoxicosis have been identified as potential risk factors for TTS. The relationship between thyroid function and stress cardiomyopathy is marked by a dual phenotype, where both impending primary hyperthyroidism and a high set point of thyroid homeostasis (encoding type 2 allostatic load ) are common phenomena. A multi-centre observation study found normal thyroid function to be the exception rather than the rule in TTS. Especially hyperthyroidism is highly prevalent in takotsubo cardiomyopathy, and it seems to predict a poor prognosis in terms of complications and mortality. This observation was confirmed by results of the international GEIST registry, which demonstrated that thyrotoxicosis is associated with significantly increased fatality, whereas hypothyroidism indicates a better survial. The cause of takotsubo cardiomyopathy is not fully understood, but several mechanisms have been proposed. It is well documented that elevated catecholamine levels have been implicated in the vast majority of TTS cases. Theories suggest a link between brain activation of stress-related biochemicals (including neuropeptides ) and the effects these chemicals have on areas of the heart, especially neuropeptide Y . More specifically, adrenal stimulation by the sympathetic nervous system has been noted in cases ranging from physical events such as ischemic stroke, to emotional events such as depression or loss of a loved-one. How these increased levels of catecholamines act in the body to produce the changes seen with TTS is not clearly understood. Research supports the widely-held understanding that microvascular dysfunction and coronary vasospasm caused by a rapid influx of catecholamines to cardiac myocytes results in apical stunning and transient cardiomyopathy. It is likely that there are multiple factors at play that could include some amount of vasospasm and failure of the microvasculature. These factors can overlap and create the complex sequela leading to ischemia and left ventricle contraction abnormality. For instance, estrogen, which confers protection to women by improving blood flow to heart muscle, is one biochemical pathway implicated in the TTS disease process. Once this protective mechanism is reduced through the decreased production of estrogen after menopause, there is thought to be an increase in endothelial dysfunction predisposing an individual to vasoconstriction and cardiac ischemia. An inciting stressful event elicits the release of catecholamines into the blood stream to create increased heart muscle activity and metabolism. This leads to further cardiac microvascular endothelial dysfunction through oxidative stress, alteration of ion-mediated channels, and electrolyte disturbances which ultimately alter myocardial cell membrane permeability and dysfunction. Coupled with direct heart muscle toxicity, this crescendo of factors are implicated in the ballooning and heart failure characteristically seen in TTS. A 2019 case involved a 60-year-old woman presenting with Takotsubo cardiomyopathy due to over-consumption of wasabi , mistaking it for avocado . Several well regarded institutions of medical research have produced clinical criteria useful in diagnosing TTS. One of the first sets of guidelines was initially published in 2004 and again in 2008 by the Mayo Clinic . Other research institutions proposing diagnostic criteria include the Japanese Takotsubo Cardiomyopathy Study Group, Gothenburg University , Johns Hopkins University , the Takotsubo Italian Network and the Heart Failure Associates TTS Taskforce of the European Society of Cardiology . All of the research institutions agree on at least two main criteria needed to accurately diagnose TTS: 1) transient left ventricular wall motion abnormality and 2) the absence of a condition obviously explaining this wall motion abnormality (coronary artery lesion, hypoperfusion, myocarditis, toxicity, etc.). Other commonly acknowledged criteria necessary for diagnosis include characteristic EKG changes and mild to modest elevation in cardiac troponin . Transient apical ballooning syndrome or takotsubo cardiomyopathy is found in 1.7–2.2% of patients presenting with acute coronary syndrome . While the original case studies reported on individuals in Japan, takotsubo cardiomyopathy has been noted more recently in the United States and Western Europe. It is likely that the syndrome previously went undiagnosed before it was described in detail in the Japanese literature. Evaluation of individuals with takotsubo cardiomyopathy typically includes a coronary angiogram to rule out occlusion of the left anterior descending artery, which will not reveal any significant blockages that would cause the left ventricular dysfunction. Provided that the individual survives their initial presentation, the left ventricular function improves within two months. [ citation needed ] The diagnosis of takotsubo cardiomyopathy may be difficult upon presentation. The ECG findings often are confused with those found during an acute anterior wall myocardial infarction . It classically mimics ST-segment elevation myocardial infarction, and is characterised by acute onset of transient ventricular apical wall motion abnormalities (ballooning) accompanied by chest pain , shortness of breath , ST-segment elevation, T-wave inversion or QT-interval prolongation on ECG . Cardiac enzymes are usually negative and are moderate at worst, and cardiac catheterization usually shows absence of significant coronary artery disease . The diagnosis is made by the pathognomonic wall motion abnormalities, in which the base of the left ventricle is contracting normally or is hyperkinetic while the remainder of the left ventricle is akinetic or dyskinetic . This is accompanied by the lack of significant coronary artery disease that would explain the wall motion abnormalities. Although apical ballooning has been described classically as the angiographic manifestation of takotsubo, it has been shown that left ventricular dysfunction in this syndrome includes not only the classic apical ballooning, but also different angiographic morphologies such as mid-ventricular ballooning and, rarely, local ballooning of other segments. The ballooning patterns were classified by Shimizu et al. as takotsubo type for apical akinesia and basal hyperkinesia, reverse takotsubo for basal akinesia and apical hyperkinesia, mid-ventricular type for mid-ventricular ballooning accompanied by basal and apical hyperkinesia, and localised type for any other segmental left ventricular ballooning with clinical characteristics of takotsubo-like left ventricular dysfunction. In short, the main criteria for the diagnosis of takotsubo cardiomyopathy are: the patient must have experienced a stressor before the symptoms began to arise; the patient's ECG reading must show abnormalities from a normal heart; the patient must not show signs of coronary blockage or other common causes of heart troubles; the levels of cardiac enzymes in the heart must be elevated or irregular; and the patient must recover complete contraction and be functioning normally in a short amount of time. The treatment of takotsubo cardiomyopathy is generally supportive in nature, for it is considered a transient disorder. Treatment is dependent on whether patients experience heart failure or acute hypotension and shock. In many individuals, left ventricular function normalizes within two months. Aspirin and other heart drugs also appear to help in the treatment of this disease, even in extreme cases. After the patient has been diagnosed, and myocardial infarction (heart attack) ruled out, the aspirin regimen may be discontinued, and treatment becomes that of supporting the patient. There is currently no internationally agreed protocol for treatment of this condition. [ citation needed ] While medical treatments are important to address the acute symptoms of takotsubo cardiomyopathy, further treatment includes lifestyle changes. It is important that the individual stay physically healthy while learning and maintaining methods to manage stress, and to cope with future difficult situations. [ citation needed ] Although the symptoms of takotsubo cardiomyopathy usually go away on their own and the condition completely resolves itself within a few weeks, some serious short and long-term complications can happen that must be treated. These most commonly include congestive heart failure and very low blood pressure , and less commonly include blood clotting in the apex of the left ventricle, irregular heart beat , and tearing of the heart wall . For patients in acute heart failure, ACE inhibitors , angiotensin receptor blockers , and beta blockers , are considered mainstays of heart failure treatment. But use of beta blockers specifically for takotsubo cardiomyopathy is controversial, because they may confer no benefit. For people with cardiogenic shock, medical treatment is based on whether a left ventricular outflow tract (LVOT) obstruction is present. Therefore, early echocardiography is necessary to determine proper management. For those with obstructed LVOTs inotropic agents should not be used, but instead should be managed like patients with hypertrophic cardiomyopathy , (e.g. phenylephrine and fluid resuscitation ). For cases in which the LVOT is not obstructed, inotropic therapy (e.g. dobutamine and dopamine ) may be used, but with the consideration that takotsubo is caused by excess catecholamines. Furthermore, mechanical circulatory support (MCS) with an intra-aortic balloon pump (IABP) is well-established as supportive treatment. For patients in acute heart failure, ACE inhibitors , angiotensin receptor blockers , and beta blockers , are considered mainstays of heart failure treatment. But use of beta blockers specifically for takotsubo cardiomyopathy is controversial, because they may confer no benefit. For people with cardiogenic shock, medical treatment is based on whether a left ventricular outflow tract (LVOT) obstruction is present. Therefore, early echocardiography is necessary to determine proper management. For those with obstructed LVOTs inotropic agents should not be used, but instead should be managed like patients with hypertrophic cardiomyopathy , (e.g. phenylephrine and fluid resuscitation ). For cases in which the LVOT is not obstructed, inotropic therapy (e.g. dobutamine and dopamine ) may be used, but with the consideration that takotsubo is caused by excess catecholamines. Furthermore, mechanical circulatory support (MCS) with an intra-aortic balloon pump (IABP) is well-established as supportive treatment. Despite the grave initial presentation in some of the patients, most of the patients survive the initial acute event, with a very low rate of in-hospital mortality or complications. Once a patient has recovered from the acute stage of the syndrome, they can expect a favorable outcome and the long-term prognosis is excellent for most. Even when ventricular systolic function is heavily compromised at presentation, it typically improves within the first few days and normalises within the first few months. Although infrequent, recurrence of the syndrome has been reported and seems to be associated with the nature of the trigger. While men experience TTS at much lower rates than women, they also experience much higher rates of complication, reoccurrence, and mortality; the cause of this sex difference is still unknown, but it is hypothesized that the social aspect of the doctor-patient interaction affects the way that physicians recognize and generate individual treatment plans for men compared to women. Stress cardiomyopathy is now a well-recognized cause of acute congestive heart failure , lethal abnormal heart rhythms , and rupture of the heart wall . Takotsubo syndrome represents about 2% of all patients (and 5–6% of all female patients) who are initially diagnosed with acute coronary syndrome (ACS). It accounts for 0.02% of all hospitalizations in the US. About 90% of TTS patients are women, whose mean age is about 68 years, and 80% of whom are older than 50 years. About 2.2% of TTS cases had the reversed (basal) variant. Recurrence rate of TTS is about 1.8% per-patient year. Rees, et al. wrote in 1967 that the death of a close relative increases the risk of dying within one year by a factor of seven. Engel wrote about sudden and rapid death during psychological stress in 1971 and itemized 8 causation categories: (1) on the impact of the collapse or death of a close person; (2) during acute grief; (3) on threat of loss of a close person; (4) during mourning or on an anniversary; (5) on loss of status or self-esteem; (6) personal danger or threat of injury; (7) after the danger is over; (8) reunion, triumph, or happy ending. He proposed these events provoke neurovegetative responses, involving both the flight-fight and conservation-withdrawal systems, conducive to lethal cardiac events, particularly in individuals with preexisting cardiovascular disease. Although the first scientific description of takotsubo cardiomyopathy was not until the 1990s, Cebelin and Hirsch wrote about human stress cardiomyopathy in 1980. The two looked at homicidal assaults that had happened in Cuyahoga County, Ohio , the past 30 years, specifically those with autopsies who had no internal injury, but had died of physical assault. They found that 11 of 15 had myofibrillar degeneration similar to animal stress studies. In the end, they concluded their data supported "the theory of catecholamine mediation of these myocardial changes in man and of the lethal potential of stress through its effect on the heart". The syndrome reached international audiences through the media in 2005 when the New England Journal of Medicine wrote about the syndrome.

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Acute hemorrhagic fever syndrome

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Smallpox

Smallpox was an infectious disease caused by variola virus (often called smallpox virus), which belongs to the genus Orthopoxvirus . The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) certified the global eradication of the disease in 1980, making smallpox the only human disease to have been eradicated to date. The initial symptoms of the disease included fever and vomiting. This was followed by formation of ulcers in the mouth and a skin rash . Over a number of days, the skin rash turned into the characteristic fluid-filled blisters with a dent in the center. The bumps then scabbed over and fell off, leaving scars. The disease was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person or (rarely) via contaminated objects . Prevention was achieved mainly through the smallpox vaccine . Once the disease had developed, certain antiviral medications could potentially have helped, but such medications did not become available until after the disease was eradicated. The risk of death was about 30%, with higher rates among babies. Often, those who survived had extensive scarring of their skin, and some were left blind. The earliest evidence of the disease dates to around 1500 BC in Egyptian mummies . The disease historically occurred in outbreaks . In 18th-century Europe, it is estimated that 400,000 people died from the disease per year, and that one-third of all cases of blindness were due to smallpox. Smallpox is estimated to have killed up to 300 million people in the 20th century and around 500 million people in the last 100 years of its existence. Earlier deaths included six European monarchs , including Louis XV of France in 1774. As recently as 1967, 15 million cases occurred a year. Inoculation for smallpox appears to have started in China around the 1500s. Europe adopted this practice from Asia in the first half of the 18th century. In 1796, Edward Jenner introduced the modern smallpox vaccine. In 1967, the WHO intensified efforts to eliminate the disease. Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest (a disease of even-toed ungulates ) in 2011. The term "smallpox" was first used in England in the 16th century to distinguish the disease from syphilis , which was then known as the "great pox". Other historical names for the disease include pox, speckled monster, and red plague. There are two forms of the smallpox. Variola major is the severe and most common form, with a more extensive rash and higher fever. Variola minor is a less common presentation, causing less severe disease, typically discrete smallpox, with historical death rates of 1% or less. Subclinical ( asymptomatic ) infections with variola virus were noted but were not common. In addition, a form called variola sine eruptione (smallpox without rash) was seen generally in vaccinated persons. This form was marked by a fever that occurred after the usual incubation period and could be confirmed only by antibody studies or, rarely, by viral culture . In addition, there were two very rare and fulminating types of smallpox, the malignant (flat) and hemorrhagic forms, which were usually fatal.The initial symptoms were similar to other viral diseases that are still extant, such as influenza and the common cold : fever of at least 38.3 °C (101 °F) , muscle pain , malaise , headache and fatigue. As the digestive tract was commonly involved, nausea, vomiting, and backache often occurred. The early prodromal stage usually lasted 2–4 days. By days 12–15, the first visible lesions – small reddish spots called enanthem – appeared on mucous membranes of the mouth, tongue, palate , and throat, and the temperature fell to near-normal. These lesions rapidly enlarged and ruptured, releasing large amounts of virus into the saliva. Variola virus tended to attack skin cells, causing the characteristic pimples, or macules , associated with the disease. A rash developed on the skin 24 to 48 hours after lesions on the mucous membranes appeared. Typically the macules first appeared on the forehead, then rapidly spread to the whole face, proximal portions of extremities, the trunk, and lastly to distal portions of extremities. The process took no more than 24 to 36 hours, after which no new lesions appeared. At this point, variola major disease could take several very different courses, which resulted in four types of smallpox disease based on the Rao classification: ordinary, modified, malignant (or flat), and hemorrhagic smallpox. Historically, ordinary smallpox had an overall fatality rate of about 30%, and the malignant and hemorrhagic forms were usually fatal. The modified form was almost never fatal. In early hemorrhagic cases, hemorrhages occurred before any skin lesions developed. The incubation period between contraction and the first obvious symptoms of the disease was 7–14 days. At least 90% of smallpox cases among unvaccinated persons were of the ordinary type. In this form of the disease, by the second day of the rash the macules had become raised papules . By the third or fourth day, the papules had filled with an opalescent fluid to become vesicles . This fluid became opaque and turbid within 24–48 hours, resulting in pustules . By the sixth or seventh day, all the skin lesions had become pustules. Between seven and ten days the pustules had matured and reached their maximum size. The pustules were sharply raised, typically round, tense, and firm to the touch. The pustules were deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaked from the pustules, and by the end of the second week, the pustules had deflated and began to dry up, forming crusts or scabs. By day 16–20 scabs had formed over all of the lesions, which had started to flake off, leaving depigmented scars. Ordinary smallpox generally produced a discrete rash, in which the pustules stood out on the skin separately. The distribution of the rash was most dense on the face, denser on the extremities than on the trunk, and denser on the distal parts of the extremities than on the proximal. The palms of the hands and soles of the feet were involved in most cases. Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%. Referring to the character of the eruption and the rapidity of its development, modified smallpox occurred mostly in previously vaccinated people. It was rare in unvaccinated people, with one case study showing 1–2% of modified cases compared to around 25% in vaccinated people. In this form, the prodromal illness still occurred but may have been less severe than in the ordinary type. There was usually no fever during the evolution of the rash. The skin lesions tended to be fewer and evolved more quickly, were more superficial, and may not have shown the uniform characteristic of more typical smallpox. Modified smallpox was rarely, if ever, fatal. This form of variola major was more easily confused with chickenpox . In malignant-type smallpox (also called flat smallpox) the lesions remained almost flush with the skin at the time when raised vesicles would have formed in the ordinary type. It is unknown why some people developed this type. Historically, it accounted for 5–10% of cases, and most (72%) were children. Malignant smallpox was accompanied by a severe prodromal phase that lasted 3–4 days, prolonged high fever, and severe symptoms of viremia . The prodromal symptoms continued even after the onset of the rash. The rash on the mucous membranes ( enanthem ) was extensive. Skin lesions matured slowly, were typically confluent or semi-confluent, and by the seventh or eighth day, they were flat and appeared to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contained little fluid, were soft and velvety to the touch, and may have contained hemorrhages. Malignant smallpox was nearly always fatal and death usually occurred between the 8th and 12th day of illness. Often, a day or two before death, the lesions turned ashen gray, which, along with abdominal distension, was a bad prognostic sign. This form is thought to be caused by deficient cell-mediated immunity to smallpox. If the person recovered, the lesions gradually faded and did not form scars or scabs. Hemorrhagic smallpox is a severe form accompanied by extensive bleeding into the skin, mucous membranes, gastrointestinal tract, and viscera . This form develops in approximately 2% of infections and occurs mostly in adults. Pustules do not typically form in hemorrhagic smallpox. Instead, bleeding occurs under the skin, making it look charred and black, hence this form of the disease is also referred to as variola nigra or "black pox". Hemorrhagic smallpox has very rarely been caused by variola minor virus. While bleeding may occur in mild cases and not affect outcomes, hemorrhagic smallpox is typically fatal. Vaccination does not appear to provide any immunity to either form of hemorrhagic smallpox and some cases even occurred among people that were revaccinated shortly before. It has two forms. The early or fulminant form of hemorrhagic smallpox (referred to as purpura variolosa ) begins with a prodromal phase characterized by a high fever, severe headache, and abdominal pain. The skin becomes dusky and erythematous, and this is rapidly followed by the development of petechiae and bleeding in the skin, conjunctiva and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before. Autopsy reveals petechiae and bleeding in the spleen, kidney, serous membranes , skeletal muscles, pericardium , liver, gonads and bladder. Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy. This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males). The case fatality rate of early hemorrhagic smallpox approaches 100%. There is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or variolosa pustula hemorrhagica ). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease. Bleeding appears in the early eruptive period (but later than that seen in purpura variolosa ), and the rash is often flat and does not progress beyond the vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form. Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin . This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on the virulence of the smallpox strain. Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence. The case fatality rate for late hemorrhagic smallpox is around 90–95%. Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox. At least 90% of smallpox cases among unvaccinated persons were of the ordinary type. In this form of the disease, by the second day of the rash the macules had become raised papules . By the third or fourth day, the papules had filled with an opalescent fluid to become vesicles . This fluid became opaque and turbid within 24–48 hours, resulting in pustules . By the sixth or seventh day, all the skin lesions had become pustules. Between seven and ten days the pustules had matured and reached their maximum size. The pustules were sharply raised, typically round, tense, and firm to the touch. The pustules were deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaked from the pustules, and by the end of the second week, the pustules had deflated and began to dry up, forming crusts or scabs. By day 16–20 scabs had formed over all of the lesions, which had started to flake off, leaving depigmented scars. Ordinary smallpox generally produced a discrete rash, in which the pustules stood out on the skin separately. The distribution of the rash was most dense on the face, denser on the extremities than on the trunk, and denser on the distal parts of the extremities than on the proximal. The palms of the hands and soles of the feet were involved in most cases. Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%. Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%. Referring to the character of the eruption and the rapidity of its development, modified smallpox occurred mostly in previously vaccinated people. It was rare in unvaccinated people, with one case study showing 1–2% of modified cases compared to around 25% in vaccinated people. In this form, the prodromal illness still occurred but may have been less severe than in the ordinary type. There was usually no fever during the evolution of the rash. The skin lesions tended to be fewer and evolved more quickly, were more superficial, and may not have shown the uniform characteristic of more typical smallpox. Modified smallpox was rarely, if ever, fatal. This form of variola major was more easily confused with chickenpox . In malignant-type smallpox (also called flat smallpox) the lesions remained almost flush with the skin at the time when raised vesicles would have formed in the ordinary type. It is unknown why some people developed this type. Historically, it accounted for 5–10% of cases, and most (72%) were children. Malignant smallpox was accompanied by a severe prodromal phase that lasted 3–4 days, prolonged high fever, and severe symptoms of viremia . The prodromal symptoms continued even after the onset of the rash. The rash on the mucous membranes ( enanthem ) was extensive. Skin lesions matured slowly, were typically confluent or semi-confluent, and by the seventh or eighth day, they were flat and appeared to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contained little fluid, were soft and velvety to the touch, and may have contained hemorrhages. Malignant smallpox was nearly always fatal and death usually occurred between the 8th and 12th day of illness. Often, a day or two before death, the lesions turned ashen gray, which, along with abdominal distension, was a bad prognostic sign. This form is thought to be caused by deficient cell-mediated immunity to smallpox. If the person recovered, the lesions gradually faded and did not form scars or scabs. Hemorrhagic smallpox is a severe form accompanied by extensive bleeding into the skin, mucous membranes, gastrointestinal tract, and viscera . This form develops in approximately 2% of infections and occurs mostly in adults. Pustules do not typically form in hemorrhagic smallpox. Instead, bleeding occurs under the skin, making it look charred and black, hence this form of the disease is also referred to as variola nigra or "black pox". Hemorrhagic smallpox has very rarely been caused by variola minor virus. While bleeding may occur in mild cases and not affect outcomes, hemorrhagic smallpox is typically fatal. Vaccination does not appear to provide any immunity to either form of hemorrhagic smallpox and some cases even occurred among people that were revaccinated shortly before. It has two forms. The early or fulminant form of hemorrhagic smallpox (referred to as purpura variolosa ) begins with a prodromal phase characterized by a high fever, severe headache, and abdominal pain. The skin becomes dusky and erythematous, and this is rapidly followed by the development of petechiae and bleeding in the skin, conjunctiva and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before. Autopsy reveals petechiae and bleeding in the spleen, kidney, serous membranes , skeletal muscles, pericardium , liver, gonads and bladder. Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy. This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males). The case fatality rate of early hemorrhagic smallpox approaches 100%. There is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or variolosa pustula hemorrhagica ). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease. Bleeding appears in the early eruptive period (but later than that seen in purpura variolosa ), and the rash is often flat and does not progress beyond the vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form. Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin . This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on the virulence of the smallpox strain. Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence. The case fatality rate for late hemorrhagic smallpox is around 90–95%. Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox. The early or fulminant form of hemorrhagic smallpox (referred to as purpura variolosa ) begins with a prodromal phase characterized by a high fever, severe headache, and abdominal pain. The skin becomes dusky and erythematous, and this is rapidly followed by the development of petechiae and bleeding in the skin, conjunctiva and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before. Autopsy reveals petechiae and bleeding in the spleen, kidney, serous membranes , skeletal muscles, pericardium , liver, gonads and bladder. Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy. This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males). The case fatality rate of early hemorrhagic smallpox approaches 100%. There is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or variolosa pustula hemorrhagica ). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease. Bleeding appears in the early eruptive period (but later than that seen in purpura variolosa ), and the rash is often flat and does not progress beyond the vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form. Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin . This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on the virulence of the smallpox strain. Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence. The case fatality rate for late hemorrhagic smallpox is around 90–95%. Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox. Smallpox is caused by infection with variola virus, which belongs to the family Poxviridae , subfamily Chordopoxvirinae , genus Orthopoxvirus . The date of the appearance of smallpox is not settled. It most probably evolved from a terrestrial African rodent virus between 68,000 and 16,000 years ago. The wide range of dates is due to the different records used to calibrate the molecular clock . One clade was the variola major strains (the more clinically severe form of smallpox) which spread from Asia between 400 and 1,600 years ago. A second clade included both alastrim (a phenotypically mild smallpox) described from the American continents and isolates from West Africa which diverged from an ancestral strain between 1,400 and 6,300 years before present. This clade further diverged into two subclades at least 800 years ago. A second estimate has placed the separation of variola virus from Taterapox (an Orthopoxvirus of some African rodents including gerbils ) at 3,000 to 4,000 years ago. This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. If the mutation rate is assumed to be similar to that of the herpesviruses , the divergence date of variola virus from Taterapox has been estimated to be 50,000 years ago. While this is consistent with the other published estimates, it suggests that the archaeological and historical evidence is very incomplete. Better estimates of mutation rates in these viruses are needed. Examination of a strain that dates from c. 1650 found that this strain was basal to the other presently sequenced strains. The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in the 18th and 19th centuries. Variola virus is large and brick-shaped and is approximately 302 to 350 nanometers by 244 to 270 nm, with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end. Four orthopoxviruses cause infection in humans: variola, vaccinia , cowpox , and monkeypox . Variola virus infects only humans in nature, although primates and other animals have been infected in an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature. The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among human DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus . To replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses , the most important of which is a viral-associated DNA-dependent RNA polymerase . Both enveloped and unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin . Infection with either variola major virus or variola minor virus confers immunity against the other. The more common, infectious form of the disease was caused by the variola major virus strain. Variola minor virus, also called alastrim, was a less common form of the virus, and much less deadly. Although variola minor had the same incubation period and pathogenetic stages as smallpox, it is believed to have had a mortality rate of less than 1%, as compared to smallpox's 30%. Like variola major, variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with variola minor virus conferred immunity against the more dangerous variola major virus. Because variola minor was a less debilitating disease than smallpox, people were more frequently ambulant and thus able to infect others more rapidly. As such, variola minor swept through the United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980. Variola minor was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola. The genome of variola major virus is about 186,000 base pairs in length. It is made from linear double stranded DNA and contains the coding sequence for about 200 genes . The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome. The coding sequence of the central region of the genome is highly consistent across orthopoxviruses , and the arrangement of genes is consistent across chordopoxviruses The center of the variola virus genome contains the majority of the essential viral genes, including the genes for structural proteins , DNA replication , transcription , and mRNA synthesis. The ends of the genome vary more across strains and species of orthopoxviruses . These regions contain proteins that modulate the hosts' immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family. These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences. These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop , a region of roughly 100 base pairs necessary for resolving concatomeric DNA (a stretch of DNA containing multiple copies of the same sequence), a few open reading frames , and short tandemly repeating sequences of varying number and length. The ITRs of poxviridae vary in length across strains and species. The coding sequence for most of the viral proteins in variola major virus have at least 90% similarity with the genome of vaccinia , a related virus used for vaccination against smallpox. Gene expression of variola virus occurs entirely within the cytoplasm of the host cell , and follows a distinct progression during infection. After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes. About half of the viral genome is transcribed prior to the replication of viral DNA. The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion. These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes. Unlike most DNA viruses, DNA replication in variola virus and other poxviruses takes place within the cytoplasm of the infected cell. The exact timing of DNA replication after infection of a host cell varies across the poxviridae . Recombination of the genome occurs within actively infected cells. Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression. The products of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral RNA polymerase and other essential enzymes for new viral particles. These proteins are then packaged into new infectious virions capable of infecting other cells. Two live samples of variola major virus remain, one in the United States at the CDC in Atlanta, and one at the Vector Institute in Koltsovo, Russia. Research with the remaining virus samples is tightly controlled, and each research proposal must be approved by the WHO and the World Health Assembly (WHA). Most research on poxviruses is performed using the closely related Vaccinia virus as a model organism. Vaccinia virus, which is used to vaccinate for smallpox, is also under research as a viral vector for vaccines for unrelated diseases. The genome of variola major virus was first sequenced in its entirety in the 1990s. The complete coding sequence is publicly available online. The current reference sequence for variola major virus was sequenced from a strain that circulated in India in 1967. In addition, there are sequences for samples of other strains that were collected during the WHO eradication campaign. A genome browser for a complete database of annotated sequences of variola virus and other poxviruses is publicly available through the Viral Bioinformatics Resource Center . The WHO currently bans genetic engineering of the variola virus. However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of variola major virus to add a marker gene . This gene, called GFP , or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light. The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome. The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether a potential treatment was effective in killing viral samples. The recommendation could only take effect if approved by the WHA . When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time. Addition of the GFP gene to the Vaccinia genome is routinely performed during research on the closely related Vaccinia virus . The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus. Vaccinia , a cousin of the variola virus, was artificially synthesized in 2002 by NIH scientists. They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles. In 2016, another group synthesized the horsepox virus using publicly available sequence data for horsepox. The researchers argued that their work would be beneficial to creating a safer and more effective vaccine for smallpox, although an effective vaccine is already available. The horsepox virus had previously seemed to have gone extinct, raising concern about potential revival of variola major and causing other scientists to question their motives. Critics found it especially concerning that the group was able to recreate viable virus in a short time frame with relatively little cost or effort. Although the WHO bans individual laboratories from synthesizing more than 20% of the genome at a time, and purchases of smallpox genome fragments are monitored and regulated, a group with malicious intentions could compile, from multiple sources, the full synthetic genome necessary to produce viable virus. Smallpox was highly contagious, but generally spread more slowly and less widely than some other viral diseases, perhaps because transmission required close contact and occurred after the onset of the rash. The overall rate of infection was also affected by the short duration of the infectious stage. In temperate areas, the number of smallpox infections was highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year. Age distribution of smallpox infections depended on acquired immunity . Vaccination immunity declined over time and was probably lost within thirty years. Smallpox was not known to be transmitted by insects or animals and there was no asymptomatic carrier state. Transmission occurred through inhalation of airborne variola virus, usually droplets expressed from the oral, nasal, or pharyngeal mucosa of an infected person. It was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person. Some infections of laundry workers with smallpox after handling contaminated bedding suggested that smallpox could be spread through direct contact with contaminated objects ( fomites ), but this was found to be rare. Also rarely, smallpox was spread by virus carried in the air in enclosed settings such as buildings, buses, and trains. The virus can cross the placenta , but the incidence of congenital smallpox was relatively low. Smallpox was not notably infectious in the prodromal period and viral shedding was usually delayed until the appearance of the rash, which was often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but this happened most frequently during the first week of the rash when most of the skin lesions were intact. Infectivity waned in 7 to 10 days when scabs formed over the lesions, but the infected person was contagious until the last smallpox scab fell off. The date of the appearance of smallpox is not settled. It most probably evolved from a terrestrial African rodent virus between 68,000 and 16,000 years ago. The wide range of dates is due to the different records used to calibrate the molecular clock . One clade was the variola major strains (the more clinically severe form of smallpox) which spread from Asia between 400 and 1,600 years ago. A second clade included both alastrim (a phenotypically mild smallpox) described from the American continents and isolates from West Africa which diverged from an ancestral strain between 1,400 and 6,300 years before present. This clade further diverged into two subclades at least 800 years ago. A second estimate has placed the separation of variola virus from Taterapox (an Orthopoxvirus of some African rodents including gerbils ) at 3,000 to 4,000 years ago. This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. If the mutation rate is assumed to be similar to that of the herpesviruses , the divergence date of variola virus from Taterapox has been estimated to be 50,000 years ago. While this is consistent with the other published estimates, it suggests that the archaeological and historical evidence is very incomplete. Better estimates of mutation rates in these viruses are needed. Examination of a strain that dates from c. 1650 found that this strain was basal to the other presently sequenced strains. The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in the 18th and 19th centuries.Variola virus is large and brick-shaped and is approximately 302 to 350 nanometers by 244 to 270 nm, with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end. Four orthopoxviruses cause infection in humans: variola, vaccinia , cowpox , and monkeypox . Variola virus infects only humans in nature, although primates and other animals have been infected in an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature. The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among human DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus . To replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses , the most important of which is a viral-associated DNA-dependent RNA polymerase . Both enveloped and unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin . Infection with either variola major virus or variola minor virus confers immunity against the other. The more common, infectious form of the disease was caused by the variola major virus strain. Variola minor virus, also called alastrim, was a less common form of the virus, and much less deadly. Although variola minor had the same incubation period and pathogenetic stages as smallpox, it is believed to have had a mortality rate of less than 1%, as compared to smallpox's 30%. Like variola major, variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with variola minor virus conferred immunity against the more dangerous variola major virus. Because variola minor was a less debilitating disease than smallpox, people were more frequently ambulant and thus able to infect others more rapidly. As such, variola minor swept through the United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980. Variola minor was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola. The genome of variola major virus is about 186,000 base pairs in length. It is made from linear double stranded DNA and contains the coding sequence for about 200 genes . The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome. The coding sequence of the central region of the genome is highly consistent across orthopoxviruses , and the arrangement of genes is consistent across chordopoxviruses The center of the variola virus genome contains the majority of the essential viral genes, including the genes for structural proteins , DNA replication , transcription , and mRNA synthesis. The ends of the genome vary more across strains and species of orthopoxviruses . These regions contain proteins that modulate the hosts' immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family. These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences. These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop , a region of roughly 100 base pairs necessary for resolving concatomeric DNA (a stretch of DNA containing multiple copies of the same sequence), a few open reading frames , and short tandemly repeating sequences of varying number and length. The ITRs of poxviridae vary in length across strains and species. The coding sequence for most of the viral proteins in variola major virus have at least 90% similarity with the genome of vaccinia , a related virus used for vaccination against smallpox. Gene expression of variola virus occurs entirely within the cytoplasm of the host cell , and follows a distinct progression during infection. After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes. About half of the viral genome is transcribed prior to the replication of viral DNA. The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion. These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes. Unlike most DNA viruses, DNA replication in variola virus and other poxviruses takes place within the cytoplasm of the infected cell. The exact timing of DNA replication after infection of a host cell varies across the poxviridae . Recombination of the genome occurs within actively infected cells. Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression. The products of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral RNA polymerase and other essential enzymes for new viral particles. These proteins are then packaged into new infectious virions capable of infecting other cells. The more common, infectious form of the disease was caused by the variola major virus strain.Variola minor virus, also called alastrim, was a less common form of the virus, and much less deadly. Although variola minor had the same incubation period and pathogenetic stages as smallpox, it is believed to have had a mortality rate of less than 1%, as compared to smallpox's 30%. Like variola major, variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with variola minor virus conferred immunity against the more dangerous variola major virus. Because variola minor was a less debilitating disease than smallpox, people were more frequently ambulant and thus able to infect others more rapidly. As such, variola minor swept through the United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980. Variola minor was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola.The genome of variola major virus is about 186,000 base pairs in length. It is made from linear double stranded DNA and contains the coding sequence for about 200 genes . The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome. The coding sequence of the central region of the genome is highly consistent across orthopoxviruses , and the arrangement of genes is consistent across chordopoxviruses The center of the variola virus genome contains the majority of the essential viral genes, including the genes for structural proteins , DNA replication , transcription , and mRNA synthesis. The ends of the genome vary more across strains and species of orthopoxviruses . These regions contain proteins that modulate the hosts' immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family. These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences. These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop , a region of roughly 100 base pairs necessary for resolving concatomeric DNA (a stretch of DNA containing multiple copies of the same sequence), a few open reading frames , and short tandemly repeating sequences of varying number and length. The ITRs of poxviridae vary in length across strains and species. The coding sequence for most of the viral proteins in variola major virus have at least 90% similarity with the genome of vaccinia , a related virus used for vaccination against smallpox. Gene expression of variola virus occurs entirely within the cytoplasm of the host cell , and follows a distinct progression during infection. After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes. About half of the viral genome is transcribed prior to the replication of viral DNA. The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion. These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes. Unlike most DNA viruses, DNA replication in variola virus and other poxviruses takes place within the cytoplasm of the infected cell. The exact timing of DNA replication after infection of a host cell varies across the poxviridae . Recombination of the genome occurs within actively infected cells. Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression. The products of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral RNA polymerase and other essential enzymes for new viral particles. These proteins are then packaged into new infectious virions capable of infecting other cells. Two live samples of variola major virus remain, one in the United States at the CDC in Atlanta, and one at the Vector Institute in Koltsovo, Russia. Research with the remaining virus samples is tightly controlled, and each research proposal must be approved by the WHO and the World Health Assembly (WHA). Most research on poxviruses is performed using the closely related Vaccinia virus as a model organism. Vaccinia virus, which is used to vaccinate for smallpox, is also under research as a viral vector for vaccines for unrelated diseases. The genome of variola major virus was first sequenced in its entirety in the 1990s. The complete coding sequence is publicly available online. The current reference sequence for variola major virus was sequenced from a strain that circulated in India in 1967. In addition, there are sequences for samples of other strains that were collected during the WHO eradication campaign. A genome browser for a complete database of annotated sequences of variola virus and other poxviruses is publicly available through the Viral Bioinformatics Resource Center . The WHO currently bans genetic engineering of the variola virus. However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of variola major virus to add a marker gene . This gene, called GFP , or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light. The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome. The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether a potential treatment was effective in killing viral samples. The recommendation could only take effect if approved by the WHA . When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time. Addition of the GFP gene to the Vaccinia genome is routinely performed during research on the closely related Vaccinia virus . The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus. Vaccinia , a cousin of the variola virus, was artificially synthesized in 2002 by NIH scientists. They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles. In 2016, another group synthesized the horsepox virus using publicly available sequence data for horsepox. The researchers argued that their work would be beneficial to creating a safer and more effective vaccine for smallpox, although an effective vaccine is already available. The horsepox virus had previously seemed to have gone extinct, raising concern about potential revival of variola major and causing other scientists to question their motives. Critics found it especially concerning that the group was able to recreate viable virus in a short time frame with relatively little cost or effort. Although the WHO bans individual laboratories from synthesizing more than 20% of the genome at a time, and purchases of smallpox genome fragments are monitored and regulated, a group with malicious intentions could compile, from multiple sources, the full synthetic genome necessary to produce viable virus. The WHO currently bans genetic engineering of the variola virus. However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of variola major virus to add a marker gene . This gene, called GFP , or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light. The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome. The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether a potential treatment was effective in killing viral samples. The recommendation could only take effect if approved by the WHA . When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time. Addition of the GFP gene to the Vaccinia genome is routinely performed during research on the closely related Vaccinia virus . The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus. Vaccinia , a cousin of the variola virus, was artificially synthesized in 2002 by NIH scientists. They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles. In 2016, another group synthesized the horsepox virus using publicly available sequence data for horsepox. The researchers argued that their work would be beneficial to creating a safer and more effective vaccine for smallpox, although an effective vaccine is already available. The horsepox virus had previously seemed to have gone extinct, raising concern about potential revival of variola major and causing other scientists to question their motives. Critics found it especially concerning that the group was able to recreate viable virus in a short time frame with relatively little cost or effort. Although the WHO bans individual laboratories from synthesizing more than 20% of the genome at a time, and purchases of smallpox genome fragments are monitored and regulated, a group with malicious intentions could compile, from multiple sources, the full synthetic genome necessary to produce viable virus. Smallpox was highly contagious, but generally spread more slowly and less widely than some other viral diseases, perhaps because transmission required close contact and occurred after the onset of the rash. The overall rate of infection was also affected by the short duration of the infectious stage. In temperate areas, the number of smallpox infections was highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year. Age distribution of smallpox infections depended on acquired immunity . Vaccination immunity declined over time and was probably lost within thirty years. Smallpox was not known to be transmitted by insects or animals and there was no asymptomatic carrier state. Transmission occurred through inhalation of airborne variola virus, usually droplets expressed from the oral, nasal, or pharyngeal mucosa of an infected person. It was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person. Some infections of laundry workers with smallpox after handling contaminated bedding suggested that smallpox could be spread through direct contact with contaminated objects ( fomites ), but this was found to be rare. Also rarely, smallpox was spread by virus carried in the air in enclosed settings such as buildings, buses, and trains. The virus can cross the placenta , but the incidence of congenital smallpox was relatively low. Smallpox was not notably infectious in the prodromal period and viral shedding was usually delayed until the appearance of the rash, which was often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but this happened most frequently during the first week of the rash when most of the skin lesions were intact. Infectivity waned in 7 to 10 days when scabs formed over the lesions, but the infected person was contagious until the last smallpox scab fell off. Once inhaled, the variola virus invaded the mucus membranes of the mouth, throat, and respiratory tract. From there, it migrated to regional lymph nodes and began to multiply. In the initial growth phase, the virus seemed to move from cell to cell, but by around the 12th day, widespread lysis of infected cells occurred and the virus could be found in the bloodstream in large numbers, a condition known as viremia . This resulted in the second wave of multiplication in the spleen , bone marrow , and lymph nodes.The clinical definition of ordinary smallpox is an illness with acute onset of fever equal to or greater than 38.3 °C (101 °F) followed by a rash characterized by firm, deep-seated vesicles or pustules in the same stage of development without other apparent cause. When a clinical case was observed, smallpox was confirmed using laboratory tests. Microscopically , poxviruses produce characteristic cytoplasmic inclusion bodies , the most important of which are known as Guarnieri bodies , and are the sites of viral replication . Guarnieri bodies are readily identified in skin biopsies stained with hematoxylin and eosin, and appear as pink blobs. They are found in virtually all poxvirus infections but the absence of Guarnieri bodies could not be used to rule out smallpox. The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopic examination of pustular fluid or scabs. All orthopoxviruses exhibit identical brick-shaped virions by electron microscopy. If particles with the characteristic morphology of herpesviruses are seen this will eliminate smallpox and other orthopoxvirus infections. Definitive laboratory identification of variola virus involved growing the virus on chorioallantoic membrane (part of a chicken embryo ) and examining the resulting pock lesions under defined temperature conditions. Strains were characterized by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measured variola virus-specific immunoglobulin and antigen were also developed to assist in the diagnosis of infection. Chickenpox was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox could be distinguished by several methods. Unlike smallpox, chickenpox does not usually affect the palms and soles. Additionally, chickenpox pustules are of varying size due to variations in the timing of pustule eruption: smallpox pustules are all very nearly the same size since the viral effect progresses more uniformly. A variety of laboratory methods were available for detecting chickenpox in the evaluation of suspected smallpox cases. The earliest procedure used to prevent smallpox was inoculation with variola minor virus (a method later known as variolation after the introduction of smallpox vaccine to avoid possible confusion), which likely occurred in India, Africa, and China well before the practice arrived in Europe. The idea that inoculation originated in India has been challenged, as few of the ancient Sanskrit medical texts described the process of inoculation. Accounts of inoculation against smallpox in China can be found as early as the late 10th century, and the procedure was widely practiced by the 16th century, during the Ming dynasty . If successful, inoculation produced lasting immunity to smallpox. Because the person was infected with variola virus, a severe infection could result, and the person could transmit smallpox to others. Variolation had a 0.5–2 percent mortality rate, considerably less than the 20–30 percent mortality rate of the disease. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers . Lady Mary Wortley Montagu observed smallpox inoculation during her stay in the Ottoman Empire , writing detailed accounts of the practice in her letters, and enthusiastically promoted the procedure in England upon her return in 1718. According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia . Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". In 1721, Cotton Mather and colleagues provoked controversy in Boston by inoculating hundreds. After publishing The present method of inoculating for the small-pox in 1767, Dr Thomas Dimsdale was invited to Russia to variolate the Empress Catherine the Great of Russia and her son, Grand Duke Paul , which he successfully did in 1768. In 1796, Edward Jenner , a doctor in Berkeley, Gloucestershire , rural England, discovered that immunity to smallpox could be produced by inoculating a person with material from a cowpox lesion. Cowpox is a poxvirus in the same family as variola. Jenner called the material used for inoculation vaccine from the root word vacca , which is Latin for cow. The procedure was much safer than variolation and did not involve a risk of smallpox transmission. Vaccination to prevent smallpox was soon practiced all over the world. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by the vaccinia virus. Vaccinia is in the same family as cowpox and variola virus but is genetically distinct from both. The origin of the vaccinia virus and how it came to be in the vaccine are not known. The current formulation of the smallpox vaccine is a live virus preparation of the infectious vaccinia virus. The vaccine is given using a bifurcated (two-pronged) needle that is dipped into the vaccine solution. The needle is used to prick the skin (usually the upper arm) several times in a few seconds. If successful, a red and itchy bump develops at the vaccine site in three or four days. In the first week, the bump becomes a large blister (called a "Jennerian vesicle") which fills with pus and begins to drain. During the second week, the blister begins to dry up, and a scab forms. The scab falls off in the third week, leaving a small scar. The antibodies induced by the vaccinia vaccine are cross-protective for other orthopoxviruses, such as monkeypox, cowpox, and variola (smallpox) viruses. Neutralizing antibodies are detectable 10 days after first-time vaccination and seven days after revaccination. Historically, the vaccine has been effective in preventing smallpox infection in 95 percent of those vaccinated. Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter. If a person is vaccinated again later, the immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was 1.3 percent; it was 7 percent among those vaccinated 11 to 20 years prior, and 11 percent among those vaccinated 20 or more years before infection. By contrast, 52 percent of unvaccinated persons died. There are side effects and risks associated with the smallpox vaccine. In the past, about 1 out of 1,000 people vaccinated for the first time experienced serious, but non-life-threatening, reactions, including toxic or allergic reaction at the site of the vaccination ( erythema multiforme ), spread of the vaccinia virus to other parts of the body, and spread to other individuals. Potentially life-threatening reactions occurred in 14 to 500 people out of every 1 million people vaccinated for the first time. Based on past experience, it is estimated that 1 or 2 people in 1 million (0.000198 percent) who receive the vaccine may die as a result, most often the result of postvaccinial encephalitis or severe necrosis in the area of vaccination (called progressive vaccinia ). Given these risks, as smallpox became effectively eradicated and the number of naturally occurring cases fell below the number of vaccine-induced illnesses and deaths, routine childhood vaccination was discontinued in the United States in 1972 and was abandoned in most European countries in the early 1970s. Routine vaccination of health care workers was discontinued in the U.S. in 1976, and among military recruits in 1990 (although military personnel deploying to the Middle East and Korea still receive the vaccination ). By 1986, routine vaccination had ceased in all countries. It is now primarily recommended for laboratory workers at risk for occupational exposure. However, the possibility of variola virus being used as a biological weapon has rekindled interest in the development of newer vaccines. The smallpox vaccine is also effective in, and therefore administered for, the prevention of monkeypox . Smallpox vaccination within three days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. Vaccination four to seven days after exposure can offer some protection from disease or may modify the severity of the disease. Other than vaccination, treatment of smallpox is primarily supportive, such as wound care and infection control, fluid therapy, and possible ventilator assistance. Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat shock , such as fluid resuscitation . People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burns . In July 2018, the Food and Drug Administration approved tecovirimat , the first drug approved for treatment of smallpox. Antiviral treatments have improved since the last large smallpox epidemics, and studies suggest that the antiviral drug cidofovir might be useful as a therapeutic agent. The drug must be administered intravenously , and may cause serious kidney toxicity. ACAM2000 is a smallpox vaccine developed by Acambis. It was approved for use in the United States by the U.S. FDA on August 31, 2007. It contains live vaccinia virus, cloned from the same strain used in an earlier vaccine , Dryvax . While the Dryvax virus was cultured in the skin of calves and freeze-dried, ACAM2000s virus is cultured in kidney epithelial cells ( Vero cells ) from an African green monkey . Efficacy and adverse reaction incidence are similar to Dryvax. The vaccine is not routinely available to the US public; it is, however, used in the military and maintained in the Strategic National Stockpile . In June 2021, brincidofovir was approved for medical use in the United States for the treatment of human smallpox disease caused by variola virus. The mortality rate from variola minor is approximately 1%, while the mortality rate from variola major is approximately 30%. Ordinary type-confluent is fatal about 50–75% of the time, ordinary-type semi-confluent about 25–50% of the time, in cases where the rash is discrete the case-fatality rate is less than 10%. The overall fatality rate for children younger than 1 year of age is 40–50%. Hemorrhagic and flat types have the highest fatality rates. The fatality rate for flat or late hemorrhagic type smallpox is 90% or greater and nearly 100% is observed in cases of early hemorrhagic smallpox. The case-fatality rate for variola minor is 1% or less. There is no evidence of chronic or recurrent infection with variola virus. In cases of flat smallpox in vaccinated people, the condition was extremely rare but less lethal, with one case series showing a 66.7% death rate. In fatal cases of ordinary smallpox, death usually occurs between days 10-16 of the illness. The cause of death from smallpox is not clear, but the infection is now known to involve multiple organs. Circulating immune complexes , overwhelming viremia, or an uncontrolled immune response may be contributing factors. In early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops. The cause of death in early hemorrhagic cases is commonly due to heart failure and pulmonary edema . In late hemorrhagic cases, high and sustained viremia, severe platelet loss and poor immune response were often cited as causes of death. In flat smallpox modes of death are similar to those in burns, with loss of fluid , protein and electrolytes , and fulminating sepsis . Complications of smallpox arise most commonly in the respiratory system and range from simple bronchitis to fatal pneumonia . Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively uncommon complication of smallpox. When this occurs, the fever usually remains elevated. Other complications include encephalitis (1 in 500 patients), which is more common in adults and may cause temporary disability; permanent pitted scars, most notably on the face; and complications involving the eyes (2% of all cases). Pustules can form on the eyelid, conjunctiva , and cornea , leading to complications such as conjunctivitis , keratitis , corneal ulcer , iritis , iridocyclitis , and atrophy of the optic nerve. Blindness results in approximately 35-40% of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and retinal hemorrhages. In 2-5% of young children with smallpox, virions reach the joints and bone, causing osteomyelitis variolosa . Bony lesions are symmetrical, most common in the elbows, legs, and characteristically cause separation of the epiphysis and marked periosteal reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis , malformed bones, flail joints, and stubby fingers. Between 65 and 80% of survivors are marked with deep pitted scars (pockmarks), most prominent on the face.Complications of smallpox arise most commonly in the respiratory system and range from simple bronchitis to fatal pneumonia . Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively uncommon complication of smallpox. When this occurs, the fever usually remains elevated. Other complications include encephalitis (1 in 500 patients), which is more common in adults and may cause temporary disability; permanent pitted scars, most notably on the face; and complications involving the eyes (2% of all cases). Pustules can form on the eyelid, conjunctiva , and cornea , leading to complications such as conjunctivitis , keratitis , corneal ulcer , iritis , iridocyclitis , and atrophy of the optic nerve. Blindness results in approximately 35-40% of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and retinal hemorrhages. In 2-5% of young children with smallpox, virions reach the joints and bone, causing osteomyelitis variolosa . Bony lesions are symmetrical, most common in the elbows, legs, and characteristically cause separation of the epiphysis and marked periosteal reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis , malformed bones, flail joints, and stubby fingers. Between 65 and 80% of survivors are marked with deep pitted scars (pockmarks), most prominent on the face.The earliest credible clinical evidence of smallpox is found in the descriptions of smallpox-like disease in medical writings from ancient India (as early as 1500 BCE), and China (1122 BCE), as well as a study of the Egyptian mummy of Ramses V , who died more than 3000 years ago (1145 BCE). It has been speculated that Egyptian traders brought smallpox to India during the 1st millennium BCE, where it remained as an endemic human disease for at least 2000 years. Smallpox was probably introduced into China during the 1st century CE from the southwest, and in the 6th century was carried from China to Japan. In Japan, the epidemic of 735–737 is believed to have killed as much as one-third of the population. At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the Yoruba religion in West Africa. In India, the Hindu goddess of smallpox, Shitala , was worshipped in temples throughout the country. A different viewpoint is that smallpox emerged 1588 CE and the earlier reported cases were incorrectly identified as smallpox. The timing of the arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not clearly described in either the Old or New Testaments of the Bible or in the literature of the Greeks or Romans. While some have identified the Plague of Athens – which was said to have originated in " Ethiopia " and Egypt – or the plague that lifted Carthage's 396 BCE siege of Syracuse – with smallpox, many scholars agree it is very unlikely such a serious disease as variola major would have escaped being described by Hippocrates if it had existed in the Mediterranean region during his lifetime. While the Antonine Plague that swept through the Roman Empire in 165 – 180 CE may have been caused by smallpox, Saint Nicasius of Rheims became the patron saint of smallpox victims for having supposedly survived a bout in 450, and Saint Gregory of Tours recorded a similar outbreak in France and Italy in 580, the first use of the term variola . Other historians speculate that Arab armies first carried smallpox from Africa into Southwestern Europe during the 7th and 8th centuries. In the 9th century the Persian physician , Rhazes , provided one of the most definitive descriptions of smallpox and was the first to differentiate smallpox from measles and chickenpox in his Kitab fi al-jadari wa-al-hasbah ( The Book of Smallpox and Measles ). During the Middle Ages several smallpox outbreaks occurred in Europe. However, smallpox had not become established there until the population growth and mobility marked by the Crusades allowed it to do so. By the 16th century, smallpox had become entrenched across most of Europe, where it had a mortality rate as high as 30 percent. This endemic occurrence of smallpox in Europe is of particular historical importance, as successive exploration and colonization by Europeans tended to spread the disease to other nations. By the 16th century, smallpox had become a predominant cause of morbidity and mortality throughout much of the world. There were no credible descriptions of smallpox-like disease in the Americas before the westward exploration by Europeans in the 15th century CE. Smallpox was introduced into the Caribbean island of Hispaniola in 1507, and into the mainland in 1520, when Spanish settlers from Hispaniola arrived in Mexico, inadvertently carrying smallpox with them. Because the native Amerindian population had no acquired immunity to this new disease, their peoples were decimated by epidemics. Such disruption and population losses were an important factor in the Spanish achieving conquest of the Aztecs and the Incas . Similarly, English settlement of the east coast of North America in 1633 in Plymouth, Massachusetts was accompanied by devastating outbreaks of smallpox among Native American populations, and subsequently among the native-born colonists. Case fatality rates during outbreaks in Native American populations were as high as 90%. Smallpox was introduced into Australia in 1789 and again in 1829, though colonial surgeons, who by 1829 were attempting to distinguish between smallpox and chickenpox (which could be almost equally fatal to Aborigines), were divided as to whether the 1829–1830 epidemic was chickenpox or smallpox. Although smallpox was never endemic on the continent, it has been described as the principal cause of death in Aboriginal populations between 1780 and 1870. By the mid-18th century, smallpox was a major endemic disease everywhere in the world except in Australia and small islands untouched by outside exploration. In 18th century Europe, smallpox was a leading cause of death, killing an estimated 400,000 Europeans each year. Up to 10 percent of Swedish infants died of smallpox each year, and the death rate of infants in Russia might have been even higher. The widespread use of variolation in a few countries, notably Great Britain, its North American colonies, and China, somewhat reduced the impact of smallpox among the wealthy classes during the latter part of the 18th century, but a real reduction in its incidence did not occur until vaccination became a common practice toward the end of the 19th century. Improved vaccines and the practice of re-vaccination led to a substantial reduction in cases in Europe and North America, but smallpox remained almost unchecked everywhere else in the world. By the mid-20th century, variola minor occurred along with variola major, in varying proportions, in many parts of Africa. Patients with variola minor experience only a mild systemic illness, are often ambulant throughout the course of the disease, and are therefore able to more easily spread disease. Infection with variola minor virus induces immunity against the more deadly variola major form. Thus, as variola minor spread all over the US, into Canada, the South American countries, and Great Britain, it became the dominant form of smallpox, further reducing mortality rates. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Dòuzhěn xīnfǎ ( 痘疹心法 , "Pox Rash Teachings") published in 1549, with earliest hints of the practice in China during the 10th century. In China, powdered smallpox scabs were blown up the noses of the healthy. People would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700: one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers . Voltaire (1742) reports that the Chinese had practiced smallpox inoculation "these hundred years". Variolation had also been witnessed in Turkey by Lady Mary Wortley Montagu , who later introduced it in the UK. An early mention of the possibility of smallpox's eradication was made in reference to the work of Johnnie Notions , a self-taught inoculator from Shetland , Scotland. Notions found success in treating people from at least the late 1780s through a method devised by himself despite having no formal medical background. His method involved exposing smallpox pus to peat smoke, burying it in the ground with camphor for up to 8 years, and then inserting the matter into a person's skin using a knife, and covering the incision with a cabbage leaf. He was reputed not to have lost a single patient. Arthur Edmondston , in writings on Notions' technique that were published in 1809, stated, "Had every practitioner been as uniformly successful in the disease as he was, the small-pox might have been banished from the face of the earth, without injuring the system, or leaving any doubt as to the fact." The English physician Edward Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox in 1796, after which various attempts were made to eliminate smallpox on a regional scale. In Russia in 1796, the first child to receive this treatment was bestowed the name "Vaccinov" by Catherine the Great , and was educated at the expense of the nation. The introduction of the vaccine to the New World took place in Trinity, Newfoundland in 1800 by Dr. John Clinch , boyhood friend and medical colleague of Jenner. As early as 1803, the Spanish Crown organized the Balmis expedition to transport the vaccine to the Spanish colonies in the Americas and the Philippines, and establish mass vaccination programs there. The U.S. Congress passed the Vaccine Act of 1813 to ensure that safe smallpox vaccine would be available to the American public. By about 1817, a robust state vaccination program existed in the Dutch East Indies . On August 26, 1807, Bavaria became the first country in the world to introduce compulsory vaccinations. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate. In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials. Nevertheless, British vaccination efforts in India, and in Burma in particular, were hampered by indigenous preference for inoculation and distrust of vaccination, despite tough legislation, improvements in the local efficacy of the vaccine and vaccine preservative, and education efforts. By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans . In 1842, the United Kingdom banned inoculation, later progressing to mandatory vaccination . The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853. In the United States, from 1843 to 1855, first Massachusetts and then other states required smallpox vaccination. Although some disliked these measures, coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. In Northern Europe a number of countries had eliminated smallpox by 1900, and by 1914, the incidence in most industrialized countries had decreased to comparatively low levels. Vaccination continued in industrialized countries as protection against reintroduction until the mid to late 1970s. Australia and New Zealand are two notable exceptions; neither experienced endemic smallpox and never vaccinated widely, relying instead on protection by distance and strict quarantines. The first hemisphere -wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization . The campaign was successful in eliminating smallpox from all countries of the Americas except Argentina, Brazil, Colombia, and Ecuador. In 1958 Professor Viktor Zhdanov , Deputy Minister of Health for the USSR , called on the World Health Assembly to undertake a global initiative to eradicate smallpox. The proposal (Resolution WHA11.54) was accepted in 1959. At this point, 2 million people were dying from smallpox every year. Overall, the progress towards eradication was disappointing, especially in Africa and in the Indian subcontinent . In 1966 an international team, the Smallpox Eradication Unit, was formed under the leadership of an American, Donald Henderson . In 1967, the World Health Organization intensified the global smallpox eradication by contributing $2.4 million annually to the effort, and adopted the new disease surveillance method promoted by Czech epidemiologist Karel Raška . In the early 1950s, an estimated 50 million cases of smallpox occurred in the world each year. To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by. This process is known as "ring vaccination". The key to this strategy was the monitoring of cases in a community (known as surveillance) and containment. The initial problem the WHO team faced was inadequate reporting of smallpox cases, as many cases did not come to the attention of the authorities. The fact that humans are the only reservoir for smallpox infection and that carriers did not exist played a significant role in the eradication of smallpox. The WHO established a network of consultants who assisted countries in setting up surveillance and containment activities. Early on, donations of vaccine were provided primarily by the Soviet Union and the United States, but by 1973, more than 80 percent of all vaccine was produced in developing countries. The Soviet Union provided one and a half billion doses between 1958 and 1979, as well as the medical staff. The last major European outbreak of smallpox was in 1972 in Yugoslavia , after a pilgrim from Kosovo returned from the Middle East, where he had contracted the virus. The epidemic infected 175 people, causing 35 deaths. Authorities declared martial law , enforced quarantine, and undertook widespread re-vaccination of the population, enlisting the help of the WHO. In two months, the outbreak was over. Prior to this, there had been a smallpox outbreak in May–July 1963 in Stockholm , Sweden, brought from the Far East by a Swedish sailor; this had been dealt with by quarantine measures and vaccination of the local population. By the end of 1975, smallpox persisted only in the Horn of Africa . Conditions were very difficult in Ethiopia and Somalia , where there were few roads. Civil war, famine, and refugees made the task even more difficult. An intensive surveillance, containment, and vaccination program was undertaken in these countries in early and mid-1977, under the direction of Australian microbiologist Frank Fenner . As the campaign neared its goal, Fenner and his team played an important role in verifying eradication. The last naturally occurring case of indigenous smallpox ( Variola minor ) was diagnosed in Ali Maow Maalin , a hospital cook in Merca, Somalia , on 26 October 1977. The last naturally occurring case of the more deadly Variola major had been detected in October 1975 in a three-year-old Bangladeshi girl, Rahima Banu . The global eradication of smallpox was certified, based on intense verification activities, by a commission of eminent scientists on 9 December 1979 and subsequently endorsed by the World Health Assembly on 8 May 1980. The first two sentences of the resolution read: Having considered the development and results of the global program on smallpox eradication initiated by WHO in 1958 and intensified since 1967 … Declares solemnly that the world and its peoples have won freedom from smallpox, which was a most devastating disease sweeping in epidemic form through many countries since earliest time, leaving death, blindness and disfigurement in its wake and which only a decade ago was rampant in Africa, Asia and South America. The cost of the eradication effort, from 1967 to 1979, was roughly US$300 million. Roughly a third came from the developed world, which had largely eradicated smallpox decades earlier. The United States, the largest contributor to the program, has reportedly recouped that investment every 26 days since in money not spent on vaccinations and the costs of incidence. The last case of smallpox in the world occurred in an outbreak in the United Kingdom in 1978 . A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on 11 September 1978. Although it has remained unclear how Parker became infected, the source of the infection was established to be the variola virus grown for research purposes at the Medical School laboratory. All known stocks of smallpox worldwide were subsequently destroyed or transferred to two WHO-designated reference laboratories with BSL-4 facilities – the United States' Centers for Disease Control and Prevention (CDC) and the Soviet Union's (now Russia's) State Research Center of Virology and Biotechnology VECTOR . WHO first recommended destruction of the virus in 1986 and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1999. Due to resistance from the U.S. and Russia, in 2002 the World Health Assembly agreed to permit the temporary retention of the virus stocks for specific research purposes. Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak. Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests; a 2010 review by a team of public health experts appointed by WHO concluded that no essential public health purpose is served by the U.S. and Russia continuing to retain virus stocks. The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program. On March 31, 2003, smallpox scabs were found inside an envelope in an 1888 book on Civil War medicine in Santa Fe, New Mexico . The envelope was labeled as containing scabs from a vaccination and gave scientists at the CDC an opportunity to study the history of smallpox vaccination in the United States. On July 1, 2014, six sealed glass vials of smallpox dated 1954, along with sample vials of other pathogens, were discovered in a cold storage room in an FDA laboratory at the National Institutes of Health location in Bethesda, Maryland . The smallpox vials were subsequently transferred to the custody of the CDC in Atlanta, where virus taken from at least two vials proved viable in culture. After studies were conducted, the CDC destroyed the virus under WHO observation on February 24, 2015. In 2017, scientists at the University of Alberta recreated an extinct horse pox virus to demonstrate that the variola virus can be recreated in a small lab at a cost of about $100,000, by a team of scientists without specialist knowledge. This makes the retention controversy irrelevant since the virus can be easily recreated even if all samples are destroyed. Although the scientists performed the research to help development of new vaccines as well as trace smallpox's history, the possibility of the techniques being used for nefarious purposes was immediately recognized, raising questions on dual use research and regulations. In September 2019, the Russian lab housing smallpox samples experienced a gas explosion that injured one worker. It did not occur near the virus storage area, and no samples were compromised, but the incident prompted a review of risks to containment. The earliest credible clinical evidence of smallpox is found in the descriptions of smallpox-like disease in medical writings from ancient India (as early as 1500 BCE), and China (1122 BCE), as well as a study of the Egyptian mummy of Ramses V , who died more than 3000 years ago (1145 BCE). It has been speculated that Egyptian traders brought smallpox to India during the 1st millennium BCE, where it remained as an endemic human disease for at least 2000 years. Smallpox was probably introduced into China during the 1st century CE from the southwest, and in the 6th century was carried from China to Japan. In Japan, the epidemic of 735–737 is believed to have killed as much as one-third of the population. At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the Yoruba religion in West Africa. In India, the Hindu goddess of smallpox, Shitala , was worshipped in temples throughout the country. A different viewpoint is that smallpox emerged 1588 CE and the earlier reported cases were incorrectly identified as smallpox. The timing of the arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not clearly described in either the Old or New Testaments of the Bible or in the literature of the Greeks or Romans. While some have identified the Plague of Athens – which was said to have originated in " Ethiopia " and Egypt – or the plague that lifted Carthage's 396 BCE siege of Syracuse – with smallpox, many scholars agree it is very unlikely such a serious disease as variola major would have escaped being described by Hippocrates if it had existed in the Mediterranean region during his lifetime. While the Antonine Plague that swept through the Roman Empire in 165 – 180 CE may have been caused by smallpox, Saint Nicasius of Rheims became the patron saint of smallpox victims for having supposedly survived a bout in 450, and Saint Gregory of Tours recorded a similar outbreak in France and Italy in 580, the first use of the term variola . Other historians speculate that Arab armies first carried smallpox from Africa into Southwestern Europe during the 7th and 8th centuries. In the 9th century the Persian physician , Rhazes , provided one of the most definitive descriptions of smallpox and was the first to differentiate smallpox from measles and chickenpox in his Kitab fi al-jadari wa-al-hasbah ( The Book of Smallpox and Measles ). During the Middle Ages several smallpox outbreaks occurred in Europe. However, smallpox had not become established there until the population growth and mobility marked by the Crusades allowed it to do so. By the 16th century, smallpox had become entrenched across most of Europe, where it had a mortality rate as high as 30 percent. This endemic occurrence of smallpox in Europe is of particular historical importance, as successive exploration and colonization by Europeans tended to spread the disease to other nations. By the 16th century, smallpox had become a predominant cause of morbidity and mortality throughout much of the world. There were no credible descriptions of smallpox-like disease in the Americas before the westward exploration by Europeans in the 15th century CE. Smallpox was introduced into the Caribbean island of Hispaniola in 1507, and into the mainland in 1520, when Spanish settlers from Hispaniola arrived in Mexico, inadvertently carrying smallpox with them. Because the native Amerindian population had no acquired immunity to this new disease, their peoples were decimated by epidemics. Such disruption and population losses were an important factor in the Spanish achieving conquest of the Aztecs and the Incas . Similarly, English settlement of the east coast of North America in 1633 in Plymouth, Massachusetts was accompanied by devastating outbreaks of smallpox among Native American populations, and subsequently among the native-born colonists. Case fatality rates during outbreaks in Native American populations were as high as 90%. Smallpox was introduced into Australia in 1789 and again in 1829, though colonial surgeons, who by 1829 were attempting to distinguish between smallpox and chickenpox (which could be almost equally fatal to Aborigines), were divided as to whether the 1829–1830 epidemic was chickenpox or smallpox. Although smallpox was never endemic on the continent, it has been described as the principal cause of death in Aboriginal populations between 1780 and 1870. By the mid-18th century, smallpox was a major endemic disease everywhere in the world except in Australia and small islands untouched by outside exploration. In 18th century Europe, smallpox was a leading cause of death, killing an estimated 400,000 Europeans each year. Up to 10 percent of Swedish infants died of smallpox each year, and the death rate of infants in Russia might have been even higher. The widespread use of variolation in a few countries, notably Great Britain, its North American colonies, and China, somewhat reduced the impact of smallpox among the wealthy classes during the latter part of the 18th century, but a real reduction in its incidence did not occur until vaccination became a common practice toward the end of the 19th century. Improved vaccines and the practice of re-vaccination led to a substantial reduction in cases in Europe and North America, but smallpox remained almost unchecked everywhere else in the world. By the mid-20th century, variola minor occurred along with variola major, in varying proportions, in many parts of Africa. Patients with variola minor experience only a mild systemic illness, are often ambulant throughout the course of the disease, and are therefore able to more easily spread disease. Infection with variola minor virus induces immunity against the more deadly variola major form. Thus, as variola minor spread all over the US, into Canada, the South American countries, and Great Britain, it became the dominant form of smallpox, further reducing mortality rates. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Dòuzhěn xīnfǎ ( 痘疹心法 , "Pox Rash Teachings") published in 1549, with earliest hints of the practice in China during the 10th century. In China, powdered smallpox scabs were blown up the noses of the healthy. People would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700: one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers . Voltaire (1742) reports that the Chinese had practiced smallpox inoculation "these hundred years". Variolation had also been witnessed in Turkey by Lady Mary Wortley Montagu , who later introduced it in the UK. An early mention of the possibility of smallpox's eradication was made in reference to the work of Johnnie Notions , a self-taught inoculator from Shetland , Scotland. Notions found success in treating people from at least the late 1780s through a method devised by himself despite having no formal medical background. His method involved exposing smallpox pus to peat smoke, burying it in the ground with camphor for up to 8 years, and then inserting the matter into a person's skin using a knife, and covering the incision with a cabbage leaf. He was reputed not to have lost a single patient. Arthur Edmondston , in writings on Notions' technique that were published in 1809, stated, "Had every practitioner been as uniformly successful in the disease as he was, the small-pox might have been banished from the face of the earth, without injuring the system, or leaving any doubt as to the fact." The English physician Edward Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox in 1796, after which various attempts were made to eliminate smallpox on a regional scale. In Russia in 1796, the first child to receive this treatment was bestowed the name "Vaccinov" by Catherine the Great , and was educated at the expense of the nation. The introduction of the vaccine to the New World took place in Trinity, Newfoundland in 1800 by Dr. John Clinch , boyhood friend and medical colleague of Jenner. As early as 1803, the Spanish Crown organized the Balmis expedition to transport the vaccine to the Spanish colonies in the Americas and the Philippines, and establish mass vaccination programs there. The U.S. Congress passed the Vaccine Act of 1813 to ensure that safe smallpox vaccine would be available to the American public. By about 1817, a robust state vaccination program existed in the Dutch East Indies . On August 26, 1807, Bavaria became the first country in the world to introduce compulsory vaccinations. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate. In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials. Nevertheless, British vaccination efforts in India, and in Burma in particular, were hampered by indigenous preference for inoculation and distrust of vaccination, despite tough legislation, improvements in the local efficacy of the vaccine and vaccine preservative, and education efforts. By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans . In 1842, the United Kingdom banned inoculation, later progressing to mandatory vaccination . The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853. In the United States, from 1843 to 1855, first Massachusetts and then other states required smallpox vaccination. Although some disliked these measures, coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. In Northern Europe a number of countries had eliminated smallpox by 1900, and by 1914, the incidence in most industrialized countries had decreased to comparatively low levels. Vaccination continued in industrialized countries as protection against reintroduction until the mid to late 1970s. Australia and New Zealand are two notable exceptions; neither experienced endemic smallpox and never vaccinated widely, relying instead on protection by distance and strict quarantines. The first hemisphere -wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization . The campaign was successful in eliminating smallpox from all countries of the Americas except Argentina, Brazil, Colombia, and Ecuador. In 1958 Professor Viktor Zhdanov , Deputy Minister of Health for the USSR , called on the World Health Assembly to undertake a global initiative to eradicate smallpox. The proposal (Resolution WHA11.54) was accepted in 1959. At this point, 2 million people were dying from smallpox every year. Overall, the progress towards eradication was disappointing, especially in Africa and in the Indian subcontinent . In 1966 an international team, the Smallpox Eradication Unit, was formed under the leadership of an American, Donald Henderson . In 1967, the World Health Organization intensified the global smallpox eradication by contributing $2.4 million annually to the effort, and adopted the new disease surveillance method promoted by Czech epidemiologist Karel Raška . In the early 1950s, an estimated 50 million cases of smallpox occurred in the world each year. To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by. This process is known as "ring vaccination". The key to this strategy was the monitoring of cases in a community (known as surveillance) and containment. The initial problem the WHO team faced was inadequate reporting of smallpox cases, as many cases did not come to the attention of the authorities. The fact that humans are the only reservoir for smallpox infection and that carriers did not exist played a significant role in the eradication of smallpox. The WHO established a network of consultants who assisted countries in setting up surveillance and containment activities. Early on, donations of vaccine were provided primarily by the Soviet Union and the United States, but by 1973, more than 80 percent of all vaccine was produced in developing countries. The Soviet Union provided one and a half billion doses between 1958 and 1979, as well as the medical staff. The last major European outbreak of smallpox was in 1972 in Yugoslavia , after a pilgrim from Kosovo returned from the Middle East, where he had contracted the virus. The epidemic infected 175 people, causing 35 deaths. Authorities declared martial law , enforced quarantine, and undertook widespread re-vaccination of the population, enlisting the help of the WHO. In two months, the outbreak was over. Prior to this, there had been a smallpox outbreak in May–July 1963 in Stockholm , Sweden, brought from the Far East by a Swedish sailor; this had been dealt with by quarantine measures and vaccination of the local population. By the end of 1975, smallpox persisted only in the Horn of Africa . Conditions were very difficult in Ethiopia and Somalia , where there were few roads. Civil war, famine, and refugees made the task even more difficult. An intensive surveillance, containment, and vaccination program was undertaken in these countries in early and mid-1977, under the direction of Australian microbiologist Frank Fenner . As the campaign neared its goal, Fenner and his team played an important role in verifying eradication. The last naturally occurring case of indigenous smallpox ( Variola minor ) was diagnosed in Ali Maow Maalin , a hospital cook in Merca, Somalia , on 26 October 1977. The last naturally occurring case of the more deadly Variola major had been detected in October 1975 in a three-year-old Bangladeshi girl, Rahima Banu . The global eradication of smallpox was certified, based on intense verification activities, by a commission of eminent scientists on 9 December 1979 and subsequently endorsed by the World Health Assembly on 8 May 1980. The first two sentences of the resolution read: Having considered the development and results of the global program on smallpox eradication initiated by WHO in 1958 and intensified since 1967 … Declares solemnly that the world and its peoples have won freedom from smallpox, which was a most devastating disease sweeping in epidemic form through many countries since earliest time, leaving death, blindness and disfigurement in its wake and which only a decade ago was rampant in Africa, Asia and South America. The cost of the eradication effort, from 1967 to 1979, was roughly US$300 million. Roughly a third came from the developed world, which had largely eradicated smallpox decades earlier. The United States, the largest contributor to the program, has reportedly recouped that investment every 26 days since in money not spent on vaccinations and the costs of incidence. The cost of the eradication effort, from 1967 to 1979, was roughly US$300 million. Roughly a third came from the developed world, which had largely eradicated smallpox decades earlier. The United States, the largest contributor to the program, has reportedly recouped that investment every 26 days since in money not spent on vaccinations and the costs of incidence. The last case of smallpox in the world occurred in an outbreak in the United Kingdom in 1978 . A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on 11 September 1978. Although it has remained unclear how Parker became infected, the source of the infection was established to be the variola virus grown for research purposes at the Medical School laboratory. All known stocks of smallpox worldwide were subsequently destroyed or transferred to two WHO-designated reference laboratories with BSL-4 facilities – the United States' Centers for Disease Control and Prevention (CDC) and the Soviet Union's (now Russia's) State Research Center of Virology and Biotechnology VECTOR . WHO first recommended destruction of the virus in 1986 and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1999. Due to resistance from the U.S. and Russia, in 2002 the World Health Assembly agreed to permit the temporary retention of the virus stocks for specific research purposes. Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak. Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests; a 2010 review by a team of public health experts appointed by WHO concluded that no essential public health purpose is served by the U.S. and Russia continuing to retain virus stocks. The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program. On March 31, 2003, smallpox scabs were found inside an envelope in an 1888 book on Civil War medicine in Santa Fe, New Mexico . The envelope was labeled as containing scabs from a vaccination and gave scientists at the CDC an opportunity to study the history of smallpox vaccination in the United States. On July 1, 2014, six sealed glass vials of smallpox dated 1954, along with sample vials of other pathogens, were discovered in a cold storage room in an FDA laboratory at the National Institutes of Health location in Bethesda, Maryland . The smallpox vials were subsequently transferred to the custody of the CDC in Atlanta, where virus taken from at least two vials proved viable in culture. After studies were conducted, the CDC destroyed the virus under WHO observation on February 24, 2015. In 2017, scientists at the University of Alberta recreated an extinct horse pox virus to demonstrate that the variola virus can be recreated in a small lab at a cost of about $100,000, by a team of scientists without specialist knowledge. This makes the retention controversy irrelevant since the virus can be easily recreated even if all samples are destroyed. Although the scientists performed the research to help development of new vaccines as well as trace smallpox's history, the possibility of the techniques being used for nefarious purposes was immediately recognized, raising questions on dual use research and regulations. In September 2019, the Russian lab housing smallpox samples experienced a gas explosion that injured one worker. It did not occur near the virus storage area, and no samples were compromised, but the incident prompted a review of risks to containment. In 1763, Pontiac's War broke out as a Native American confederacy led by Pontiac attempted to counter British control over the Great Lakes region. A group of Native American warriors laid siege to British-held Fort Pitt on June 22. In response, Henry Bouquet , the commander of the fort, ordered his subordinate Simeon Ecuyer to give smallpox-infested blankets from the infirmary to a Delaware delegation outside the fort. Bouquet had discussed this with his superior, Sir Jeffrey Amherst , who wrote to Bouquet stating: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet agreed with the proposal, writing back that "I will try to inocculate [ sic ] the Indians by means of Blankets that may fall in their hands". On 24 June 1763, William Trent, a local trader and commander of the Fort Pitt militia, wrote, "Out of our regard for them, we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect." The effectiveness of this effort to broadcast the disease is unknown. There are also accounts that smallpox was used as a weapon during the American Revolutionary War (1775–1783). According to a theory put forward in Journal of Australian Studies ( JAS ) by independent researcher Christopher Warren, Royal Marines used smallpox in 1789 against indigenous tribes in New South Wales . This theory was also considered earlier in Bulletin of the History of Medicine and by David Day. However it is disputed by some medical academics, including Professor Jack Carmody, who in 2010 claimed that the rapid spread of the outbreak in question was more likely indicative of chickenpox —a more infectious disease which, at the time, was often confused, even by surgeons, with smallpox, and may have been comparably deadly to Aborigines and other peoples without natural immunity to it. Carmody noted that in the 8-month voyage of the First Fleet and the following 14 months there were no reports of smallpox amongst the colonists and that, since smallpox has an incubation period of 10–12 days, it is unlikely it was present in the First Fleet; however, Warren argued in the JAS article that the likely source was bottles of variola virus possessed by First Fleet surgeons . Ian and Jennifer Glynn, in The life and death of smallpox , confirm that bottles of "variolous matter" were carried to Australia for use as a vaccine, but think it unlikely the virus could have survived till 1789. In 2007, Christopher Warren offered evidence that the British smallpox may have been still viable. However, the only non-Aborigine reported to have died in this outbreak was a seaman called Joseph Jeffries, who was recorded as being of "American Indian" origin. W. S. Carus, an expert in biological weapons, has written that there is circumstantial evidence that smallpox was deliberately introduced to the Aboriginal population. However Carmody and the Australian National University's Boyd Hunter continue to support the chickenpox hypothesis. In a 2013 lecture at the Australian National University, Carmody pointed out that chickenpox, unlike smallpox, was known to be present in the Sydney Cove colony. He also suggested that all c. 18th century (and earlier) identifications of smallpox outbreaks were dubious because: "surgeons … would have been unaware of the distinction between smallpox and chickenpox – the latter having traditionally been considered a milder form of smallpox." During World War II , scientists from the United Kingdom, United States, and Japan ( Unit 731 of the Imperial Japanese Army ) were involved in research into producing a biological weapon from smallpox. Plans of large scale production were never carried through as they considered that the weapon would not be very effective due to the wide-scale availability of a vaccine . In 1947, the Soviet Union established a smallpox weapons factory in the city of Zagorsk , 75 km to the northeast of Moscow. An outbreak of weaponized smallpox occurred during testing at a facility on an island in the Aral Sea in 1971. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army and a senior researcher within the Soviet program of biological weapons , described the incident: On Vozrozhdeniya Island in the Aral Sea , the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk . A research ship of the Aral fleet came to within 15 km of the island (it was forbidden to come any closer than 40 km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation – 400 gr. of which was exploded on the island – "got her" and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of the Ministry of Defense and requested to forbid the stop of the Alma-Ata –Moscow train in Aralsk. As a result, the epidemic around the country was prevented. I called Andropov , who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island. Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt , two cities where the boat docked. Responding to international pressures, in 1991 the Soviet government allowed a joint U.S.–British inspection team to tour four of its main weapons facilities at Biopreparat . The inspectors were met with evasion and denials from the Soviet scientists and were eventually ordered out of the facility. In 1992, Soviet defector Ken Alibek alleged that the Soviet bioweapons program at Zagorsk had produced a large stockpile – as much as twenty tons – of weaponized smallpox (possibly engineered to resist vaccines, Alibek further alleged), along with refrigerated warheads to deliver it. Alibek's stories about the former Soviet program's smallpox activities have never been independently verified. In 1997, the Russian government announced that all of its remaining smallpox samples would be moved to the Vector Institute in Koltsovo . With the breakup of the Soviet Union and unemployment of many of the weapons program's scientists, U.S. government officials have expressed concern that smallpox and the expertise to weaponize it may have become available to other governments or terrorist groups who might wish to use virus as means of biological warfare. Specific allegations made against Iraq in this respect proved to be false. Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull , Ramses V , the Kangxi Emperor (survived), Shunzhi Emperor and Tongzhi Emperor of China, Emperor Komei of Japan (died of smallpox in 1867), and Date Masamune of Japan (who lost an eye to the disease). Cuitláhuac , the 10th tlatoani (ruler) of the Aztec city of Tenochtitlan , died of smallpox in 1520, shortly after its introduction to the Americas , and the Incan emperor Huayna Capac died of it in 1527 (causing a civil war of succession in the Inca empire and the eventual conquest by the Spaniards). More recent public figures include Guru Har Krishan , 8th Guru of the Sikhs, in 1664, Louis I of Spain in 1724 (died), Peter II of Russia in 1730 (died), George Washington (survived), Louis XV of France in 1774 (died) and Maximilian III Joseph of Bavaria in 1777 (died). Prominent families throughout the world often had several people infected by and/or perish from the disease. For example, several relatives of Henry VIII of England survived the disease but were scarred by it. These include his sister Margaret , his wife Anne of Cleves , and his two daughters: Mary I in 1527 and Elizabeth I in 1562. Elizabeth tried to disguise the pockmarks with heavy makeup. Mary, Queen of Scots , contracted the disease as a child but had no visible scarring. In Europe, deaths from smallpox often changed dynastic succession. Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those higher in the succession line. He himself died of the disease in 1774. Peter II of Russia died of the disease at 14 years of age. Also, before becoming emperor, Peter III of Russia caught the virus and suffered greatly from it. [ citation needed ] He was left scarred and disfigured. His wife, Catherine the Great , was spared but fear of the virus clearly had its effects on her. She feared for the safety of her son, Paul , so much that she made sure that large crowds were kept at bay and sought to isolate him. Eventually, she decided to have herself inoculated by a British doctor, Thomas Dimsdale . While this was considered a controversial method at the time, she succeeded. Paul was later inoculated as well. Catherine then sought to have inoculations throughout her empire stating: "My objective was, through my example, to save from death the multitude of my subjects who, not knowing the value of this technique, and frightened of it, were left in danger." By 1800, approximately two million inoculations had been administered in the Russian Empire. In China, the Qing dynasty had extensive protocols to protect Manchus from Peking 's endemic smallpox. U.S. Presidents George Washington , Andrew Jackson , and Abraham Lincoln all contracted and recovered from the disease. Washington became infected with smallpox on a visit to Barbados in 1751. Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not. Lincoln contracted the disease during his presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863. The famous theologian Jonathan Edwards died of smallpox in 1758 following an inoculation. Soviet leader Joseph Stalin fell ill with smallpox at the age of seven. His face was badly scarred by the disease. He later had photographs retouched to make his pockmarks less apparent. Hungarian poet Ferenc Kölcsey , who wrote the Hungarian national anthem, lost his right eye to smallpox. In the face of the devastation of smallpox, various smallpox gods and goddesses have been worshipped throughout parts of the Old World , for example in China and India. In China, the smallpox goddess was referred to as T'ou-Shen Niang-Niang ( Chinese : 痘疹娘娘 ). Chinese believers actively worked to appease the goddess and pray for her mercy, by such measures as referring to smallpox pustules as "beautiful flowers" as a euphemism intended to avert offending the goddess, for example (the Chinese word for smallpox is 天花 , literally "heaven flower"). In a related New Year's Eve custom it was prescribed that the children of the house wear ugly masks while sleeping, so as to conceal any beauty and thereby avoid attracting the goddess, who would be passing through sometime that night. If a case of smallpox did occur, shrines would be set up in the homes of the victims, to be worshipped and offered to as the disease ran its course. If the victim recovered, the shrines were removed and carried away in a special paper chair or boat for burning. If the patient did not recover, the shrine was destroyed and cursed, to expel the goddess from the house. In the Yoruba language smallpox is known as ṣọpọná, but it was also written as shakpanna, shopona, ṣhapana, and ṣọpọnọ. The word is a combination of 3 words, the verb ṣán, meaning to cover or plaster (referring to the pustules characteristic of smallpox), kpa or pa, meaning to kill, and enia, meaning human. Roughly translated, it means One who kills a person by covering them with pustules. Among the Yorùbá people of West Africa, and also in Dahomean religion , Trinidad, and in Brazil , The deity Sopona , also known as Obaluaye , is the deity of smallpox and other deadly diseases (like leprosy, HIV/AIDS, and fevers). One of the most feared deities of the orisha pantheon, smallpox was seen as a form of punishment from Shopona. Worship of Shopona was highly controlled by his priests, and it was believed that priests could also spread smallpox when angered. However, Shopona was also seen as a healer who could cure the diseases he inflicted, and he was often called upon by his victims to heal them. The British government banned the worship of the god because it was believed his priests were purposely spreading smallpox to their opponents. India's first records of smallpox can be found in a medical book that dates back to 400 CE. This book describes a disease that sounds exceptionally like smallpox. India, like China and the Yorùbá, created a goddess in response to its exposure to smallpox. The Hindu goddess Shitala was both worshipped and feared during her reign. It was believed that this goddess was both evil and kind and had the ability to inflict victims when angered, as well as calm the fevers of the already affected. Portraits of the goddess show her holding a broom in her right hand to continue to move the disease and a pot of cool water in the other hand in an attempt to soothe patients. Shrines were created where many Indian natives, both healthy and not, went to worship and attempt to protect themselves from this disease. Some Indian women, in an attempt to ward off Shitala, placed plates of cooling foods and pots of water on the roofs of their homes. In cultures that did not recognize a smallpox deity, there was often nonetheless a belief in smallpox demons , who were accordingly blamed for the disease. Such beliefs were prominent in Japan, Europe, Africa, and other parts of the world. Nearly all cultures who believed in the demon also believed that it was afraid of the color red. This led to the invention of the so-called red treatment, where patients and their rooms would be decorated in red. The practice spread to Europe in the 12th century and was practiced by (among others) Charles V of France and Elizabeth I of England . Afforded scientific credibility through the studies by Niels Ryberg Finsen showing that red light reduced scarring, this belief persisted even until the 1930s.In 1763, Pontiac's War broke out as a Native American confederacy led by Pontiac attempted to counter British control over the Great Lakes region. A group of Native American warriors laid siege to British-held Fort Pitt on June 22. In response, Henry Bouquet , the commander of the fort, ordered his subordinate Simeon Ecuyer to give smallpox-infested blankets from the infirmary to a Delaware delegation outside the fort. Bouquet had discussed this with his superior, Sir Jeffrey Amherst , who wrote to Bouquet stating: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet agreed with the proposal, writing back that "I will try to inocculate [ sic ] the Indians by means of Blankets that may fall in their hands". On 24 June 1763, William Trent, a local trader and commander of the Fort Pitt militia, wrote, "Out of our regard for them, we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect." The effectiveness of this effort to broadcast the disease is unknown. There are also accounts that smallpox was used as a weapon during the American Revolutionary War (1775–1783). According to a theory put forward in Journal of Australian Studies ( JAS ) by independent researcher Christopher Warren, Royal Marines used smallpox in 1789 against indigenous tribes in New South Wales . This theory was also considered earlier in Bulletin of the History of Medicine and by David Day. However it is disputed by some medical academics, including Professor Jack Carmody, who in 2010 claimed that the rapid spread of the outbreak in question was more likely indicative of chickenpox —a more infectious disease which, at the time, was often confused, even by surgeons, with smallpox, and may have been comparably deadly to Aborigines and other peoples without natural immunity to it. Carmody noted that in the 8-month voyage of the First Fleet and the following 14 months there were no reports of smallpox amongst the colonists and that, since smallpox has an incubation period of 10–12 days, it is unlikely it was present in the First Fleet; however, Warren argued in the JAS article that the likely source was bottles of variola virus possessed by First Fleet surgeons . Ian and Jennifer Glynn, in The life and death of smallpox , confirm that bottles of "variolous matter" were carried to Australia for use as a vaccine, but think it unlikely the virus could have survived till 1789. In 2007, Christopher Warren offered evidence that the British smallpox may have been still viable. However, the only non-Aborigine reported to have died in this outbreak was a seaman called Joseph Jeffries, who was recorded as being of "American Indian" origin. W. S. Carus, an expert in biological weapons, has written that there is circumstantial evidence that smallpox was deliberately introduced to the Aboriginal population. However Carmody and the Australian National University's Boyd Hunter continue to support the chickenpox hypothesis. In a 2013 lecture at the Australian National University, Carmody pointed out that chickenpox, unlike smallpox, was known to be present in the Sydney Cove colony. He also suggested that all c. 18th century (and earlier) identifications of smallpox outbreaks were dubious because: "surgeons … would have been unaware of the distinction between smallpox and chickenpox – the latter having traditionally been considered a milder form of smallpox." During World War II , scientists from the United Kingdom, United States, and Japan ( Unit 731 of the Imperial Japanese Army ) were involved in research into producing a biological weapon from smallpox. Plans of large scale production were never carried through as they considered that the weapon would not be very effective due to the wide-scale availability of a vaccine . In 1947, the Soviet Union established a smallpox weapons factory in the city of Zagorsk , 75 km to the northeast of Moscow. An outbreak of weaponized smallpox occurred during testing at a facility on an island in the Aral Sea in 1971. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army and a senior researcher within the Soviet program of biological weapons , described the incident: On Vozrozhdeniya Island in the Aral Sea , the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk . A research ship of the Aral fleet came to within 15 km of the island (it was forbidden to come any closer than 40 km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation – 400 gr. of which was exploded on the island – "got her" and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of the Ministry of Defense and requested to forbid the stop of the Alma-Ata –Moscow train in Aralsk. As a result, the epidemic around the country was prevented. I called Andropov , who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island. Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt , two cities where the boat docked. Responding to international pressures, in 1991 the Soviet government allowed a joint U.S.–British inspection team to tour four of its main weapons facilities at Biopreparat . The inspectors were met with evasion and denials from the Soviet scientists and were eventually ordered out of the facility. In 1992, Soviet defector Ken Alibek alleged that the Soviet bioweapons program at Zagorsk had produced a large stockpile – as much as twenty tons – of weaponized smallpox (possibly engineered to resist vaccines, Alibek further alleged), along with refrigerated warheads to deliver it. Alibek's stories about the former Soviet program's smallpox activities have never been independently verified. In 1997, the Russian government announced that all of its remaining smallpox samples would be moved to the Vector Institute in Koltsovo . With the breakup of the Soviet Union and unemployment of many of the weapons program's scientists, U.S. government officials have expressed concern that smallpox and the expertise to weaponize it may have become available to other governments or terrorist groups who might wish to use virus as means of biological warfare. Specific allegations made against Iraq in this respect proved to be false. Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull , Ramses V , the Kangxi Emperor (survived), Shunzhi Emperor and Tongzhi Emperor of China, Emperor Komei of Japan (died of smallpox in 1867), and Date Masamune of Japan (who lost an eye to the disease). Cuitláhuac , the 10th tlatoani (ruler) of the Aztec city of Tenochtitlan , died of smallpox in 1520, shortly after its introduction to the Americas , and the Incan emperor Huayna Capac died of it in 1527 (causing a civil war of succession in the Inca empire and the eventual conquest by the Spaniards). More recent public figures include Guru Har Krishan , 8th Guru of the Sikhs, in 1664, Louis I of Spain in 1724 (died), Peter II of Russia in 1730 (died), George Washington (survived), Louis XV of France in 1774 (died) and Maximilian III Joseph of Bavaria in 1777 (died). Prominent families throughout the world often had several people infected by and/or perish from the disease. For example, several relatives of Henry VIII of England survived the disease but were scarred by it. These include his sister Margaret , his wife Anne of Cleves , and his two daughters: Mary I in 1527 and Elizabeth I in 1562. Elizabeth tried to disguise the pockmarks with heavy makeup. Mary, Queen of Scots , contracted the disease as a child but had no visible scarring. In Europe, deaths from smallpox often changed dynastic succession. Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those higher in the succession line. He himself died of the disease in 1774. Peter II of Russia died of the disease at 14 years of age. Also, before becoming emperor, Peter III of Russia caught the virus and suffered greatly from it. [ citation needed ] He was left scarred and disfigured. His wife, Catherine the Great , was spared but fear of the virus clearly had its effects on her. She feared for the safety of her son, Paul , so much that she made sure that large crowds were kept at bay and sought to isolate him. Eventually, she decided to have herself inoculated by a British doctor, Thomas Dimsdale . While this was considered a controversial method at the time, she succeeded. Paul was later inoculated as well. Catherine then sought to have inoculations throughout her empire stating: "My objective was, through my example, to save from death the multitude of my subjects who, not knowing the value of this technique, and frightened of it, were left in danger." By 1800, approximately two million inoculations had been administered in the Russian Empire. In China, the Qing dynasty had extensive protocols to protect Manchus from Peking 's endemic smallpox. U.S. Presidents George Washington , Andrew Jackson , and Abraham Lincoln all contracted and recovered from the disease. Washington became infected with smallpox on a visit to Barbados in 1751. Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not. Lincoln contracted the disease during his presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863. The famous theologian Jonathan Edwards died of smallpox in 1758 following an inoculation. Soviet leader Joseph Stalin fell ill with smallpox at the age of seven. His face was badly scarred by the disease. He later had photographs retouched to make his pockmarks less apparent. Hungarian poet Ferenc Kölcsey , who wrote the Hungarian national anthem, lost his right eye to smallpox. In the face of the devastation of smallpox, various smallpox gods and goddesses have been worshipped throughout parts of the Old World , for example in China and India. In China, the smallpox goddess was referred to as T'ou-Shen Niang-Niang ( Chinese : 痘疹娘娘 ). Chinese believers actively worked to appease the goddess and pray for her mercy, by such measures as referring to smallpox pustules as "beautiful flowers" as a euphemism intended to avert offending the goddess, for example (the Chinese word for smallpox is 天花 , literally "heaven flower"). In a related New Year's Eve custom it was prescribed that the children of the house wear ugly masks while sleeping, so as to conceal any beauty and thereby avoid attracting the goddess, who would be passing through sometime that night. If a case of smallpox did occur, shrines would be set up in the homes of the victims, to be worshipped and offered to as the disease ran its course. If the victim recovered, the shrines were removed and carried away in a special paper chair or boat for burning. If the patient did not recover, the shrine was destroyed and cursed, to expel the goddess from the house. In the Yoruba language smallpox is known as ṣọpọná, but it was also written as shakpanna, shopona, ṣhapana, and ṣọpọnọ. The word is a combination of 3 words, the verb ṣán, meaning to cover or plaster (referring to the pustules characteristic of smallpox), kpa or pa, meaning to kill, and enia, meaning human. Roughly translated, it means One who kills a person by covering them with pustules. Among the Yorùbá people of West Africa, and also in Dahomean religion , Trinidad, and in Brazil , The deity Sopona , also known as Obaluaye , is the deity of smallpox and other deadly diseases (like leprosy, HIV/AIDS, and fevers). One of the most feared deities of the orisha pantheon, smallpox was seen as a form of punishment from Shopona. Worship of Shopona was highly controlled by his priests, and it was believed that priests could also spread smallpox when angered. However, Shopona was also seen as a healer who could cure the diseases he inflicted, and he was often called upon by his victims to heal them. The British government banned the worship of the god because it was believed his priests were purposely spreading smallpox to their opponents. India's first records of smallpox can be found in a medical book that dates back to 400 CE. This book describes a disease that sounds exceptionally like smallpox. India, like China and the Yorùbá, created a goddess in response to its exposure to smallpox. The Hindu goddess Shitala was both worshipped and feared during her reign. It was believed that this goddess was both evil and kind and had the ability to inflict victims when angered, as well as calm the fevers of the already affected. Portraits of the goddess show her holding a broom in her right hand to continue to move the disease and a pot of cool water in the other hand in an attempt to soothe patients. Shrines were created where many Indian natives, both healthy and not, went to worship and attempt to protect themselves from this disease. Some Indian women, in an attempt to ward off Shitala, placed plates of cooling foods and pots of water on the roofs of their homes. In cultures that did not recognize a smallpox deity, there was often nonetheless a belief in smallpox demons , who were accordingly blamed for the disease. Such beliefs were prominent in Japan, Europe, Africa, and other parts of the world. Nearly all cultures who believed in the demon also believed that it was afraid of the color red. This led to the invention of the so-called red treatment, where patients and their rooms would be decorated in red. The practice spread to Europe in the 12th century and was practiced by (among others) Charles V of France and Elizabeth I of England . Afforded scientific credibility through the studies by Niels Ryberg Finsen showing that red light reduced scarring, this belief persisted even until the 1930s.

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Acute hemorrhagic fever syndrome

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Fever

Fever or pyrexia in humans is a body temperature above the normal range due to an increase in the body's temperature set point in the hypothalamus . There is no single agreed-upon upper limit for normal temperature: sources use values ranging between 37.2 and 38.3 °C (99.0 and 100.9 °F) in humans. The increase in set point triggers increased muscle contractions and causes a feeling of cold or chills . This results in greater heat production and efforts to conserve heat. When the set point temperature returns to normal, a person feels hot, becomes flushed , and may begin to sweat . Rarely a fever may trigger a febrile seizure , with this being more common in young children. Fevers do not typically go higher than 41 to 42 °C (106 to 108 °F) . A fever can be caused by many medical conditions ranging from non-serious to life-threatening . This includes viral , bacterial , and parasitic infections —such as influenza , the common cold , meningitis , urinary tract infections , appendicitis , Lassa , COVID-19 , and malaria . Non-infectious causes include vasculitis , deep vein thrombosis , connective tissue disease , side effects of medication or vaccination, and cancer . It differs from hyperthermia , in that hyperthermia is an increase in body temperature over the temperature set point, due to either too much heat production or not enough heat loss . Treatment to reduce fever is generally not required. Treatment of associated pain and inflammation, however, may be useful and help a person rest. Medications such as ibuprofen or paracetamol (acetaminophen) may help with this as well as lower temperature. Children younger than three months require medical attention, as might people with serious medical problems such as a compromised immune system or people with other symptoms. Hyperthermia requires treatment. Fever is one of the most common medical signs . It is part of about 30% of healthcare visits by children and occurs in up to 75% of adults who are seriously sick. While fever evolved as a defense mechanism, treating a fever does not appear to improve or worsen outcomes. Fever is often viewed with greater concern by parents and healthcare professionals than is usually deserved, a phenomenon known as "fever phobia." A fever is usually accompanied by sickness behavior , which consists of lethargy , depression , loss of appetite , sleepiness , hyperalgesia , dehydration, and the inability to concentrate. Sleeping with a fever can often cause intense or confusing nightmares, commonly called "fever dreams". Mild to severe delirium (which can also cause hallucinations ) may also present itself during high fevers. A range for normal temperatures has been found. Central temperatures, such as rectal temperatures, are more accurate than peripheral temperatures. Fever is generally agreed to be present if the elevated temperature is caused by a raised set point and: In adults, the normal range of oral temperatures in healthy individuals is 35.7–37.7 °C (96.3–99.9 °F) among men and 33.2–38.1 °C (91.8–100.6 °F) among women, while when taken rectally it is 36.7–37.5 °C (98.1–99.5 °F) among men and 36.8–37.1 °C (98.2–98.8 °F) among women, and for ear measurement it is 35.5–37.5 °C (95.9–99.5 °F) among men and 35.7–37.5 °C (96.3–99.5 °F) among women. Normal body temperatures vary depending on many factors, including age, sex, time of day, ambient temperature, activity level, and more. Normal daily temperature variation has been described as 0.5 °C (0.9 °F). : 4012 A raised temperature is not always a fever. For example, the temperature rises in healthy people when they exercise, but this is not considered a fever, as the set point is normal. On the other hand, a "normal" temperature may be a fever, if it is unusually high for that person; for example, medically frail elderly people have a decreased ability to generate body heat, so a "normal" temperature of 37.3 °C (99.1 °F) may represent a clinically significant fever. Hyperthermia is an elevation of body temperature over the temperature set point, due to either too much heat production or not enough heat loss . Hyperthermia is thus not considered fever. : 103 Hyperthermia should not be confused with hyperpyrexia (which is a very high fever). : 102 Clinically, it is important to distinguish between fever and hyperthermia as hyperthermia may quickly lead to death and does not respond to antipyretic medications. The distinction may however be difficult to make in an emergency setting, and is often established by identifying possible causes. : 103Hyperthermia is an elevation of body temperature over the temperature set point, due to either too much heat production or not enough heat loss . Hyperthermia is thus not considered fever. : 103 Hyperthermia should not be confused with hyperpyrexia (which is a very high fever). : 102 Clinically, it is important to distinguish between fever and hyperthermia as hyperthermia may quickly lead to death and does not respond to antipyretic medications. The distinction may however be difficult to make in an emergency setting, and is often established by identifying possible causes. : 103Various patterns of measured patient temperatures have been observed, some of which may be indicative of a particular medical diagnosis : Among the types of intermittent fever are ones specific to cases of malaria caused by different pathogens. These are: In addition, there is disagreement regarding whether a specific fever pattern is associated with Hodgkin's lymphoma —the Pel–Ebstein fever , with patients argued to present high temperature for one week, followed by low for the next week, and so on, where the generality of this pattern is debated. Persistent fever that cannot be explained after repeated routine clinical inquiries is called fever of unknown origin . A neutropenic fever , also called febrile neutropenia, is a fever in the absence of normal immune system function. Because of the lack of infection-fighting neutrophils , a bacterial infection can spread rapidly; this fever is, therefore, usually considered to require urgent medical attention. This kind of fever is more commonly seen in people receiving immune-suppressing chemotherapy than in apparently healthy people. Hyperpyrexia is an extreme elevation of body temperature which, depending upon the source, is classified as a core body temperature greater than or equal to 40 or 41 °C (104 or 106 °F) ; the range of hyperpyrexias includes cases considered severe (≥ 40 °C) and extreme (≥ 42 °C). It differs from hyperthermia in that one's thermoregulatory system's set point for body temperature is set above normal, then heat is generated to achieve it. In contrast, hyperthermia involves body temperature rising above its set point due to outside factors. The high temperatures of hyperpyrexia are considered medical emergencies , as they may indicate a serious underlying condition or lead to severe morbidity (including permanent brain damage ), or to death. A common cause of hyperpyrexia is an intracranial hemorrhage . Other causes in emergency room settings include sepsis , Kawasaki syndrome , neuroleptic malignant syndrome , drug overdose , serotonin syndrome , and thyroid storm . Hyperpyrexia is an extreme elevation of body temperature which, depending upon the source, is classified as a core body temperature greater than or equal to 40 or 41 °C (104 or 106 °F) ; the range of hyperpyrexias includes cases considered severe (≥ 40 °C) and extreme (≥ 42 °C). It differs from hyperthermia in that one's thermoregulatory system's set point for body temperature is set above normal, then heat is generated to achieve it. In contrast, hyperthermia involves body temperature rising above its set point due to outside factors. The high temperatures of hyperpyrexia are considered medical emergencies , as they may indicate a serious underlying condition or lead to severe morbidity (including permanent brain damage ), or to death. A common cause of hyperpyrexia is an intracranial hemorrhage . Other causes in emergency room settings include sepsis , Kawasaki syndrome , neuroleptic malignant syndrome , drug overdose , serotonin syndrome , and thyroid storm . Fever is a common symptom of many medical conditions: Adult and pediatric manifestations for the same disease may differ; for instance, in COVID-19 , one metastudy describes 92.8% of adults versus 43.9% of children presenting with fever. In addition, fever can result from a reaction to an incompatible blood product. Teething is not a cause of fever. Fever is thought to contribute to host defense, as the reproduction of pathogens with strict temperature requirements can be hindered, and the rates of some important immunological reactions are increased by temperature. Fever has been described in teaching texts as assisting the healing process in various ways, including: A fever response to an infectious disease is generally regarded as protective, whereas fever in non-infections may be maladaptive. Studies have not been consistent on whether treating fever generally worsens or improves mortality risk. Benefits or harms may depend on the type of infection, health status of the patient and other factors. Studies using warm-blooded vertebrates suggest that they recover more rapidly from infections or critical illness due to fever. In sepsis , fever is associated with reduced mortality. Fever is thought to contribute to host defense, as the reproduction of pathogens with strict temperature requirements can be hindered, and the rates of some important immunological reactions are increased by temperature. Fever has been described in teaching texts as assisting the healing process in various ways, including:A fever response to an infectious disease is generally regarded as protective, whereas fever in non-infections may be maladaptive. Studies have not been consistent on whether treating fever generally worsens or improves mortality risk. Benefits or harms may depend on the type of infection, health status of the patient and other factors. Studies using warm-blooded vertebrates suggest that they recover more rapidly from infections or critical illness due to fever. In sepsis , fever is associated with reduced mortality. Temperature is regulated in the hypothalamus . The trigger of a fever, called a pyrogen, results in the release of prostaglandin E2 (PGE2). PGE2 in turn acts on the hypothalamus, which creates a systemic response in the body, causing heat-generating effects to match a new higher temperature set point. There are four receptors in which PGE2 can bind (EP1-4), with a previous study showing the EP3 subtype is what mediates the fever response. Hence, the hypothalamus can be seen as working like a thermostat . When the set point is raised, the body increases its temperature through both active generation of heat and retention of heat. Peripheral vasoconstriction both reduces heat loss through the skin and causes the person to feel cold. Norepinephrine increases thermogenesis in brown adipose tissue , and muscle contraction through shivering raises the metabolic rate . If these measures are insufficient to make the blood temperature in the brain match the new set point in the hypothalamus, the brain orchestrates heat effector mechanisms via the autonomic nervous system or primary motor center for shivering. These may be: [ citation needed ] When the hypothalamic set point moves back to baseline—either spontaneously or via medication—normal functions such as sweating, and the reverse of the foregoing processes (e.g., vasodilation, end of shivering, and nonshivering heat production) are used to cool the body to the new, lower setting. [ citation needed ] This contrasts with hyperthermia , in which the normal setting remains, and the body overheats through undesirable retention of excess heat or over-production of heat. Hyperthermia is usually the result of an excessively hot environment ( heat stroke ) or an adverse reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances surrounding it and its response to anti-pyretic medications. [ verification needed ] In infants, the autonomic nervous system may also activate brown adipose tissue to produce heat (non-exercise-associated thermogenesis , also known as non-shivering thermogenesis). [ citation needed ] Increased heart rate and vasoconstriction contribute to increased blood pressure in fever. [ citation needed ] A pyrogen is a substance that induces fever. In the presence of an infectious agent, such as bacteria, viruses, viroids, etc ., the immune response of the body is to inhibit their growth and eliminate them. The most common pyrogens are endotoxins, which are lipopolysaccharides (LPS) produced by Gram-negative bacteria such as E. coli . But pyrogens include non-endotoxic substances (derived from microorganisms other than gram-negative-bacteria or from chemical substances) as well. The types of pyrogens include internal (endogenous) and external (exogenous) to the body. [ citation needed ] The "pyrogenicity" of given pyrogens varies: in extreme cases, bacterial pyrogens can act as superantigens and cause rapid and dangerous fevers. Endogenous pyrogens are cytokines released from monocytes (which are part of the immune system ). In general, they stimulate chemical responses, often in the presence of an antigen , leading to a fever. Whilst they can be a product of external factors like exogenous pyrogens, they can also be induced by internal factors like damage associated molecular patterns such as cases like rheumatoid arthritis or lupus. Major endogenous pyrogens are interleukin 1 (α and β) : 1237–1248 and interleukin 6 (IL-6). Minor endogenous pyrogens include interleukin-8 , tumor necrosis factor-β , macrophage inflammatory protein -α and macrophage inflammatory protein-β as well as interferon-α , interferon-β , and interferon-γ . : 1237–1248 Tumor necrosis factor-α (TNF) also acts as a pyrogen, mediated by interleukin 1 (IL-1) release. These cytokine factors are released into general circulation, where they migrate to the brain's circumventricular organs where they are more easily absorbed than in areas protected by the blood–brain barrier . [ citation needed ] The cytokines then bind to endothelial receptors on vessel walls to receptors on microglial cells , resulting in activation of the arachidonic acid pathway . [ citation needed ] Of these, IL-1β, TNF, and IL-6 are able to raise the temperature setpoint of an organism and cause fever. These proteins produce a cyclooxygenase which induces the hypothalamic production of PGE2 which then stimulates the release of neurotransmitters such as cyclic adenosine monophosphate and increases body temperature. Exogenous pyrogens are external to the body and are of microbial origin. In general, these pyrogens, including bacterial cell wall products, may act on Toll-like receptors in the hypothalamus and elevate the thermoregulatory setpoint. An example of a class of exogenous pyrogens are bacterial lipopolysaccharides (LPS) present in the cell wall of gram-negative bacteria . According to one mechanism of pyrogen action, an immune system protein, lipopolysaccharide-binding protein (LBP), binds to LPS, and the LBP–LPS complex then binds to a CD14 receptor on a macrophage . The LBP-LPS binding to CD14 results in cellular synthesis and release of various endogenous cytokines , e.g., interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNFα). A further downstream event is activation of the arachidonic acid pathway . PGE2 release comes from the arachidonic acid pathway. This pathway (as it relates to fever), is mediated by the enzymes phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and prostaglandin E2 synthase . These enzymes ultimately mediate the synthesis and release of PGE2. [ citation needed ] PGE2 is the ultimate mediator of the febrile response. The setpoint temperature of the body will remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the preoptic area (POA) through the prostaglandin E receptor 3 (EP3). EP3-expressing neurons in the POA innervate the dorsomedial hypothalamus (DMH), the rostral raphe pallidus nucleus in the medulla oblongata (rRPa), and the paraventricular nucleus (PVN) of the hypothalamus. Fever signals sent to the DMH and rRPa lead to stimulation of the sympathetic output system, which evokes non-shivering thermogenesis to produce body heat and skin vasoconstriction to decrease heat loss from the body surface. It is presumed that the innervation from the POA to the PVN mediates the neuroendocrine effects of fever through the pathway involving pituitary gland and various endocrine organs . [ citation needed ]Temperature is regulated in the hypothalamus . The trigger of a fever, called a pyrogen, results in the release of prostaglandin E2 (PGE2). PGE2 in turn acts on the hypothalamus, which creates a systemic response in the body, causing heat-generating effects to match a new higher temperature set point. There are four receptors in which PGE2 can bind (EP1-4), with a previous study showing the EP3 subtype is what mediates the fever response. Hence, the hypothalamus can be seen as working like a thermostat . When the set point is raised, the body increases its temperature through both active generation of heat and retention of heat. Peripheral vasoconstriction both reduces heat loss through the skin and causes the person to feel cold. Norepinephrine increases thermogenesis in brown adipose tissue , and muscle contraction through shivering raises the metabolic rate . If these measures are insufficient to make the blood temperature in the brain match the new set point in the hypothalamus, the brain orchestrates heat effector mechanisms via the autonomic nervous system or primary motor center for shivering. These may be: [ citation needed ] When the hypothalamic set point moves back to baseline—either spontaneously or via medication—normal functions such as sweating, and the reverse of the foregoing processes (e.g., vasodilation, end of shivering, and nonshivering heat production) are used to cool the body to the new, lower setting. [ citation needed ] This contrasts with hyperthermia , in which the normal setting remains, and the body overheats through undesirable retention of excess heat or over-production of heat. Hyperthermia is usually the result of an excessively hot environment ( heat stroke ) or an adverse reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances surrounding it and its response to anti-pyretic medications. [ verification needed ] In infants, the autonomic nervous system may also activate brown adipose tissue to produce heat (non-exercise-associated thermogenesis , also known as non-shivering thermogenesis). [ citation needed ] Increased heart rate and vasoconstriction contribute to increased blood pressure in fever. [ citation needed ]A pyrogen is a substance that induces fever. In the presence of an infectious agent, such as bacteria, viruses, viroids, etc ., the immune response of the body is to inhibit their growth and eliminate them. The most common pyrogens are endotoxins, which are lipopolysaccharides (LPS) produced by Gram-negative bacteria such as E. coli . But pyrogens include non-endotoxic substances (derived from microorganisms other than gram-negative-bacteria or from chemical substances) as well. The types of pyrogens include internal (endogenous) and external (exogenous) to the body. [ citation needed ] The "pyrogenicity" of given pyrogens varies: in extreme cases, bacterial pyrogens can act as superantigens and cause rapid and dangerous fevers. Endogenous pyrogens are cytokines released from monocytes (which are part of the immune system ). In general, they stimulate chemical responses, often in the presence of an antigen , leading to a fever. Whilst they can be a product of external factors like exogenous pyrogens, they can also be induced by internal factors like damage associated molecular patterns such as cases like rheumatoid arthritis or lupus. Major endogenous pyrogens are interleukin 1 (α and β) : 1237–1248 and interleukin 6 (IL-6). Minor endogenous pyrogens include interleukin-8 , tumor necrosis factor-β , macrophage inflammatory protein -α and macrophage inflammatory protein-β as well as interferon-α , interferon-β , and interferon-γ . : 1237–1248 Tumor necrosis factor-α (TNF) also acts as a pyrogen, mediated by interleukin 1 (IL-1) release. These cytokine factors are released into general circulation, where they migrate to the brain's circumventricular organs where they are more easily absorbed than in areas protected by the blood–brain barrier . [ citation needed ] The cytokines then bind to endothelial receptors on vessel walls to receptors on microglial cells , resulting in activation of the arachidonic acid pathway . [ citation needed ] Of these, IL-1β, TNF, and IL-6 are able to raise the temperature setpoint of an organism and cause fever. These proteins produce a cyclooxygenase which induces the hypothalamic production of PGE2 which then stimulates the release of neurotransmitters such as cyclic adenosine monophosphate and increases body temperature. Exogenous pyrogens are external to the body and are of microbial origin. In general, these pyrogens, including bacterial cell wall products, may act on Toll-like receptors in the hypothalamus and elevate the thermoregulatory setpoint. An example of a class of exogenous pyrogens are bacterial lipopolysaccharides (LPS) present in the cell wall of gram-negative bacteria . According to one mechanism of pyrogen action, an immune system protein, lipopolysaccharide-binding protein (LBP), binds to LPS, and the LBP–LPS complex then binds to a CD14 receptor on a macrophage . The LBP-LPS binding to CD14 results in cellular synthesis and release of various endogenous cytokines , e.g., interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNFα). A further downstream event is activation of the arachidonic acid pathway . Endogenous pyrogens are cytokines released from monocytes (which are part of the immune system ). In general, they stimulate chemical responses, often in the presence of an antigen , leading to a fever. Whilst they can be a product of external factors like exogenous pyrogens, they can also be induced by internal factors like damage associated molecular patterns such as cases like rheumatoid arthritis or lupus. Major endogenous pyrogens are interleukin 1 (α and β) : 1237–1248 and interleukin 6 (IL-6). Minor endogenous pyrogens include interleukin-8 , tumor necrosis factor-β , macrophage inflammatory protein -α and macrophage inflammatory protein-β as well as interferon-α , interferon-β , and interferon-γ . : 1237–1248 Tumor necrosis factor-α (TNF) also acts as a pyrogen, mediated by interleukin 1 (IL-1) release. These cytokine factors are released into general circulation, where they migrate to the brain's circumventricular organs where they are more easily absorbed than in areas protected by the blood–brain barrier . [ citation needed ] The cytokines then bind to endothelial receptors on vessel walls to receptors on microglial cells , resulting in activation of the arachidonic acid pathway . [ citation needed ] Of these, IL-1β, TNF, and IL-6 are able to raise the temperature setpoint of an organism and cause fever. These proteins produce a cyclooxygenase which induces the hypothalamic production of PGE2 which then stimulates the release of neurotransmitters such as cyclic adenosine monophosphate and increases body temperature. Exogenous pyrogens are external to the body and are of microbial origin. In general, these pyrogens, including bacterial cell wall products, may act on Toll-like receptors in the hypothalamus and elevate the thermoregulatory setpoint. An example of a class of exogenous pyrogens are bacterial lipopolysaccharides (LPS) present in the cell wall of gram-negative bacteria . According to one mechanism of pyrogen action, an immune system protein, lipopolysaccharide-binding protein (LBP), binds to LPS, and the LBP–LPS complex then binds to a CD14 receptor on a macrophage . The LBP-LPS binding to CD14 results in cellular synthesis and release of various endogenous cytokines , e.g., interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNFα). A further downstream event is activation of the arachidonic acid pathway . PGE2 release comes from the arachidonic acid pathway. This pathway (as it relates to fever), is mediated by the enzymes phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and prostaglandin E2 synthase . These enzymes ultimately mediate the synthesis and release of PGE2. [ citation needed ] PGE2 is the ultimate mediator of the febrile response. The setpoint temperature of the body will remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the preoptic area (POA) through the prostaglandin E receptor 3 (EP3). EP3-expressing neurons in the POA innervate the dorsomedial hypothalamus (DMH), the rostral raphe pallidus nucleus in the medulla oblongata (rRPa), and the paraventricular nucleus (PVN) of the hypothalamus. Fever signals sent to the DMH and rRPa lead to stimulation of the sympathetic output system, which evokes non-shivering thermogenesis to produce body heat and skin vasoconstriction to decrease heat loss from the body surface. It is presumed that the innervation from the POA to the PVN mediates the neuroendocrine effects of fever through the pathway involving pituitary gland and various endocrine organs . [ citation needed ]Fever does not necessarily need to be treated, and most people with a fever recover without specific medical attention. Although it is unpleasant, fever rarely rises to a dangerous level even if untreated. Damage to the brain generally does not occur until temperatures reach 42.0 °C (107.6 °F) , and it is rare for an untreated fever to exceed 40.6 °C (105.1 °F) . Treating fever in people with sepsis does not affect outcomes. Small trials have shown no benefit of treating fevers of 38.5 °C (101.3 °F) or higher of critically ill patients in ICUs, and one trial was terminated early because patients receiving aggressive fever treatment were dying more often. According to the NIH, the two assumptions which are generally used to argue in favor of treating fevers have not been experimentally validated. These are that (1) a fever is noxious, and (2) suppression of a fever will reduce its noxious effect. Most of the other studies supporting the association of fever with poorer outcomes have been observational in nature. In theory, these critically ill patients and those faced with additional physiologic stress may benefit from fever reduction, but the evidence on both sides of the argument appears to be mostly equivocal. Limited evidence supports sponging or bathing feverish children with tepid water. The use of a fan or air conditioning may somewhat reduce the temperature and increase comfort. If the temperature reaches the extremely high level of hyperpyrexia , aggressive cooling is required (generally produced mechanically via conduction by applying numerous ice packs across most of the body or direct submersion in ice water). In general, people are advised to keep adequately hydrated. Whether increased fluid intake improves symptoms or shortens respiratory illnesses such as the common cold is not known. Medications that lower fevers are called antipyretics . The antipyretic ibuprofen is effective in reducing fevers in children. It is more effective than acetaminophen (paracetamol) in children. Ibuprofen and acetaminophen may be safely used together in children with fevers. The efficacy of acetaminophen by itself in children with fevers has been questioned. Ibuprofen is also superior to aspirin in children with fevers. Additionally, aspirin is not recommended in children and young adults (those under the age of 16 or 19 depending on the country) due to the risk of Reye's syndrome . Using both paracetamol and ibuprofen at the same time or alternating between the two is more effective at decreasing fever than using only paracetamol or ibuprofen. It is not clear if it increases child comfort. Response or nonresponse to medications does not predict whether or not a child has a serious illness. With respect to the effect of antipyretics on the risk of death in those with infection, studies have found mixed results as of 2019. Animal models have found increased mortality with the use of antipyretics in influenza but as of 2010 there have been no randomized placebo-controlled trials in humans that gave data on mortality. Limited evidence supports sponging or bathing feverish children with tepid water. The use of a fan or air conditioning may somewhat reduce the temperature and increase comfort. If the temperature reaches the extremely high level of hyperpyrexia , aggressive cooling is required (generally produced mechanically via conduction by applying numerous ice packs across most of the body or direct submersion in ice water). In general, people are advised to keep adequately hydrated. Whether increased fluid intake improves symptoms or shortens respiratory illnesses such as the common cold is not known. Medications that lower fevers are called antipyretics . The antipyretic ibuprofen is effective in reducing fevers in children. It is more effective than acetaminophen (paracetamol) in children. Ibuprofen and acetaminophen may be safely used together in children with fevers. The efficacy of acetaminophen by itself in children with fevers has been questioned. Ibuprofen is also superior to aspirin in children with fevers. Additionally, aspirin is not recommended in children and young adults (those under the age of 16 or 19 depending on the country) due to the risk of Reye's syndrome . Using both paracetamol and ibuprofen at the same time or alternating between the two is more effective at decreasing fever than using only paracetamol or ibuprofen. It is not clear if it increases child comfort. Response or nonresponse to medications does not predict whether or not a child has a serious illness. With respect to the effect of antipyretics on the risk of death in those with infection, studies have found mixed results as of 2019. Animal models have found increased mortality with the use of antipyretics in influenza but as of 2010 there have been no randomized placebo-controlled trials in humans that gave data on mortality. Fever is one of the most common medical signs . It is part of about 30% of healthcare visits by children, and occurs in up to 75% of adults who are seriously sick. About 5% of people who go to an emergency room have a fever. A number of types of fever were known as early as 460 BC to 370 BC when Hippocrates was practicing medicine including that due to malaria (tertian or every 2 days and quartan or every 3 days). It also became clear around this time that fever was a symptom of disease rather than a disease in and of itself. Infections presenting with fever were a major source of mortality in humans for about 200,000 years. Until the late nineteenth century, approximately half of all humans died from infections before the age of fifteen. An older term, febricula (a diminutive form of the Latin word for fever), was once used to refer to a low-grade fever lasting only a few days. This term fell out of use in the early 20th century, and the symptoms it referred to are now thought to have been caused mainly by various minor viral respiratory infections . Fever is often viewed with greater concern by parents and healthcare professionals than might be deserved, a phenomenon known as fever phobia, which is based in both caregiver's and parents' misconceptions about fever in children. Among them, many parents incorrectly believe that fever is a disease rather than a medical sign , that even low fevers are harmful, and that any temperature even briefly or slightly above the oversimplified "normal" number marked on a thermometer is a clinically significant fever. They are also afraid of harmless side effects like febrile seizures and dramatically overestimate the likelihood of permanent damage from typical fevers. The underlying problem, according to professor of pediatrics Barton D. Schmitt, is that "as parents we tend to suspect that our children's brains may melt." As a result of these misconceptions parents are anxious, give the child fever-reducing medicine when the temperature is technically normal or only slightly elevated, and interfere with the child's sleep to give the child more medicine. Fever is often viewed with greater concern by parents and healthcare professionals than might be deserved, a phenomenon known as fever phobia, which is based in both caregiver's and parents' misconceptions about fever in children. Among them, many parents incorrectly believe that fever is a disease rather than a medical sign , that even low fevers are harmful, and that any temperature even briefly or slightly above the oversimplified "normal" number marked on a thermometer is a clinically significant fever. They are also afraid of harmless side effects like febrile seizures and dramatically overestimate the likelihood of permanent damage from typical fevers. The underlying problem, according to professor of pediatrics Barton D. Schmitt, is that "as parents we tend to suspect that our children's brains may melt." As a result of these misconceptions parents are anxious, give the child fever-reducing medicine when the temperature is technically normal or only slightly elevated, and interfere with the child's sleep to give the child more medicine. Fever is an important metric for the diagnosis of disease in domestic animals . The body temperature of animals, which is taken rectally, is different from one species to another. For example, a horse is said to have a fever above 101 °F ( 38.3 °C ). In species that allow the body to have a wide range of "normal" temperatures, such as camels , whose body temperature varies as the environmental temperature varies, the body temperature which constitutes a febrile state differs depending on the environmental temperature. Fever can also be behaviorally induced by invertebrates that do not have immune-system based fever. For instance, some species of grasshopper will thermoregulate to achieve body temperatures that are 2–5 °C higher than normal in order to inhibit the growth of fungal pathogens such as Beauveria bassiana and Metarhizium acridum . Honeybee colonies are also able to induce a fever in response to a fungal parasite Ascosphaera apis .

Wiki

Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/West_Nile_fever/html

West Nile fever

West Nile fever is an infection by the West Nile virus , which is typically spread by mosquitoes . In about 80% of infections people have few or no symptoms . About 20% of people develop a fever , headache, vomiting, or a rash. In less than 1% of people, encephalitis or meningitis occurs, with associated neck stiffness, confusion, or seizures. Recovery may take weeks to months. The risk of death among those in whom the nervous system is affected is about 10 percent. West Nile virus (WNV) is usually spread by mosquitoes that become infected when they feed on infected birds, which often carry the disease . Rarely the virus is spread through blood transfusions, organ transplants, or from mother to baby during pregnancy, delivery, or breastfeeding, but it otherwise does not spread directly between people. Risks for severe disease include being over 60 years old and having other health problems. Diagnosis is typically based on symptoms and blood tests. There is no human vaccine . The best way to reduce the risk of infection is to avoid mosquito bites. Mosquito populations may be reduced by eliminating standing pools of water, such as in old tires, buckets, gutters, and swimming pools. When mosquitoes cannot be avoided, mosquito repellent , window screens , and mosquito nets reduce the likelihood of being bitten. There is no specific treatment for the disease; pain medications may reduce symptoms. The virus was discovered in Uganda in 1937, and was first detected in North America in 1999. WNV has occurred in Europe, Africa, Asia, Australia, and North America. In the United States thousands of cases are reported a year, with most occurring in August and September. It can occur in outbreaks of disease. Severe disease may also occur in horses, for which a vaccine is available. A surveillance system in birds is useful for early detection of a potential human outbreak. About 80% of those infected with West Nile virus (WNV) show no symptoms and go unreported. About 20% of infected people develop symptoms. These vary in severity, and begin 3 to 14 days after being bitten. Most people with mild symptoms of WNV recover completely, though fatigue and weakness may last for weeks or months. Symptoms may range from mild, such as fever , to severe, such as paralysis and meningitis . A severe infection can last weeks and can, rarely, cause permanent brain damage . Death may ensue if the central nervous system is affected. Medical conditions such as cancer and diabetes , and age over 60 years, increase the risk of developing severe symptoms. Headache can be a prominent symptom of WNV fever, meningitis, encephalitis, meningoencephalitis, and it may or may not be present in poliomyelitis-like syndrome. Thus, headache is not a useful indicator of neuroinvasive disease.WNV is one of the Japanese encephalitis antigenic serocomplex of viruses. Image reconstructions and cryoelectron microscopy reveal a 45–50 nm virion covered with a relatively smooth protein surface. This structure is similar to the dengue fever virus; both belong to the genus Flavivirus within the family Flaviviridae . The genetic material of WNV is a positive-sense , single strand of RNA , which is between 11,000 and 12,000 nucleotides long; these genes encode seven nonstructural proteins and three structural proteins. The RNA strand is held within a nucleocapsid formed from 12- kDa protein blocks; the capsid is contained within a host-derived membrane altered by two viral membrane proteins. West Nile virus has been seen to replicate faster and spread more easily to birds at higher temperatures; one of several ways climate change could affect the epidemiology of this disease. The prime method of spread of the West Nile virus (WNV) is the female mosquito. In Europe, cats were identified as being hosts for West Nile virus . The important mosquito vectors vary according to area; in the United States, Culex pipiens (Eastern United States, and urban and residential areas of the United States north of 36–39°N), Culex tarsalis (Midwest and West), and Culex quinquefasciatus (Southeast) are the main vector species. The mosquito species that are most frequently infected with WNV feed primarily on birds. Different species of mosquitos take a blood meal from different types of vertebrate hosts , Mosquitoes show further selectivity, exhibiting preference for different species of birds. In the United States, WNV mosquito vectors feed preferentially on members of the Corvidae and thrush family . Among the preferred species within these families are the American crow , a corvid, and the American robin ( Turdus migratorius ). Some species of birds develop sufficient viral levels (>~10 4.2 log PFU/ml; ) after being infected to transmit the infection to biting mosquitoes that in turn go on to infect other birds. In birds that die from WNV, death usually occurs after 4 to 6 days. In mammals and several species of birds, the virus does not multiply as readily and so does not develop high viremia during infection. Mosquitoes biting such hosts are not believed to ingest sufficient virus to become infected, making them so-called dead-end hosts . As a result of the differential infectiousness of hosts, the feeding patterns of mosquitoes play an important role in WNV transmission, and they are partly genetically controlled, even within a species. Direct human-to-human transmission initially was believed to be caused only by occupational exposure, such as in a laboratory setting, or conjunctival exposure to infected blood. The US outbreak identified additional transmission methods through blood transfusion, organ transplant, intrauterine exposure, and breast feeding. Since 2003, blood banks in the United States routinely screen for the virus among their donors. As a precautionary measure, the UK's National Blood Service initially ran a test for this disease in donors who donate within 28 days of a visit to the United States, Canada, or the northeastern provinces of Italy, and the Scottish National Blood Transfusion Service asks prospective donors to wait 28 days after returning from North America or the northeastern provinces of Italy before donating. There also have been reports of possible transmission of the virus from mother to child during pregnancy or breastfeeding or exposure to the virus in a lab, but these are rare cases and not conclusively confirmed. Recently, the potential for mosquito saliva to affect the course of WNV disease was demonstrated. Mosquitoes inoculate their saliva into the skin while obtaining blood. Mosquito saliva is a pharmacological cocktail of secreted molecules, principally proteins, that can affect vascular constriction, blood coagulation , platelet aggregation , inflammation , and immunity . It clearly alters the immune response in a manner that may be advantageous to a virus. Studies have shown it can specifically modulate the immune response during early virus infection, and mosquito feeding can exacerbate WNV infection, leading to higher viremia and more severe forms of disease. Vertical transmission , the transmission of a viral or bacterial disease from the female of the species to her offspring, has been observed in various West Nile virus studies, amongst different species of mosquitoes in both the laboratory and in nature. Mosquito progeny infected vertically in autumn may potentially serve as a mechanism for WNV to overwinter and initiate enzootic horizontal transmission the following spring, although it likely plays little role in transmission in the summer and fall. Risk factors independently associated with developing a clinical infection with WNV include a suppressed immune system and a patient history of organ transplantation. For neuroinvasive disease the additional risk factors include older age (>50+), male sex, hypertension , and diabetes mellitus . A genetic factor also appears to increase susceptibility to West Nile disease. A mutation of the gene CCR5 gives some protection against HIV but leads to more serious complications of WNV infection. Carriers of two mutated copies of CCR5 made up 4.0 to 4.5% of a sample of people with West Nile disease, while the incidence of the gene in the general population is only 1.0%. The most at risk occupations in the U.S. are outdoor workers, for example farmers, loggers, landscapers/groundskeepers, construction workers, painters, summer camp workers and pavers. Two reports of accidental exposure by laboratory personnel working with infected fluids or tissues have been received. While this appears to be a rare occurrence, it highlights the need for proper handling of infected materials. The World Health Organization states that there are no known cases of health care workers acquiring the virus from infected patients when the appropriate infection control precautions are observed. WNV is one of the Japanese encephalitis antigenic serocomplex of viruses. Image reconstructions and cryoelectron microscopy reveal a 45–50 nm virion covered with a relatively smooth protein surface. This structure is similar to the dengue fever virus; both belong to the genus Flavivirus within the family Flaviviridae . The genetic material of WNV is a positive-sense , single strand of RNA , which is between 11,000 and 12,000 nucleotides long; these genes encode seven nonstructural proteins and three structural proteins. The RNA strand is held within a nucleocapsid formed from 12- kDa protein blocks; the capsid is contained within a host-derived membrane altered by two viral membrane proteins. West Nile virus has been seen to replicate faster and spread more easily to birds at higher temperatures; one of several ways climate change could affect the epidemiology of this disease. The prime method of spread of the West Nile virus (WNV) is the female mosquito. In Europe, cats were identified as being hosts for West Nile virus . The important mosquito vectors vary according to area; in the United States, Culex pipiens (Eastern United States, and urban and residential areas of the United States north of 36–39°N), Culex tarsalis (Midwest and West), and Culex quinquefasciatus (Southeast) are the main vector species. The mosquito species that are most frequently infected with WNV feed primarily on birds. Different species of mosquitos take a blood meal from different types of vertebrate hosts , Mosquitoes show further selectivity, exhibiting preference for different species of birds. In the United States, WNV mosquito vectors feed preferentially on members of the Corvidae and thrush family . Among the preferred species within these families are the American crow , a corvid, and the American robin ( Turdus migratorius ). Some species of birds develop sufficient viral levels (>~10 4.2 log PFU/ml; ) after being infected to transmit the infection to biting mosquitoes that in turn go on to infect other birds. In birds that die from WNV, death usually occurs after 4 to 6 days. In mammals and several species of birds, the virus does not multiply as readily and so does not develop high viremia during infection. Mosquitoes biting such hosts are not believed to ingest sufficient virus to become infected, making them so-called dead-end hosts . As a result of the differential infectiousness of hosts, the feeding patterns of mosquitoes play an important role in WNV transmission, and they are partly genetically controlled, even within a species. Direct human-to-human transmission initially was believed to be caused only by occupational exposure, such as in a laboratory setting, or conjunctival exposure to infected blood. The US outbreak identified additional transmission methods through blood transfusion, organ transplant, intrauterine exposure, and breast feeding. Since 2003, blood banks in the United States routinely screen for the virus among their donors. As a precautionary measure, the UK's National Blood Service initially ran a test for this disease in donors who donate within 28 days of a visit to the United States, Canada, or the northeastern provinces of Italy, and the Scottish National Blood Transfusion Service asks prospective donors to wait 28 days after returning from North America or the northeastern provinces of Italy before donating. There also have been reports of possible transmission of the virus from mother to child during pregnancy or breastfeeding or exposure to the virus in a lab, but these are rare cases and not conclusively confirmed. Recently, the potential for mosquito saliva to affect the course of WNV disease was demonstrated. Mosquitoes inoculate their saliva into the skin while obtaining blood. Mosquito saliva is a pharmacological cocktail of secreted molecules, principally proteins, that can affect vascular constriction, blood coagulation , platelet aggregation , inflammation , and immunity . It clearly alters the immune response in a manner that may be advantageous to a virus. Studies have shown it can specifically modulate the immune response during early virus infection, and mosquito feeding can exacerbate WNV infection, leading to higher viremia and more severe forms of disease. Vertical transmission , the transmission of a viral or bacterial disease from the female of the species to her offspring, has been observed in various West Nile virus studies, amongst different species of mosquitoes in both the laboratory and in nature. Mosquito progeny infected vertically in autumn may potentially serve as a mechanism for WNV to overwinter and initiate enzootic horizontal transmission the following spring, although it likely plays little role in transmission in the summer and fall. Vertical transmission , the transmission of a viral or bacterial disease from the female of the species to her offspring, has been observed in various West Nile virus studies, amongst different species of mosquitoes in both the laboratory and in nature. Mosquito progeny infected vertically in autumn may potentially serve as a mechanism for WNV to overwinter and initiate enzootic horizontal transmission the following spring, although it likely plays little role in transmission in the summer and fall. Risk factors independently associated with developing a clinical infection with WNV include a suppressed immune system and a patient history of organ transplantation. For neuroinvasive disease the additional risk factors include older age (>50+), male sex, hypertension , and diabetes mellitus . A genetic factor also appears to increase susceptibility to West Nile disease. A mutation of the gene CCR5 gives some protection against HIV but leads to more serious complications of WNV infection. Carriers of two mutated copies of CCR5 made up 4.0 to 4.5% of a sample of people with West Nile disease, while the incidence of the gene in the general population is only 1.0%. The most at risk occupations in the U.S. are outdoor workers, for example farmers, loggers, landscapers/groundskeepers, construction workers, painters, summer camp workers and pavers. Two reports of accidental exposure by laboratory personnel working with infected fluids or tissues have been received. While this appears to be a rare occurrence, it highlights the need for proper handling of infected materials. The World Health Organization states that there are no known cases of health care workers acquiring the virus from infected patients when the appropriate infection control precautions are observed. Preliminary diagnosis is often based on the patient's clinical symptoms, places and dates of travel (if patient is from a non endemic country or area), activities, and epidemiologic history of the location where infection occurred. A recent history of mosquito bites and an acute febrile illness associated with neurologic signs and symptoms should cause clinical suspicion of WNV. Diagnosis of West Nile virus infections is generally accomplished by serologic testing of blood serum or cerebrospinal fluid (CSF), which is obtained via a lumbar puncture . Initial screening could be done using the ELISA technique detecting immunoglobulins in the sera of the tested individuals. Typical findings of WNV infection include lymphocytic pleocytosis , elevated protein level, reference glucose and lactic acid levels, and no erythrocytes . Definitive diagnosis of WNV is obtained through detection of virus-specific antibody IgM and neutralizing antibodies . Cases of West Nile virus meningitis and encephalitis that have been serologically confirmed produce similar degrees of CSF pleocytosis and are often associated with substantial CSF neutrophilia . Specimens collected within eight days following onset of illness may not test positive for West Nile IgM, and testing should be repeated. A positive test for West Nile IgG in the absence of a positive West Nile IgM is indicative of a previous flavivirus infection and is not by itself evidence of an acute West Nile virus infection. If cases of suspected West Nile virus infection, sera should be collected on both the acute and convalescent phases of the illness. Convalescent specimens should be collected 2–3 weeks after acute specimens. It is common in serologic testing for cross-reactions to occur among flaviviruses such as dengue virus (DENV) and tick-borne encephalitis virus ; this necessitates caution when evaluating serologic results of flaviviral infections. Four FDA -cleared WNV IgM ELISA kits are commercially available from different manufacturers in the U.S., each of these kits is indicated for use on serum to aid in the presumptive laboratory diagnosis of WNV infection in patients with clinical symptoms of meningitis or encephalitis. Positive WNV test results obtained via use of these kits should be confirmed by additional testing at a state health department laboratory or CDC. In fatal cases, nucleic acid amplification, histopathology with immunohistochemistry , and virus culture of autopsy tissues can also be useful. Only a few state laboratories or other specialized laboratories, including those at CDC, are capable of doing this specialized testing. A number of various diseases may present with symptoms similar to those caused by a clinical West Nile virus infection. Those causing neuroinvasive disease symptoms include the enterovirus infection and bacterial meningitis. Accounting for differential diagnoses is a crucial step in the definitive diagnosis of WNV infection. Consideration of a differential diagnosis is required when a patient presents with unexplained febrile illness, extreme headache, encephalitis or meningitis. Diagnostic and serologic laboratory testing using polymerase chain reaction (PCR) testing and viral culture of CSF to identify the specific pathogen causing the symptoms, is the only currently available means of differentiating between causes of encephalitis and meningitis. A number of various diseases may present with symptoms similar to those caused by a clinical West Nile virus infection. Those causing neuroinvasive disease symptoms include the enterovirus infection and bacterial meningitis. Accounting for differential diagnoses is a crucial step in the definitive diagnosis of WNV infection. Consideration of a differential diagnosis is required when a patient presents with unexplained febrile illness, extreme headache, encephalitis or meningitis. Diagnostic and serologic laboratory testing using polymerase chain reaction (PCR) testing and viral culture of CSF to identify the specific pathogen causing the symptoms, is the only currently available means of differentiating between causes of encephalitis and meningitis. Many of the guidelines for preventing occupational West Nile virus exposure are common to all mosquito-borne diseases . Public health measures include taking steps to reduce mosquito populations. Personal recommendations are to reduce the likelihood of being bitten. General measures to avoid bites include: West Nile virus can be sampled from the environment by the pooling of trapped mosquitoes via ovitraps , carbon dioxide -baited light traps, and gravid traps, testing blood samples drawn from wild birds, dogs, and sentinel monkeys, and testing brains of dead birds found by various animal control agencies and the public. [ citation needed ] Testing of the mosquito samples requires the use of reverse-transcriptase PCR ( RT-PCR ) to directly amplify and show the presence of virus in the submitted samples. When using the blood sera of wild birds and sentinel chickens, samples must be tested for the presence of WNV antibodies by use of immunohistochemistry (IHC) or enzyme-linked immunosorbent assay (ELISA). Dead birds, after necropsy , or their oral swab samples collected on specific RNA-preserving filter paper card, can have their virus presence tested by either RT-PCR or IHC, where virus shows up as brown-stained tissue because of a substrate- enzyme reaction. West Nile control is achieved through mosquito control , by elimination of mosquito breeding sites such as abandoned pools, applying larvacide to active breeding areas, and targeting the adult population via lethal ovitraps and aerial spraying of pesticides . [ citation needed ] Environmentalists have condemned attempts to control the transmitting mosquitoes by spraying pesticide, saying the detrimental health effects of spraying outweigh the relatively few lives that may be saved, and more environmentally friendly ways of controlling mosquitoes are available. They also question the effectiveness of insecticide spraying, as they believe mosquitoes that are resting or flying above the level of spraying will not be killed; the most common vector in the northeastern United States, Culex pipiens , is a canopy feeder. [ citation needed ]West Nile virus can be sampled from the environment by the pooling of trapped mosquitoes via ovitraps , carbon dioxide -baited light traps, and gravid traps, testing blood samples drawn from wild birds, dogs, and sentinel monkeys, and testing brains of dead birds found by various animal control agencies and the public. [ citation needed ] Testing of the mosquito samples requires the use of reverse-transcriptase PCR ( RT-PCR ) to directly amplify and show the presence of virus in the submitted samples. When using the blood sera of wild birds and sentinel chickens, samples must be tested for the presence of WNV antibodies by use of immunohistochemistry (IHC) or enzyme-linked immunosorbent assay (ELISA). Dead birds, after necropsy , or their oral swab samples collected on specific RNA-preserving filter paper card, can have their virus presence tested by either RT-PCR or IHC, where virus shows up as brown-stained tissue because of a substrate- enzyme reaction. West Nile control is achieved through mosquito control , by elimination of mosquito breeding sites such as abandoned pools, applying larvacide to active breeding areas, and targeting the adult population via lethal ovitraps and aerial spraying of pesticides . [ citation needed ] Environmentalists have condemned attempts to control the transmitting mosquitoes by spraying pesticide, saying the detrimental health effects of spraying outweigh the relatively few lives that may be saved, and more environmentally friendly ways of controlling mosquitoes are available. They also question the effectiveness of insecticide spraying, as they believe mosquitoes that are resting or flying above the level of spraying will not be killed; the most common vector in the northeastern United States, Culex pipiens , is a canopy feeder. [ citation needed ]No specific treatment is available for WNV infection. Most people recover without treatment. In mild cases, over-the-counter pain relievers can help ease mild headaches and muscle aches in adults. In severe cases supportive care is provided, often in hospital, with intravenous fluids , pain medication, respiratory support, and prevention of secondary infections. While the general prognosis is favorable, current studies indicate that West Nile Fever can often be more severe than previously recognized, with studies of various recent outbreaks indicating that it may take as long as 60 to 90 days to recover. Patients with milder WNF are just as likely as those with more severe manifestations of neuroinvasive disease to experience multiple somatic complaints such as tremor, and dysfunction in motor skills and executive functions for over a year. People with milder symptoms are just as likely as people with more severe symptoms to experience adverse outcomes. Recovery is marked by a long convalescence with fatigue . One study found that neuroinvasive WNV infection was associated with an increased risk for subsequent kidney disease. WNV was first isolated from a feverish 37-year-old woman at Omogo in the West Nile District of Uganda in 1937 during research on yellow fever virus . A series of serosurveys in 1939 in central Africa found anti-WNV positive results ranging from 1.4% (Congo) to 46.4% (White Nile region, Sudan). It was subsequently identified in Egypt (1942) and India (1953), a 1950 serosurvey in Egypt found 90% of those over 40 years in age had WNV antibodies. The ecology was characterized in 1953 with studies in Egypt and Israel . The virus became recognized as a cause of severe human meningoencephalitis in elderly patients during an outbreak in Israel in 1957. The disease was first noted in horses in Egypt and France in the early 1960s and found to be widespread in southern Europe, southwest Asia and Australia. [ citation needed ] The first appearance of WNV in the Western Hemisphere was in 1999 with encephalitis reported in humans, dogs, cats, and horses, and the subsequent spread in the United States may be an important milestone in the evolving history of this virus. The American outbreak began in College Point, Queens in New York City and was later spread to the neighboring states of New Jersey and Connecticut . The virus is believed to have entered in an infected bird or mosquito, although there is no clear evidence. West Nile virus is now endemic in Africa, Europe, the Middle East, west and central Asia, Oceania (subtype Kunjin ), and most recently, North America and is spreading into Central and South America. Outbreaks of West Nile virus encephalitis in humans have occurred in Algeria (1994), Romania (1996 to 1997), the Czech Republic (1997), Congo (1998), Russia (1999), the United States (1999 to 2009), Canada (1999–2007), Israel (2000) and Greece (2010). Epizootics of disease in horses occurred in Morocco (1996), Italy (1998), the United States (1999 to 2001), and France (2000), Mexico (2003) and Sardinia (2011). [ citation needed ] Outdoor workers (including biological fieldworkers, construction workers, farmers, landscapers, and painters), healthcare personnel, and laboratory personnel who perform necropsies on animals are at risk of contracting WNV. In 2012, the US experienced one of its worst epidemics in which 286 people died, with the state of Texas being hard hit by this virus. Drought has been associated with a higher number of West Nile virus cases in the following year. As drought can decrease fish and other populations that eat mosquito eggs, higher numbers of mosquitoes can result. Higher temperatures are linked to decreased time for replication and increased viral load in birds and mosquitoes. Drought has been associated with a higher number of West Nile virus cases in the following year. As drought can decrease fish and other populations that eat mosquito eggs, higher numbers of mosquitoes can result. Higher temperatures are linked to decreased time for replication and increased viral load in birds and mosquitoes. A vaccine for horses ( ATCvet code: QI05AA10 ( WHO ) ) based on killed viruses exists; some zoos have given this vaccine to their birds, although its effectiveness is unknown. Dogs and cats show few if any signs of infection. There have been no known cases of direct canine-human or feline-human transmission; although these pets can become infected, it is unlikely they are, in turn, capable of infecting native mosquitoes and thus continuing the disease cycle. AMD3100 , which had been proposed as an antiretroviral drug for HIV, has shown promise against West Nile encephalitis. Morpholino antisense oligos conjugated to cell penetrating peptides have been shown to partially protect mice from WNV disease. There have also been attempts to treat infections using ribavirin , intravenous immunoglobulin , or alpha interferon . GenoMed, a U.S. biotech company, has found that blocking angiotensin II can treat the " cytokine storm " of West Nile virus encephalitis as well as other viruses. As of 2019, six vaccines had progressed to human trials but none had been licensed in the United States. Only the two live attenuated vaccines produced strong immunity after a single dose.

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Acute hemorrhagic fever syndrome

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Argentine hemorrhagic fever

Argentine hemorrhagic fever (AHF) or O'Higgins disease , also known in Argentina as mal de los rastrojos (stubble disease) is a hemorrhagic fever and zoonotic infectious disease occurring in Argentina. It is caused by the Junín virus (an arenavirus , closely related to the Machupo virus , causative agent of Bolivian hemorrhagic fever ). Its reservoir of infection is the drylands vesper mouse , a rodent found in Argentina and Paraguay.The disease was first reported in the town of O'Higgins [ es ] in Buenos Aires province, Argentina in 1958, giving it one of the names by which it is known. Theories about its nature included: Weil's disease , leptospirosis , chemical pollution. It was associated with fields containing stubble after the harvest, giving it another of its names. The endemic area of AHF covers approximately 150,000 km 2 , compromising the provinces of Buenos Aires , Córdoba , Santa Fe and La Pampa , with an estimated risk population of 5 million. [ citation needed ] The natural reservoir of infection, a small rodent known locally as ratón maicero ("maize mouse"; Calomys musculinus ), has chronic asymptomatic infection, and spreads the virus through its saliva and urine . Infection is produced through contact of skin or mucous membranes, or through inhalation of infected particles. It is found mostly in people who reside or work in rural areas; 80% of those infected are males between 15 and 60 years of age. [ citation needed ]AHF is a grave acute disease which may progress to recovery or death in 1 to 2 weeks. The incubation time of the disease is between 10 and 12 days, after which the first symptoms appear: fever, headaches, weakness, loss of appetite and will. These intensify less than a week later, forcing the infected to lie down, and producing stronger symptoms such as vascular, renal, hematological and neurological alterations. This stage lasts about 3 weeks. [ citation needed ] If untreated, the mortality of AHF reaches 15–30%. The specific treatment includes plasma of recovered patients, which, if started early, is extremely effective and reduces mortality to 1%. Ribavirin also has shown some promise in treating arenaviral diseases. The disease was first detected in the 1950s in the Junín Partido in Buenos Aires, after which its agent, the Junín virus, was named upon its identification in 1958. In the early years, about 1,000 cases per year were recorded, with a high mortality rate (more than 30%). The initial introduction of treatment serums in the 1970s reduced this lethality. The Candid #1 vaccine for AHF was created in 1985 by Argentine virologist Dr. Julio Barrera Oro. The vaccine was manufactured by the Salk Institute in the United States, and became available in Argentina in 1990. Antibodies produced by Candid #1 vaccination have also demonstrated cross-reactivity with Machupo virus in Rhesus macaques, and thus Candid #1 been considered for prophylactic use against Bolivian hemorrhagic fever . Candid #1 has been applied to adult high-risk population and is 95.5% effective. Between 1991 and 2005 more than 240,000 people were vaccinated, achieving a great decrease in the numbers of reported cases (94 suspect and 19 confirmed in 2005). On 29 August 2006 the Maiztegui Institute obtained certification for the production of the vaccine in Argentina. The vaccine produced in Argentina was found to be of similar effectiveness to the US vaccine. Details of the vaccine were published in 2011, and a protocol for production of the vaccine was published in 2018. Demand for the vaccine is insufficient to be commercially appealing due to the small target population, and it is considered an orphan drug ; the Argentine government committed itself to manufacture and sponsor Candid #1 vaccine. The Candid #1 vaccine for AHF was created in 1985 by Argentine virologist Dr. Julio Barrera Oro. The vaccine was manufactured by the Salk Institute in the United States, and became available in Argentina in 1990. Antibodies produced by Candid #1 vaccination have also demonstrated cross-reactivity with Machupo virus in Rhesus macaques, and thus Candid #1 been considered for prophylactic use against Bolivian hemorrhagic fever . Candid #1 has been applied to adult high-risk population and is 95.5% effective. Between 1991 and 2005 more than 240,000 people were vaccinated, achieving a great decrease in the numbers of reported cases (94 suspect and 19 confirmed in 2005). On 29 August 2006 the Maiztegui Institute obtained certification for the production of the vaccine in Argentina. The vaccine produced in Argentina was found to be of similar effectiveness to the US vaccine. Details of the vaccine were published in 2011, and a protocol for production of the vaccine was published in 2018. Demand for the vaccine is insufficient to be commercially appealing due to the small target population, and it is considered an orphan drug ; the Argentine government committed itself to manufacture and sponsor Candid #1 vaccine. Argentine hemorrhagic fever was one of three hemorrhagic fevers and one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program. The Soviet Union also conducted research and developing programs on the potential of the hemorragic fever as a biological weapon.

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Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/SARS-related_coronavirus/html

SARS-related coronavirus

SARS coronavirus SARS-related coronavirus Severe acute respiratory syndrome coronavirus Severe-acute-respiratory-syndrome–related coronavirus ( SARSr-CoV or SARS-CoV ) [note 1] is a species of virus consisting of many known strains. Two strains of the virus have caused outbreaks of severe respiratory diseases in humans: severe acute respiratory syndrome coronavirus 1 (SARS-CoV or SARS-CoV-1), which caused the 2002–2004 outbreak of severe acute respiratory syndrome (SARS), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is causing the ongoing pandemic of COVID-19 . There are hundreds of other strains of SARSr-CoV, which are only known to infect non-human mammal species: bats are a major reservoir of many strains of SARSr-CoV; several strains have been identified in Himalayan palm civets , which were likely ancestors of SARS-CoV-1. These enveloped , positive-sense single-stranded RNA viruses enter host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. The SARSr-CoV species is a member of the genus Betacoronavirus and the only species of the subgenus Sarbecovirus ( SAR S Be ta co rona virus ). The SARS-related coronavirus was one of several viruses identified by the World Health Organization (WHO) in 2016 as a likely cause of a future epidemic in a new plan developed after the Ebola epidemic for urgent research and development before and during an epidemic towards diagnostic tests , vaccines and medicines . This prediction came to pass with the COVID-19 pandemic . SARS-related coronavirus is a member of the genus Betacoronavirus (group 2) and monotypic of the subgenus Sarbecovirus (subgroup B). Sarbecoviruses, unlike embecoviruses or alphacoronaviruses , have only one papain-like proteinase ( PLpro ) instead of two in the open reading frame ORF1ab . SARSr-CoV was determined to be an early split-off from the betacoronaviruses based on a set of conserved domains that it shares with the group. Bats serve as the main host reservoir species for the SARS-related coronaviruses like SARS-CoV-1 and SARS-CoV-2. The virus has coevolved in the bat host reservoir over a long period of time. Only recently have strains of SARS-related coronavirus been observed to have evolved into having been able to make the cross-species jump from bats to humans, as in the case of the strains SARS-CoV-1 and SARS-CoV-2 . Both of these strains descended from a single ancestor but made the cross-species jump into humans separately. SARS-CoV-2 is not a direct descendant of SARS-CoV-1. The SARS-related coronavirus is an enveloped, positive-sense, single-stranded RNA virus . Its genome is about 30 kb , which is one of the largest among RNA viruses. The virus has 14 open reading frames which overlap in some cases. The genome has the usual 5′ methylated cap and a 3′ polyadenylated tail . There are 265 nucleotides in the 5'UTR and 342 nucleotides in the 3'UTR . The 5' methylated cap and 3' polyadenylated tail allows the positive-sense RNA genome to be directly translated by the host cell's ribosome on viral entry . SARSr-CoV is similar to other coronaviruses in that its genome expression starts with translation by the host cell's ribosomes of its initial two large overlapping open reading frames (ORFs), 1a and 1b, both of which produce polyproteins . The functions of several of the viral proteins are known. ORFs 1a and 1b encode the replicase/transcriptase polyprotein, and later ORFs 2, 4, 5, and 9a encode, respectively, the four major structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N). The later ORFs also encode for eight unique proteins (orf3a to orf9b), known as the accessory proteins , many with no known homologues. The different functions of the accessory proteins are not well understood. SARS coronaviruses have been genetically engineered in several laboratories. Phylogenetic analysis showed that the evolutionary branch composed of Bat coronavirus BtKY72 and BM48-31 was the base group of SARS–related CoVs evolutionary tree, which separated from other SARS–related CoVs earlier than SARS-CoV-1 and SARS-CoV-2. Bat CoV BtKY72 Bat CoV BM48-31 SARS-CoV-1 related coronavirus SARS-CoV-2 related coronavirus A phylogenetic tree based on whole-genome sequences of SARS-CoV-1 and related coronaviruses is: 16BO133 , 86.3% to SARS-CoV-1, Rhinolophus ferrumequinum , North Jeolla , South Korea JTMC15 , 86.4% to SARS-CoV-1, Rhinolophus ferrumequinum , Tonghua , Jilin Bat SARS CoV Rf1, 87.8% to SARS-CoV-1, Rhinolophus ferrumequinum , Yichang , Hubei BtCoV HKU3, 87.9% to SARS-CoV-1, Rhinolophus sinicus , Hong Kong and Guangdong LYRa11 , 90.9% to SARS-CoV-1, Rhinolophus affinis , Baoshan , Yunnan Bat SARS-CoV/Rp3, 92.6% to SARS-CoV-1, Rhinolophus pearsoni , Nanning , Guangxi Bat SL-CoV YNLF_31C, 93.5% to SARS-CoV-1, Rhinolophus ferrumequinum , Lufeng , Yunnan Bat SL-CoV YNLF_34C, 93.5% to SARS-CoV-1, Rhinolophus ferrumequinum , Lufeng , Yunnan SHC014-CoV , 95.4% to SARS-CoV-1, Rhinolophus sinicus , Kunming , Yunnan WIV1 , 95.6% to SARS-CoV-1, Rhinolophus sinicus , Kunming , Yunnan WIV16 , 96.0% to SARS-CoV-1, Rhinolophus sinicus Kunming , Yunnan Civet SARS-CoV , 99.8% to SARS-CoV-1, Paguma larvata , market in Guangdong, China SARS-CoV-1 SARS-CoV-2 , 79% to SARS-CoV-1 A phylogenetic tree based on whole-genome sequences of SARS-CoV-2 and related coronaviruses is: ( Bat ) Rc-o319 , 81% to SARS-CoV-2, Rhinolophus cornutus , Iwate , Japan Bat SL-ZXC21 , 88% to SARS-CoV-2, Rhinolophus pusillus , Zhoushan , Zhejiang Bat SL-ZC45 , 88% to SARS-CoV-2, Rhinolophus pusillus , Zhoushan, Zhejiang Pangolin SARSr-CoV-GX, 85.3% to SARS-CoV-2, Manis javanica , smuggled from Southeast Asia Pangolin SARSr-CoV-GD, 90.1% to SARS-CoV-2, Manis javanica , smuggled from Southeast Asia Bat RshSTT182, 92.6% to SARS-CoV-2, Rhinolophus shameli , Steung Treng , Cambodia Bat RshSTT200, 92.6% to SARS-CoV-2, Rhinolophus shameli , Steung Treng, Cambodia (Bat) RacCS203 , 91.5% to SARS-CoV-2, Rhinolophus acuminatus , Chachoengsao , Thailand (Bat) RmYN02 , 93.3% to SARS-CoV-2, Rhinolophus malayanus , Mengla , Yunnan (Bat) RpYN06 , 94.4% to SARS-CoV-2, Rhinolophus pusillus , Xishuangbanna , Yunnan (Bat) RaTG13 , 96.1% to SARS-CoV-2, Rhinolophus affinis , Mojiang , Yunnan (Bat) BANAL-52 , 96.8% to SARS-CoV-2, Rhinolophus malayanus , Vientiane , Laos SARS-CoV-2 SARS-CoV-1 , 79% to SARS-CoV-2A phylogenetic tree based on whole-genome sequences of SARS-CoV-1 and related coronaviruses is: 16BO133 , 86.3% to SARS-CoV-1, Rhinolophus ferrumequinum , North Jeolla , South Korea JTMC15 , 86.4% to SARS-CoV-1, Rhinolophus ferrumequinum , Tonghua , Jilin Bat SARS CoV Rf1, 87.8% to SARS-CoV-1, Rhinolophus ferrumequinum , Yichang , Hubei BtCoV HKU3, 87.9% to SARS-CoV-1, Rhinolophus sinicus , Hong Kong and Guangdong LYRa11 , 90.9% to SARS-CoV-1, Rhinolophus affinis , Baoshan , Yunnan Bat SARS-CoV/Rp3, 92.6% to SARS-CoV-1, Rhinolophus pearsoni , Nanning , Guangxi Bat SL-CoV YNLF_31C, 93.5% to SARS-CoV-1, Rhinolophus ferrumequinum , Lufeng , Yunnan Bat SL-CoV YNLF_34C, 93.5% to SARS-CoV-1, Rhinolophus ferrumequinum , Lufeng , Yunnan SHC014-CoV , 95.4% to SARS-CoV-1, Rhinolophus sinicus , Kunming , Yunnan WIV1 , 95.6% to SARS-CoV-1, Rhinolophus sinicus , Kunming , Yunnan WIV16 , 96.0% to SARS-CoV-1, Rhinolophus sinicus Kunming , Yunnan Civet SARS-CoV , 99.8% to SARS-CoV-1, Paguma larvata , market in Guangdong, China SARS-CoV-1 SARS-CoV-2 , 79% to SARS-CoV-1 A phylogenetic tree based on whole-genome sequences of SARS-CoV-2 and related coronaviruses is: ( Bat ) Rc-o319 , 81% to SARS-CoV-2, Rhinolophus cornutus , Iwate , Japan Bat SL-ZXC21 , 88% to SARS-CoV-2, Rhinolophus pusillus , Zhoushan , Zhejiang Bat SL-ZC45 , 88% to SARS-CoV-2, Rhinolophus pusillus , Zhoushan, Zhejiang Pangolin SARSr-CoV-GX, 85.3% to SARS-CoV-2, Manis javanica , smuggled from Southeast Asia Pangolin SARSr-CoV-GD, 90.1% to SARS-CoV-2, Manis javanica , smuggled from Southeast Asia Bat RshSTT182, 92.6% to SARS-CoV-2, Rhinolophus shameli , Steung Treng , Cambodia Bat RshSTT200, 92.6% to SARS-CoV-2, Rhinolophus shameli , Steung Treng, Cambodia (Bat) RacCS203 , 91.5% to SARS-CoV-2, Rhinolophus acuminatus , Chachoengsao , Thailand (Bat) RmYN02 , 93.3% to SARS-CoV-2, Rhinolophus malayanus , Mengla , Yunnan (Bat) RpYN06 , 94.4% to SARS-CoV-2, Rhinolophus pusillus , Xishuangbanna , Yunnan (Bat) RaTG13 , 96.1% to SARS-CoV-2, Rhinolophus affinis , Mojiang , Yunnan (Bat) BANAL-52 , 96.8% to SARS-CoV-2, Rhinolophus malayanus , Vientiane , Laos SARS-CoV-2 SARS-CoV-1 , 79% to SARS-CoV-2The morphology of the SARS-related coronavirus is characteristic of the coronavirus family as a whole. The viruses are large pleomorphic spherical particles with bulbous surface projections that form a corona around the particles in electron micrographs. The size of the virus particles is in the 80–90 nm range. The envelope of the virus in electron micrographs appears as a distinct pair of electron dense shells. The viral envelope consists of a lipid bilayer where the membrane (M), envelope (E) and spike (S) proteins are anchored. The spike proteins provide the virus with its bulbous surface projections, known as peplomers . The spike protein's interaction with its complement host cell receptor is central in determining the tissue tropism , infectivity , and species range of the virus. Inside the envelope, there is the nucleocapsid , which is formed from multiple copies of the nucleocapsid (N) protein, which are bound to the positive-sense single-stranded (~30 kb ) RNA genome in a continuous beads-on-a-string type conformation. The lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host. SARS-related coronavirus follows the replication strategy typical of all coronaviruses. The attachment of the SARS-related coronavirus to the host cell is mediated by the spike protein and its receptor. The spike protein receptor binding domain (RBD) recognizes and attaches to the angiotensin-converting enzyme 2 (ACE2) receptor. Following attachment, the virus can enter the host cell by two different paths. The path the virus takes depends on the host protease available to cleave and activate the receptor-attached spike protein. The attachment of sarbecoviruses to ACE2 has been shown to be an evolutionarily conserved feature, present in many species of the taxon. The first path the SARS coronavirus can take to enter the host cell is by endocytosis and uptake of the virus in an endosome . The receptor-attached spike protein is then activated by the host's pH-dependent cysteine protease cathepsin L . Activation of the receptor-attached spike protein causes a conformational change , and the subsequent fusion of the viral envelope with the endosomal wall . Alternatively, the virus can enter the host cell directly by proteolytic cleavage of the receptor-attached spike protein by the host's TMPRSS2 or TMPRSS11D serine proteases at the cell surface. In the SARS coronavirus, the activation of the C-terminal part of the spike protein triggers the fusion of the viral envelope with the host cell membrane by inducing conformational changes which are not fully understood. After fusion the nucleocapsid passes into the cytoplasm , where the viral genome is released. The genome acts as a messenger RNA , and the cell's ribosome translates two-thirds of the genome, which corresponds to the open reading frame ORF1a and ORF1b , into two large overlapping polyproteins, pp1a and pp1ab. The larger polyprotein pp1ab is a result of a -1 ribosomal frameshift caused by a slippery sequence (UUUAAAC) and a downstream RNA pseudoknot at the end of open reading frame ORF1a. The ribosomal frameshift allows for the continuous translation of ORF1a followed by ORF1b. The polyproteins contain their own proteases , PLpro and 3CLpro , which cleave the polyproteins at different specific sites. The cleavage of polyprotein pp1ab yields 16 nonstructural proteins (nsp1 to nsp16). Product proteins include various replication proteins such as RNA-dependent RNA polymerase (RdRp), RNA helicase , and exoribonuclease (ExoN). The two SARS-CoV-2 proteases (PLpro and 3CLpro) also interfere with the immune system response to the viral infection by cleaving three immune system proteins. PLpro cleaves IRF3 and 3CLpro cleaves both NLRP12 and TAB1 . "Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients." A number of the nonstructural replication proteins coalesce to form a multi-protein replicase-transcriptase complex (RTC). The main replicase-transcriptase protein is the RNA-dependent RNA polymerase (RdRp). It is directly involved in the replication and transcription of RNA from an RNA strand. The other nonstructural proteins in the complex assist in the replication and transcription process. The protein nsp14 is a 3'-5' exoribonuclease which provides extra fidelity to the replication process. The exoribonuclease provides a proofreading function to the complex which the RNA-dependent RNA polymerase lacks. Similarly, proteins nsp7 and nsp8 form a hexadecameric sliding clamp as part of the complex which greatly increases the processivity of the RNA-dependent RNA polymerase. The coronaviruses require the increased fidelity and processivity during RNA synthesis because of the relatively large genome size in comparison to other RNA viruses. One of the main functions of the replicase-transcriptase complex is to transcribe the viral genome. RdRp directly mediates the synthesis of negative-sense subgenomic RNA molecules from the positive-sense genomic RNA. This is followed by the transcription of these negative-sense subgenomic RNA molecules to their corresponding positive-sense mRNAs . The other important function of the replicase-transcriptase complex is to replicate the viral genome. RdRp directly mediates the synthesis of negative-sense genomic RNA from the positive-sense genomic RNA. This is followed by the replication of positive-sense genomic RNA from the negative-sense genomic RNA. The replicated positive-sense genomic RNA becomes the genome of the progeny viruses . The various smaller mRNAs are transcripts from the last third of the virus genome which follows the reading frames ORF1a and ORF1b. These mRNAs are translated into the four structural proteins (S, E, M, and N) that will become part of the progeny virus particles and also eight other accessory proteins (orf3 to orf9b) which assist the virus. When two SARS-CoV genomes are present in a host cell, they may interact with each other to form recombinant genomes that can be transmitted to progeny viruses. Recombination likely occurs during genome replication when the RNA polymerase switches from one template to another (copy choice recombination). Human SARS-CoV appears to have had a complex history of recombination between ancestral coronaviruses that were hosted in several different animal groups. RNA translation occurs inside the endoplasmic reticulum . The viral structural proteins S, E and M move along the secretory pathway into the Golgi intermediate compartment . There, the M proteins direct most protein-protein interactions required for assembly of viruses following its binding to the nucleocapsid. Progeny viruses are released from the host cell by exocytosis through secretory vesicles. The attachment of the SARS-related coronavirus to the host cell is mediated by the spike protein and its receptor. The spike protein receptor binding domain (RBD) recognizes and attaches to the angiotensin-converting enzyme 2 (ACE2) receptor. Following attachment, the virus can enter the host cell by two different paths. The path the virus takes depends on the host protease available to cleave and activate the receptor-attached spike protein. The attachment of sarbecoviruses to ACE2 has been shown to be an evolutionarily conserved feature, present in many species of the taxon. The first path the SARS coronavirus can take to enter the host cell is by endocytosis and uptake of the virus in an endosome . The receptor-attached spike protein is then activated by the host's pH-dependent cysteine protease cathepsin L . Activation of the receptor-attached spike protein causes a conformational change , and the subsequent fusion of the viral envelope with the endosomal wall . Alternatively, the virus can enter the host cell directly by proteolytic cleavage of the receptor-attached spike protein by the host's TMPRSS2 or TMPRSS11D serine proteases at the cell surface. In the SARS coronavirus, the activation of the C-terminal part of the spike protein triggers the fusion of the viral envelope with the host cell membrane by inducing conformational changes which are not fully understood. After fusion the nucleocapsid passes into the cytoplasm , where the viral genome is released. The genome acts as a messenger RNA , and the cell's ribosome translates two-thirds of the genome, which corresponds to the open reading frame ORF1a and ORF1b , into two large overlapping polyproteins, pp1a and pp1ab. The larger polyprotein pp1ab is a result of a -1 ribosomal frameshift caused by a slippery sequence (UUUAAAC) and a downstream RNA pseudoknot at the end of open reading frame ORF1a. The ribosomal frameshift allows for the continuous translation of ORF1a followed by ORF1b. The polyproteins contain their own proteases , PLpro and 3CLpro , which cleave the polyproteins at different specific sites. The cleavage of polyprotein pp1ab yields 16 nonstructural proteins (nsp1 to nsp16). Product proteins include various replication proteins such as RNA-dependent RNA polymerase (RdRp), RNA helicase , and exoribonuclease (ExoN). The two SARS-CoV-2 proteases (PLpro and 3CLpro) also interfere with the immune system response to the viral infection by cleaving three immune system proteins. PLpro cleaves IRF3 and 3CLpro cleaves both NLRP12 and TAB1 . "Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients." A number of the nonstructural replication proteins coalesce to form a multi-protein replicase-transcriptase complex (RTC). The main replicase-transcriptase protein is the RNA-dependent RNA polymerase (RdRp). It is directly involved in the replication and transcription of RNA from an RNA strand. The other nonstructural proteins in the complex assist in the replication and transcription process. The protein nsp14 is a 3'-5' exoribonuclease which provides extra fidelity to the replication process. The exoribonuclease provides a proofreading function to the complex which the RNA-dependent RNA polymerase lacks. Similarly, proteins nsp7 and nsp8 form a hexadecameric sliding clamp as part of the complex which greatly increases the processivity of the RNA-dependent RNA polymerase. The coronaviruses require the increased fidelity and processivity during RNA synthesis because of the relatively large genome size in comparison to other RNA viruses. One of the main functions of the replicase-transcriptase complex is to transcribe the viral genome. RdRp directly mediates the synthesis of negative-sense subgenomic RNA molecules from the positive-sense genomic RNA. This is followed by the transcription of these negative-sense subgenomic RNA molecules to their corresponding positive-sense mRNAs . The other important function of the replicase-transcriptase complex is to replicate the viral genome. RdRp directly mediates the synthesis of negative-sense genomic RNA from the positive-sense genomic RNA. This is followed by the replication of positive-sense genomic RNA from the negative-sense genomic RNA. The replicated positive-sense genomic RNA becomes the genome of the progeny viruses . The various smaller mRNAs are transcripts from the last third of the virus genome which follows the reading frames ORF1a and ORF1b. These mRNAs are translated into the four structural proteins (S, E, M, and N) that will become part of the progeny virus particles and also eight other accessory proteins (orf3 to orf9b) which assist the virus. When two SARS-CoV genomes are present in a host cell, they may interact with each other to form recombinant genomes that can be transmitted to progeny viruses. Recombination likely occurs during genome replication when the RNA polymerase switches from one template to another (copy choice recombination). Human SARS-CoV appears to have had a complex history of recombination between ancestral coronaviruses that were hosted in several different animal groups. RNA translation occurs inside the endoplasmic reticulum . The viral structural proteins S, E and M move along the secretory pathway into the Golgi intermediate compartment . There, the M proteins direct most protein-protein interactions required for assembly of viruses following its binding to the nucleocapsid. Progeny viruses are released from the host cell by exocytosis through secretory vesicles.

Wiki

Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/MERS/html

MERS

Middle East respiratory syndrome ( MERS ) is a viral respiratory infection caused by Middle East respiratory syndrome–related coronavirus (MERS-CoV). Symptoms may range from none, to mild, to severe depending on age and risk level. Typical symptoms include fever , cough , diarrhea , and shortness of breath . The disease is typically more severe in those with other health problems. The first case was identified in June 2012 by Egyptian physician Ali Mohamed Zaki at the Dr. Soliman Fakeeh Hospital in Jeddah , Saudi Arabia, and most cases have occurred in the Arabian Peninsula . Over 2,600 cases have been reported as of January 2021, including 45 cases in the year 2020. About 35% of those who are diagnosed with the disease die from it. Larger outbreaks have occurred in South Korea in 2015 and in Saudi Arabia in 2018 . MERS-CoV is a virus in the coronavirus family believed to be originally from bats. However, humans are typically infected from camels , either during direct contact or indirectly through respiratory droplets. Spread between humans typically requires close contact with an infected person. Its spread is uncommon outside of hospitals. Thus, its risk to the global population is currently deemed to be significantly low. Diagnosis is by rRT-PCR testing of blood and respiratory samples. As of 2021 [ update ] , there is no specific vaccine or treatment for the disease, but a number are being developed. The World Health Organization (WHO) recommends that those who come in contact with camels wash their hands and not touch sick camels. They also recommend that camel-based food products be appropriately cooked. Treatments that help with the symptoms and support body functioning may be used. Previous infection with MERS can confer cross-reactive immunity to SARS-CoV-2 and provide partial protection against COVID-19 . However, co-infection with SARS-CoV-2 and MERS is possible and could lead to a recombination event. Early reports compared the viruses to severe acute respiratory syndrome ( SARS ), and it has been referred to as Saudi Arabia's SARS-like virus. The first person, in June 2012 , had a fever , cough , expectoration , and shortness of breath. One review of 47 laboratory confirmed cases in Saudi Arabia gave the most common presenting symptoms as fever in 98%, cough in 83%, shortness of breath in 72% and myalgia in 32% of people. There were also frequent gastrointestinal symptoms with diarrhea in 26%, vomiting in 21%, abdominal pain in 17% of people. 72% of people required mechanical ventilation . There were also 3.3 males for every female. One study of a hospital-based outbreak of MERS had an estimated incubation period of 5.5 days (95% confidence interval 1.9 to 14.7 days). MERS can range from asymptomatic disease to severe pneumonia leading to acute respiratory distress syndrome (ARDS). Kidney failure , disseminated intravascular coagulation (DIC), and pericarditis have also been reported. Middle East respiratory syndrome is caused by the MERS coronavirus (MERS-CoV), a species with single-stranded RNA belonging to the genus betacoronavirus which is distinct from SARS coronavirus and the common-cold coronavirus. Its genomes are phylogenetically classified into two clades , Clades A and B. Early cases of MERS were of Clade A clusters (EMC/2012 and Jordan-N3/2012), while new cases are genetically different in general (Clade B). The virus grows readily on Vero cells and LLC-MK2 cells. In November 2012, Egyptian virologist Dr. Ali Zaki sent a virus sample from the first confirmed case in Saudi Arabia to virologist Ron Fouchier , a leading coronavirus researcher at the Erasmus Medical Center (EMC) in Rotterdam , the Netherlands. The second laboratory-proven case was in London, confirmed by the UK Health Protection Agency (HPA). The HPA named the virus the London1_novel CoV 2012. A study performed between 2010 and 2013, in which the incidence of MERS was evaluated in 310 dromedary camels , revealed high titers of neutralizing antibodies to MERS-CoV in the blood serum of these animals. A further study sequenced MERS-CoV from nasal swabs of dromedary camels in Saudi Arabia and found they had sequences identical to previously sequenced human isolates. Some individual camels were also found to have more than one genomic variant in their nasopharynx . There is also a 2014 report of a Saudi Arabian man who became ill seven days after applying topical medicine to the noses of several sick camels and later he and one of the camels were found to have identical strains of MERS-CoV. It is still unclear how the virus is transmitted from camels to humans. In 2014, the Saudi Ministry of Agriculture advised people to avoid contact with camels or wear breathing masks when around them. In response "some people have refused to listen to the government's advice" and kiss their camels in defiance of their government's advice. In 2020, the World Health Organization advised avoiding contact with camels and to eat only fully cooked camel meat, pasteurized camel milk, and to avoid drinking camel urine . There has been evidence of limited, but not sustained spread of MERS-CoV from person to person, both in households as well as in health care settings like hospitals. Most transmission has occurred "in the circumstances of close contact with severely ill persons in healthcare or household settings" and there is no evidence of transmission from asymptomatic cases. Cluster sizes have ranged from 1 to 26 people, with an average of 2.7. Middle East respiratory syndrome is caused by the MERS coronavirus (MERS-CoV), a species with single-stranded RNA belonging to the genus betacoronavirus which is distinct from SARS coronavirus and the common-cold coronavirus. Its genomes are phylogenetically classified into two clades , Clades A and B. Early cases of MERS were of Clade A clusters (EMC/2012 and Jordan-N3/2012), while new cases are genetically different in general (Clade B). The virus grows readily on Vero cells and LLC-MK2 cells. In November 2012, Egyptian virologist Dr. Ali Zaki sent a virus sample from the first confirmed case in Saudi Arabia to virologist Ron Fouchier , a leading coronavirus researcher at the Erasmus Medical Center (EMC) in Rotterdam , the Netherlands. The second laboratory-proven case was in London, confirmed by the UK Health Protection Agency (HPA). The HPA named the virus the London1_novel CoV 2012. A study performed between 2010 and 2013, in which the incidence of MERS was evaluated in 310 dromedary camels , revealed high titers of neutralizing antibodies to MERS-CoV in the blood serum of these animals. A further study sequenced MERS-CoV from nasal swabs of dromedary camels in Saudi Arabia and found they had sequences identical to previously sequenced human isolates. Some individual camels were also found to have more than one genomic variant in their nasopharynx . There is also a 2014 report of a Saudi Arabian man who became ill seven days after applying topical medicine to the noses of several sick camels and later he and one of the camels were found to have identical strains of MERS-CoV. It is still unclear how the virus is transmitted from camels to humans. In 2014, the Saudi Ministry of Agriculture advised people to avoid contact with camels or wear breathing masks when around them. In response "some people have refused to listen to the government's advice" and kiss their camels in defiance of their government's advice. In 2020, the World Health Organization advised avoiding contact with camels and to eat only fully cooked camel meat, pasteurized camel milk, and to avoid drinking camel urine . There has been evidence of limited, but not sustained spread of MERS-CoV from person to person, both in households as well as in health care settings like hospitals. Most transmission has occurred "in the circumstances of close contact with severely ill persons in healthcare or household settings" and there is no evidence of transmission from asymptomatic cases. Cluster sizes have ranged from 1 to 26 people, with an average of 2.7. A study performed between 2010 and 2013, in which the incidence of MERS was evaluated in 310 dromedary camels , revealed high titers of neutralizing antibodies to MERS-CoV in the blood serum of these animals. A further study sequenced MERS-CoV from nasal swabs of dromedary camels in Saudi Arabia and found they had sequences identical to previously sequenced human isolates. Some individual camels were also found to have more than one genomic variant in their nasopharynx . There is also a 2014 report of a Saudi Arabian man who became ill seven days after applying topical medicine to the noses of several sick camels and later he and one of the camels were found to have identical strains of MERS-CoV. It is still unclear how the virus is transmitted from camels to humans. In 2014, the Saudi Ministry of Agriculture advised people to avoid contact with camels or wear breathing masks when around them. In response "some people have refused to listen to the government's advice" and kiss their camels in defiance of their government's advice. In 2020, the World Health Organization advised avoiding contact with camels and to eat only fully cooked camel meat, pasteurized camel milk, and to avoid drinking camel urine . There has been evidence of limited, but not sustained spread of MERS-CoV from person to person, both in households as well as in health care settings like hospitals. Most transmission has occurred "in the circumstances of close contact with severely ill persons in healthcare or household settings" and there is no evidence of transmission from asymptomatic cases. Cluster sizes have ranged from 1 to 26 people, with an average of 2.7. According to World Health Organization , the interim case definition is that a confirmed case is identified in a person with a positive lab test by "molecular diagnostics including either a positive PCR on at least two specific genomic targets or a single positive target with sequencing on a second". According to the WHO, a probable case is: In the United States, the Centers for Disease Control and Prevention (CDC) recommend investigating any person with: Fever and pneumonia or acute respiratory distress syndrome (based on clinical or radiological evidence) and either: a history of travel from countries in or near the Arabian Peninsula within 14 days before symptom onset, or close contact with a symptomatic traveler who developed fever and acute respiratory illness (not necessarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula or a member of a cluster of people with severe acute respiratory illness (e.g. fever and pneumonia requiring hospitalization) of unknown cause in which MERS-CoV is being evaluated, in consultation with state and local health departments. Fever and symptoms of respiratory illness (not necessarily pneumonia; e.g., cough, shortness of breath) and being in a healthcare facility (as a patient, worker, or visitor) within 14 days before symptom onset in a country or territory in or near the Arabian Peninsula in which recent healthcare-associated cases of MERS have been identified. Fever or symptoms of respiratory illness (not necessarily pneumonia; e.g., cough, shortness of breath) and close contact with a confirmed MERS case while the case was ill. a history of travel from countries in or near the Arabian Peninsula within 14 days before symptom onset, or close contact with a symptomatic traveler who developed fever and acute respiratory illness (not necessarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula or a member of a cluster of people with severe acute respiratory illness (e.g. fever and pneumonia requiring hospitalization) of unknown cause in which MERS-CoV is being evaluated, in consultation with state and local health departments. Chest X-ray findings tend to show bilateral patchy infiltrates consistent with viral pneumonitis and acute respiratory distress syndrome (ARDS). Lower lobes tend to be more involved. CT scans show interstitial infiltrates. MERS cases have been reported to have low white blood cell count , and in particular low lymphocytes . For PCR [ clarification needed ] testing, the World Health Organization (WHO) recommends obtaining samples from the lower respiratory tract via bronchoalveolar lavage (BAL), sputum sample or tracheal aspirate as these have the highest viral loads. There have also been studies utilizing upper respiratory sampling via nasopharyngeal swab . Several highly sensitive, confirmatory real-time RT-PCR assays exist for rapid identification of MERS-CoV from patient-derived samples. These assays attempt to amplify upE (targets elements upstream of the E gene), open reading frame 1B (targets the ORF1b gene) and open reading frame 1A (targets the ORF1a gene). The WHO recommends the upE target for screening assays as it is highly sensitive. In addition, hemi-nested sequencing amplicons targeting RdRp (present in all coronaviruses ) and nucleocapsid (N) gene (specific to MERS-CoV) fragments can be generated for confirmation via sequencing. Reports of potential polymorphisms in the N gene between isolates highlight the necessity for sequence-based characterization. [ citation needed ] The WHO recommended testing algorithm is to start with an upE RT-PCR and if positive confirm with ORF 1A assay or RdRp or N gene sequence assay for confirmation. If both an upE and secondary assay are positive it is considered a confirmed case. Protocols for biologically safe immunofluorescence assays (IFA) have also been developed; however, antibodies against betacoronaviruses are known to cross-react within the genus. This effectively limits their use to confirmatory applications. A more specific protein-microarray based assay has also been developed that did not show any cross-reactivity against population samples and serum known to be positive for other betacoronaviruses. Due to the limited validation done so far with serological assays, WHO guidance is that "cases where the testing laboratory has reported positive serological test results in the absence of PCR testing or sequencing, are considered probable cases of MERS-CoV infection, if they meet the other conditions of that case definition." According to the WHO, a probable case is: In the United States, the Centers for Disease Control and Prevention (CDC) recommend investigating any person with: Fever and pneumonia or acute respiratory distress syndrome (based on clinical or radiological evidence) and either: a history of travel from countries in or near the Arabian Peninsula within 14 days before symptom onset, or close contact with a symptomatic traveler who developed fever and acute respiratory illness (not necessarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula or a member of a cluster of people with severe acute respiratory illness (e.g. fever and pneumonia requiring hospitalization) of unknown cause in which MERS-CoV is being evaluated, in consultation with state and local health departments. Fever and symptoms of respiratory illness (not necessarily pneumonia; e.g., cough, shortness of breath) and being in a healthcare facility (as a patient, worker, or visitor) within 14 days before symptom onset in a country or territory in or near the Arabian Peninsula in which recent healthcare-associated cases of MERS have been identified. Fever or symptoms of respiratory illness (not necessarily pneumonia; e.g., cough, shortness of breath) and close contact with a confirmed MERS case while the case was ill. a history of travel from countries in or near the Arabian Peninsula within 14 days before symptom onset, or close contact with a symptomatic traveler who developed fever and acute respiratory illness (not necessarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula or a member of a cluster of people with severe acute respiratory illness (e.g. fever and pneumonia requiring hospitalization) of unknown cause in which MERS-CoV is being evaluated, in consultation with state and local health departments.Chest X-ray findings tend to show bilateral patchy infiltrates consistent with viral pneumonitis and acute respiratory distress syndrome (ARDS). Lower lobes tend to be more involved. CT scans show interstitial infiltrates. MERS cases have been reported to have low white blood cell count , and in particular low lymphocytes . For PCR [ clarification needed ] testing, the World Health Organization (WHO) recommends obtaining samples from the lower respiratory tract via bronchoalveolar lavage (BAL), sputum sample or tracheal aspirate as these have the highest viral loads. There have also been studies utilizing upper respiratory sampling via nasopharyngeal swab . Several highly sensitive, confirmatory real-time RT-PCR assays exist for rapid identification of MERS-CoV from patient-derived samples. These assays attempt to amplify upE (targets elements upstream of the E gene), open reading frame 1B (targets the ORF1b gene) and open reading frame 1A (targets the ORF1a gene). The WHO recommends the upE target for screening assays as it is highly sensitive. In addition, hemi-nested sequencing amplicons targeting RdRp (present in all coronaviruses ) and nucleocapsid (N) gene (specific to MERS-CoV) fragments can be generated for confirmation via sequencing. Reports of potential polymorphisms in the N gene between isolates highlight the necessity for sequence-based characterization. [ citation needed ] The WHO recommended testing algorithm is to start with an upE RT-PCR and if positive confirm with ORF 1A assay or RdRp or N gene sequence assay for confirmation. If both an upE and secondary assay are positive it is considered a confirmed case. Protocols for biologically safe immunofluorescence assays (IFA) have also been developed; however, antibodies against betacoronaviruses are known to cross-react within the genus. This effectively limits their use to confirmatory applications. A more specific protein-microarray based assay has also been developed that did not show any cross-reactivity against population samples and serum known to be positive for other betacoronaviruses. Due to the limited validation done so far with serological assays, WHO guidance is that "cases where the testing laboratory has reported positive serological test results in the absence of PCR testing or sequencing, are considered probable cases of MERS-CoV infection, if they meet the other conditions of that case definition." While the mechanism of spread of MERS-CoV is currently not known, based on experience with prior coronaviruses, such as SARS, the WHO currently recommends that all individuals coming into contact with MERS suspects should (in addition to standard precautions): [ citation needed ] Wear a medical mask Wear eye protection (i.e. goggles or a face shield) Wear a clean, non sterile, long sleeved gown; and gloves (some procedures may require sterile gloves) Perform hand hygiene before and after contact with the person and his or her surroundings and immediately after removal of personal protective equipment (PPE) For procedures which carry a risk of aerosolization, such as intubation, the WHO recommends that care providers also: [ citation needed ] Wear a particulate respirator and, when putting on a disposable particulate respirator, always check the seal Wear eye protection (i.e. goggles or a face shield) Wear a clean, non-sterile, long-sleeved gown and gloves (some of these procedures require sterile gloves) Wear an impermeable apron for some procedures with expected high fluid volumes that might penetrate the gown Perform procedures in an adequately ventilated room; i.e. minimum of 6 to 12 air changes per hour in facilities with a mechanically ventilated room and at least 60 liters/second/patient in facilities with natural ventilation Limit the number of persons present in the room to the absolute minimum required for the person's care and support Perform hand hygiene before and after contact with the person and his or her surroundings and after PPE removal. The duration of infectivity is also unknown so it is unclear how long people must be isolated, but current recommendations are for 24 hours after resolution of symptoms. In the SARS outbreak the virus was not cultured from people after the resolution of their symptoms. It is believed that the existing SARS research may provide a useful template for developing vaccines and therapeutics against a MERS-CoV infection. As of March 2020 there was one ( DNA based ) MERS vaccine which completed phase I clinical trials in humans, and three others in progress all of which are viral vectored vaccines, two adenoviral vectored ( ChAdOx1 -MERS, BVRS-GamVac ) and one MVA vectored (MVA-MERS-S ). As of 2020, there is no specific vaccine or treatment for the disease. Using extra-corporeal membrane oxygenation (ECMO) seems to improve outcomes significantly. Neither the combination of antivirals and interferons ( ribavirin + interferon alfa-2a or interferon alfa-2b) nor corticosteroids improved outcomes. MERS has had a relatively low population-wide reproduction number in previous outbreaks, but such outbreaks have occurred due to superspreading events. Total laboratory-confirmed cases of MERS world-wide per year have been as follows: MERS was also implicated in an outbreak in April 2014 in Saudi Arabia , where MERS has infected 688 people and 282 MERS-related deaths have been reported since 2012. In response to newly reported cases and deaths, and the resignation of four doctors at Jeddah's King Fahd Hospital who refused to treat MERS patients for fear of infection, the government removed the Minister of Health and set up three MERS treatment centers. Eighteen more cases were reported in early May. In June 2014, Saudi Arabia announced 113 previously unreported cases of MERS, revising the death toll to 282. [ citation needed ] A hospital-related outbreak in Riyadh in the summer of 2015 increased fears of an epidemic occurring during the annual Hajj pilgrimage that was to begin in late September. After a period of few cases, cases began increasing in the middle of the summer. The CDC placed the travel health alert to level 2, which calls for taking enhanced precautions. In May 2019, 14 cases of MERS were reported to the World Health Organization (WHO) by Saudi authorities, of which five were fatal. All those who died had comorbidities and other relatively serious health problems ranging from only diabetes mellitus in one person (aged 35) to complicated combinations of diabetes mellitus, hypertension and ischemic heart disease in two (65 and 80 years old) and diabetes mellitus, hypertension and nephropathy in another one who was 73 years old. Another patient who died and was 64 years old, had diabetes mellitus and hypertension. All those who died were males and three of them were reported to have had contact with, and exposure to, camels. Among the nine persons who survived were two females who were believed to have had contact with a person infected with MERS, one being a 23-year-old healthcare worker. Of the total 14 cases, four were females and 10 were males. All females survived. Reports of fatal cases were from Riyadh, Jeddah, Madinah and Najran. WHO did not recommend screening of travelers upon arrival or traveling restrictions. On 2 May 2014, the Centers for Disease Control and Prevention (CDC) confirmed the first diagnosis of MERS in the United States at Community Hospital in Munster, Indiana . The man diagnosed was a health care worker who had been in Saudi Arabia a week earlier, and was reported to be in good condition. A second patient who also traveled from Saudi Arabia was reported in Orlando, Florida on 12 May 2014. On 14 May 2014, officials in the Netherlands reported the first case had appeared. In May 2015, the first case in South Korea was confirmed in a man who had visited Saudi Arabia, United Arab Emirates and Bahrain. Another man from South Korea, who was travelling to China, was diagnosed as the first case in China. So far, no Chinese citizen has been found infected. As of 27 June 2015, 19 people in South Korea have died from this outbreak , with 184 confirmed cases of infection. There have been at least 6508 quarantined. [ excessive citations ] In 2018 a case was found in South Korea; the patient had recently returned from Kuwait (via Dubai). One study found that severe cases of illness had higher viral loads than milder cases, and that concentrations peaked in the second week of illness. In April 2014, MERS emerged in the Philippines with a suspected case of a home-bound Overseas Filipino Worker (OFW). Several suspected cases involving individuals who were on the same flight as the initial suspected case are being tracked but are believed to have dispersed throughout the country. Another suspected MERS-involved death in Sultan Kudarat province caused the Department of Health (DOH) to put out an alert. On 6 July 2015 the DOH confirmed the second case of MERS in the Philippines. A 36-year-old male foreigner from the Middle East was tested positive. On 27 July 2015, the accident and emergency department at Manchester Royal Infirmary closed after two patients were treated for suspected MERS infection. The facility was reopened later that evening, and it was later confirmed by Public Health England that the two patients had tested negative for the disease. In January 2016, a larger outbreak of MERS among camels in Kenya was reported. By 5 February 2016 more than 500 camels had died of the disease. On 12 February 2016, the disease was reported to be MERS. No human cases were identified, although one study found antibodies in healthy humans in Kenya. The table above provides a comparison between the 2014 Saudi Arabia outbreak and the South Korean outbreak in 2015 of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection. MERS was also implicated in an outbreak in April 2014 in Saudi Arabia , where MERS has infected 688 people and 282 MERS-related deaths have been reported since 2012. In response to newly reported cases and deaths, and the resignation of four doctors at Jeddah's King Fahd Hospital who refused to treat MERS patients for fear of infection, the government removed the Minister of Health and set up three MERS treatment centers. Eighteen more cases were reported in early May. In June 2014, Saudi Arabia announced 113 previously unreported cases of MERS, revising the death toll to 282. [ citation needed ] A hospital-related outbreak in Riyadh in the summer of 2015 increased fears of an epidemic occurring during the annual Hajj pilgrimage that was to begin in late September. After a period of few cases, cases began increasing in the middle of the summer. The CDC placed the travel health alert to level 2, which calls for taking enhanced precautions. In May 2019, 14 cases of MERS were reported to the World Health Organization (WHO) by Saudi authorities, of which five were fatal. All those who died had comorbidities and other relatively serious health problems ranging from only diabetes mellitus in one person (aged 35) to complicated combinations of diabetes mellitus, hypertension and ischemic heart disease in two (65 and 80 years old) and diabetes mellitus, hypertension and nephropathy in another one who was 73 years old. Another patient who died and was 64 years old, had diabetes mellitus and hypertension. All those who died were males and three of them were reported to have had contact with, and exposure to, camels. Among the nine persons who survived were two females who were believed to have had contact with a person infected with MERS, one being a 23-year-old healthcare worker. Of the total 14 cases, four were females and 10 were males. All females survived. Reports of fatal cases were from Riyadh, Jeddah, Madinah and Najran. WHO did not recommend screening of travelers upon arrival or traveling restrictions. On 2 May 2014, the Centers for Disease Control and Prevention (CDC) confirmed the first diagnosis of MERS in the United States at Community Hospital in Munster, Indiana . The man diagnosed was a health care worker who had been in Saudi Arabia a week earlier, and was reported to be in good condition. A second patient who also traveled from Saudi Arabia was reported in Orlando, Florida on 12 May 2014. On 14 May 2014, officials in the Netherlands reported the first case had appeared. In May 2015, the first case in South Korea was confirmed in a man who had visited Saudi Arabia, United Arab Emirates and Bahrain. Another man from South Korea, who was travelling to China, was diagnosed as the first case in China. So far, no Chinese citizen has been found infected. As of 27 June 2015, 19 people in South Korea have died from this outbreak , with 184 confirmed cases of infection. There have been at least 6508 quarantined. [ excessive citations ] In 2018 a case was found in South Korea; the patient had recently returned from Kuwait (via Dubai). One study found that severe cases of illness had higher viral loads than milder cases, and that concentrations peaked in the second week of illness. In April 2014, MERS emerged in the Philippines with a suspected case of a home-bound Overseas Filipino Worker (OFW). Several suspected cases involving individuals who were on the same flight as the initial suspected case are being tracked but are believed to have dispersed throughout the country. Another suspected MERS-involved death in Sultan Kudarat province caused the Department of Health (DOH) to put out an alert. On 6 July 2015 the DOH confirmed the second case of MERS in the Philippines. A 36-year-old male foreigner from the Middle East was tested positive. On 27 July 2015, the accident and emergency department at Manchester Royal Infirmary closed after two patients were treated for suspected MERS infection. The facility was reopened later that evening, and it was later confirmed by Public Health England that the two patients had tested negative for the disease. In January 2016, a larger outbreak of MERS among camels in Kenya was reported. By 5 February 2016 more than 500 camels had died of the disease. On 12 February 2016, the disease was reported to be MERS. No human cases were identified, although one study found antibodies in healthy humans in Kenya. The table above provides a comparison between the 2014 Saudi Arabia outbreak and the South Korean outbreak in 2015 of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection. Collaborative efforts were used in the identification of the MERS-CoV. Egyptian virologist Dr. Ali Mohamed Zaki isolated and identified a previously unknown coronavirus from the lungs of a 60-year-old Saudi Arabian man with pneumonia and acute kidney injury . After routine diagnostics failed to identify the causative agent, Zaki contacted Ron Fouchier, a leading virologist at the Erasmus Medical Center (EMC) in Rotterdam, the Netherlands, for advice. Fouchier sequenced the virus from a sample sent by Zaki. Fouchier used a broad-spectrum "pan-coronavirus" real-time reverse-transcription polymerase chain reaction (RT-qPCR) method to test for distinguishing features of a number of known coronaviruses (such as OC43, 229E, NL63, and SARS-CoV ), as well as for RNA-dependent RNA polymerase (RdRp), a gene conserved in all coronaviruses known to infect humans. While the screens for known coronaviruses were all negative, the RdRp screen was positive. On 15 September 2012, Dr. Zaki's findings were posted on ProMED-mail , the Program for Monitoring Emerging Diseases, a public health on-line forum. The United Kingdom's Health Protection Agency (HPA) confirmed the diagnosis of severe respiratory illness associated with a new type of coronavirus in a second patient, a 49-year-old Qatari man who had recently been flown into the UK. He died from an acute, serious respiratory illness in a London hospital. In September 2012, the UK HPA named it the London1 novel CoV/2012 and produced the virus' preliminary phylogenetic tree, the genetic sequence of the virus based on the virus's RNA obtained from the Qatari case. On 25 September 2012, the WHO announced that it was "engaged in further characterizing the novel coronavirus" and that it had "immediately alerted all its Member States about the virus and has been leading the coordination and providing guidance to health authorities and technical health agencies". The Erasmus Medical Center (EMC) in Rotterdam "tested, sequenced and identified" a sample provided to EMC virologist Ron Fouchier by Ali Mohamed Zaki in November 2012. On 8 November 2012, in an article published in the New England Journal of Medicine , Dr. Zaki and co-authors from the Erasmus Medical Center published more details, including a tentative name, Human Coronavirus-Erasmus Medical Center (HCoV-EMC), the virus's genetic makeup, and closest relatives (including SARS). In May 2013, the Coronavirus Study Group of the International Committee on Taxonomy of Viruses adopted the official designation, the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which was adopted by WHO to "provide uniformity and facilitate communication about the disease". Prior to the designation, WHO had used the non-specific designation 'Novel coronavirus 2012' or simply 'the novel coronavirus'. When rhesus macaques were given interferon-α2b and ribavirin and exposed to MERS, they developed less pneumonia than control animals. Five critically ill people with MERS in Saudi Arabia with acute respiratory distress syndrome (ARDS) and on ventilators were given interferon-α2b and ribavirin but all ended up dying of the disease. The treatment was started late in their disease (a mean of 19 days after hospital admission) and they had already failed trials of steroids so it remains to be seen whether it may have benefit earlier in the course of disease. Another proposed therapy is inhibition of viral protease or kinase enzymes. Researchers are investigating a number of medications, including using interferon, chloroquine , chlorpromazine , loperamide , lopinavir , remdesivir and galidesivir as well as other agents such as mycophenolic acid , camostat and nitazoxanide .

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Acute hemorrhagic fever syndrome

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List of skin conditions

Many skin conditions affect the human integumentary system —the organ system covering the entire surface of the body and composed of skin , hair , nails , and related muscle and glands . The major function of this system is as a barrier against the external environment. The skin weighs an average of four kilograms, covers an area of two square metres, and is made of three distinct layers: the epidermis , dermis , and subcutaneous tissue . The two main types of human skin are: glabrous skin , the hairless skin on the palms and soles (also referred to as the "palmoplantar" surfaces), and hair-bearing skin. Within the latter type, the hairs occur in structures called pilosebaceous units , each with hair follicle , sebaceous gland , and associated arrector pili muscle. In the embryo , the epidermis, hair, and glands form from the ectoderm , which is chemically influenced by the underlying mesoderm that forms the dermis and subcutaneous tissues. The epidermis is the most superficial layer of skin, a squamous epithelium with several strata : the stratum corneum , stratum lucidum , stratum granulosum , stratum spinosum , and stratum basale . Nourishment is provided to these layers by diffusion from the dermis since the epidermis is without direct blood supply. The epidermis contains four cell types: keratinocytes , melanocytes , Langerhans cells , and Merkel cells . Of these, keratinocytes are the major component, constituting roughly 95 percent of the epidermis. This stratified squamous epithelium is maintained by cell division within the stratum basale, in which differentiating cells slowly displace outwards through the stratum spinosum to the stratum corneum, where cells are continually shed from the surface. In normal skin, the rate of production equals the rate of loss; about two weeks are needed for a cell to migrate from the basal cell layer to the top of the granular cell layer, and an additional two weeks to cross the stratum corneum. The dermis is the layer of skin between the epidermis and subcutaneous tissue, and comprises two sections, the papillary dermis and the reticular dermis . The superficial papillary dermis interdigitates with the overlying rete ridges of the epidermis, between which the two layers interact through the basement membrane zone. Structural components of the dermis are collagen , elastic fibers , and ground substance . Within these components are the pilosebaceous units, arrector pili muscles, and the eccrine and apocrine glands . The dermis contains two vascular networks that run parallel to the skin surface—one superficial and one deep plexus—which are connected by vertical communicating vessels. The function of blood vessels within the dermis is fourfold: to supply nutrition, to regulate temperature, to modulate inflammation, and to participate in wound healing. The subcutaneous tissue is a layer of fat between the dermis and underlying fascia . This tissue may be further divided into two components, the actual fatty layer, or panniculus adiposus , and a deeper vestigial layer of muscle, the panniculus carnosus . The main cellular component of this tissue is the adipocyte , or fat cell. The structure of this tissue is composed of septal (i.e. linear strands) and lobular compartments, which differ in microscopic appearance. Functionally, the subcutaneous fat insulates the body, absorbs trauma, and serves as a reserve energy source. Conditions of the human integumentary system constitute a broad spectrum of diseases, also known as dermatoses , as well as many nonpathologic states (like, in certain circumstances, melanonychia and racquet nails ). While only a small number of skin diseases account for most visits to the physician , thousands of skin conditions have been described. Classification of these conditions often presents many nosological challenges, since underlying etiologies and pathogenetics are often not known. Therefore, most current textbooks present a classification based on location (for example, conditions of the mucous membrane ), morphology ( chronic blistering conditions ), etiology ( skin conditions resulting from physical factors ), and so on. Clinically, the diagnosis of any particular skin condition is made by gathering pertinent information regarding the presenting skin lesion (s), including the location (such as arms, head, legs), symptoms ( pruritus , pain), duration (acute or chronic), arrangement (solitary, generalized, annular, linear), morphology ( macules , papules , vesicles ), and color (red, blue, brown, black, white, yellow). Diagnosis of many conditions often also requires a skin biopsy which yields histologic information that can be correlated with the clinical presentation and any laboratory data. Acneiform eruptions are caused by changes in the pilosebaceous unit . Autoinflammatory syndromes are a group of inherited disorders characterized by bouts of inflammatory skin lesions and periodic fevers . Chronic blistering cutaneous conditions have a prolonged course and present with vesicles and bullae . Conditions of the mucous membranes involve the moist linings of the eyes, nose, mouth, genitals, and anus. Conditions of the skin appendages are those affecting the glands of the skin, hair , nails , and arrector pili muscles. Conditions of the subcutaneous fat are those affecting the layer of adipose tissue that lies between the dermis and underlying fascia . Cutaneous congenital anomalies are a diverse group of disorders that result from faulty morphogenesis , the biological process that forms the shape of a human body . Connective tissue diseases are caused by a complex array of autoimmune responses that target or affect collagen or ground substance . Abnormalities of dermal fibrous and elastic tissue are caused by problems in the regulation of collagen synthesis or degradation. Abnormalities of dermal fibrous and elastic tissue are caused by problems in the regulation of collagen synthesis or degradation. Dermal and subcutaneous growths result from (1) reactive or neoplastic proliferation of cellular components of the dermis or subcutaneous tissue , or (2) neoplasms invading or aberrantly present in the dermis. Dermatitis is a general term for " inflammation of the skin". Atopic dermatitis is a chronic dermatitis associated with a hereditary tendency to develop allergies to food and inhalant substances. Contact dermatitis is caused by certain substances coming in contact with the skin. Eczema refers to a broad range of conditions that begin as spongiotic dermatitis and may progress to a lichenified stage. Pustular dermatitis is an inflammation of the skin that presents with pustular lesions . Seborrheic dermatitis is a chronic , superficial, inflammatory disease characterized by scaling on an erythematous base. Atopic dermatitis is a chronic dermatitis associated with a hereditary tendency to develop allergies to food and inhalant substances. Contact dermatitis is caused by certain substances coming in contact with the skin. Eczema refers to a broad range of conditions that begin as spongiotic dermatitis and may progress to a lichenified stage. Pustular dermatitis is an inflammation of the skin that presents with pustular lesions . Seborrheic dermatitis is a chronic , superficial, inflammatory disease characterized by scaling on an erythematous base. Disturbances of human pigmentation, either loss or reduction, may be related to loss of melanocytes or the inability of melanocytes to produce melanin or transport melanosomes correctly. Drug eruptions are adverse drug reactions that present with cutaneous manifestations. Endocrine conditions often present with cutaneous findings as the skin interacts with the endocrine system in many ways. Eosinophilic cutaneous conditions encompass a wide variety of diseases that are characterized histologically by the presence of eosinophils in the inflammatory infiltrate, or evidence of eosinophil degranulation . Epidermal nevi , neoplasms , and cysts are skin lesions that develop from the epidermal layer of the skin. Erythemas are reactive skin conditions in which there is blanchable redness. Genodermatoses are inherited genetic skin conditions often grouped into three categories: chromosomal , single gene , and polygenetic . Infection-related cutaneous conditions may be caused by bacteria , fungi , yeast , viruses , or parasites . Bacterium-related cutaneous conditions often have distinct morphologic characteristics that may be an indication of a generalized systemic process or simply an isolated superficial infection. Mycobacterium -related cutaneous conditions are caused by Mycobacterium infections. Mycosis-related cutaneous conditions are caused by fungi or yeasts , and may present as either a superficial or deep infection of the skin, hair, or nails. Parasitic infestations, stings, and bites in humans are caused by several groups of organisms belonging to the following phyla : Annelida , Arthropoda , Bryozoa , Chordata , Cnidaria , Cyanobacteria , Echinodermata , Nemathelminthes , Platyhelminthes , and Protozoa . Virus-related cutaneous conditions are caused by two main groups of viruses – DNA and RNA types–both of which are obligatory intracellular parasites . Bacterium-related cutaneous conditions often have distinct morphologic characteristics that may be an indication of a generalized systemic process or simply an isolated superficial infection. Mycobacterium -related cutaneous conditions are caused by Mycobacterium infections. Mycobacterium -related cutaneous conditions are caused by Mycobacterium infections. Mycosis-related cutaneous conditions are caused by fungi or yeasts , and may present as either a superficial or deep infection of the skin, hair, or nails. Parasitic infestations, stings, and bites in humans are caused by several groups of organisms belonging to the following phyla : Annelida , Arthropoda , Bryozoa , Chordata , Cnidaria , Cyanobacteria , Echinodermata , Nemathelminthes , Platyhelminthes , and Protozoa . Virus-related cutaneous conditions are caused by two main groups of viruses – DNA and RNA types–both of which are obligatory intracellular parasites . Lichenoid eruptions are dermatoses related to the unique, common inflammatory disorder lichen planus , which affects the skin, mucous membranes , nails, and hair. Lymphoid-related cutaneous conditions are a group of disorders characterized by collections of lymphocyte cells within the skin. Melanocytic nevi and neoplasms are caused by either a proliferation of (1) melanocytes , or (2) nevus cells , a form of melanocyte that lack dendritic processes. Melanoma is a malignant proliferation of melanocytes and the most aggressive type of skin cancer. Melanoma is a malignant proliferation of melanocytes and the most aggressive type of skin cancer. Monocyte- and macrophage-related cutaneous conditions are characterized histologically by infiltration of the skin by monocyte or macrophage cells, often divided into several categories, including granulomatous disease , histiocytoses , and sarcoidosis . Mucinoses are a group of conditions caused by dermal fibroblasts producing abnormally large amounts of mucopolysaccharides . Neurocutaneous conditions are due organic nervous system disease or are psychiatric in etiology . Noninfectious immunodeficiency-related cutaneous conditions are caused by T-cell or B-cell dysfunction. Nutrition-related cutaneous conditions are caused by malnutrition due to an improper or inadequate diet . Papulosquamous hyperkeratotic cutaneous conditions are those that present with papules and scales caused by a thickening of the stratum corneum . Palmoplantar keratodermas are a diverse group of hereditary and acquired keratodermas in which there is hyperkeratosis of the skin of the palms and soles. Palmoplantar keratodermas are a diverse group of hereditary and acquired keratodermas in which there is hyperkeratosis of the skin of the palms and soles. Pregnancy-related cutaneous conditions are a group of skin changes observed during pregnancy . Pruritus , commonly known as itchiness, is a sensation exclusive to the skin, and characteristic of many skin conditions. Psoriasis is a common, chronic, and recurrent inflammatory disease of the skin characterized by circumscribed, erythematous , dry, scaling plaques . Reactive neutrophilic cutaneous conditions constitute a spectrum of disease mediated by neutrophils , and typically associated with underlying diseases, such as inflammatory bowel disease and hematologic malignancy . Recalcitrant palmoplantar eruptions are skin conditions of the palms and soles which are resistant to treatment. Skin conditions resulting from errors in metabolism are caused by enzymatic defects that lead to an accumulation or deficiency of various cellular components, including, but not limited to, amino acids , carbohydrates , and lipids . Skin conditions resulting from physical factors occur from a number of causes, including, but not limited to, hot and cold temperatures, friction , and moisture . Ionizing radiation-induced cutaneous conditions result from exposure to ionizing radiation . Ionizing radiation-induced cutaneous conditions result from exposure to ionizing radiation . Urticaria is a vascular reaction of the skin characterized by the appearance of wheals , which are firm, elevated swellings of the skin. Angioedema , which can occur alone or with urticaria, is characterized by a well-defined, edematous swelling that involves subcutaneous tissues, abdominal organs, or upper airway. Vascular-related cutaneous conditions result from dysfunction of the blood or blood vessels in the dermis, or lymphatics in the subcutaneous tissues .

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Acute hemorrhagic fever syndrome

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Hemolytic–uremic syndrome

Hemolytic–uremic syndrome ( HUS ) is a group of blood disorders characterized by low red blood cells , acute kidney injury (previously called acute renal failure), and low platelets . Initial symptoms typically include bloody diarrhea , fever , vomiting , and weakness. Kidney problems and low platelets then occur as the diarrhea progresses. Children are more commonly affected, but most children recover without permanent damage to their health, although some children may have serious and sometimes life-threatening complications. Adults, especially the elderly, may present a more complicated presentation. Complications may include neurological problems and heart failure . Most cases occur after infectious diarrhea due to a specific type of E. coli called O157:H7 . Other causes include S. pneumoniae , Shigella , Salmonella , and certain medications. The underlying mechanism typically involves the production of Shiga toxin by the bacteria. Atypical hemolytic uremic syndrome (aHUS) is often due to a genetic mutation and presents differently. However, both can lead to widespread inflammation and multiple blood clots in small blood vessels , a condition known as thrombotic microangiopathy . Treatment involves supportive care and may include dialysis , steroids , blood transfusions , or plasmapheresis . About 1.5 per 100,000 people are affected per year. Less than 5% of those with the condition die. Of the remainder, up to 25% have ongoing kidney problems. HUS was first defined as a syndrome in 1955. After eating contaminated food, the first symptoms of infection can emerge anywhere from 1 to 10 days later, but usually after 3 to 4 days. These early symptoms can include diarrhea (which is often bloody), stomach cramps, mild fever, or vomiting that results in dehydration and reduced urine. HUS typically develops about 5–10 days after the first symptoms, but can take up to 3 weeks to manifest, and occurs at a time when the diarrhea is improving. Related symptoms and signs include lethargy, decreased urine output , blood in the urine , kidney failure , low platelets , (which are needed for blood clotting), and destruction of red blood cells ( microangiopathic hemolytic anemia ). High blood pressure , jaundice (a yellow tinge in skin and the whites of the eyes), seizures, and bleeding into the skin can also occur. In some cases, there are prominent neurologic changes. People with HUS commonly exhibit the symptoms of thrombotic microangiopathy (TMA), which can include abdominal pain, low platelet count, elevated lactate dehydrogenase LDH, (an enzyme released from damaged cells, and which is therefore a marker of cellular damage) decreased haptoglobin (indicative of the breakdown of red blood cells) anemia (low red blood cell count), schistocytes (damaged red blood cells), elevated creatinine (a protein waste product generated by muscle metabolism and eliminated renally), proteinuria (indicative of kidney injury), confusion, fatigue, swelling , nausea/vomiting, and diarrhea. Additionally, patients with aHUS typically present with an abrupt onset of systemic signs and symptoms such as acute kidney failure, hypertension (high blood pressure), myocardial infarction (heart attack), stroke, lung complications, pancreatitis (inflammation of the pancreas), liver necrosis (death of liver cells or tissue), encephalopathy (brain dysfunction), seizure, and coma. Failure of neurologic, cardiac, renal, and gastrointestinal (GI) organs, as well as death, can occur unpredictably at any time, either very quickly or following prolonged symptomatic or asymptomatic disease progression. Shiga-toxin producing E. coli (STEC) HUS occurs after ingestion of a strain of bacteria expressing Shiga toxin such as enterohemorrhagic Escherichia coli (EHEC), of which E. coli O157:H7 is the most common serotype . Atypical HUS (aHUS) represents 5–10% of HUS cases and is largely due to one or several genetic mutations that cause chronic, uncontrolled, and excessive activation of the complement system , which is a group of immune signaling factors that promote inflammation, enhance the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the body, and directly attack the pathogen's cell membrane. This results in platelet activation, endothelial cell damage, and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count, hemolysis (breakdown of red blood cells), damage to multiple organs, and ultimately death. Early signs of systemic complement-mediated TMA include thrombocytopenia (platelet count below 150,000 or a decrease from baseline of at least 25%) and evidence of microangiopathic hemolysis, which is characterized by elevated LDH levels, decreased haptoglobin, decreased hemoglobin (the oxygen-containing component of blood), and/or the presence of schistocytes. Despite the use of supportive care, an estimated 33–40% of patients will die or have end-stage renal disease (ESRD) with the first clinical manifestation of aHUS, and 65% of patients will die, require dialysis, or have permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI) therapy. Patients who survive the presenting signs and symptoms of aHUS endure a chronic thrombotic and inflammatory state, which puts them at lifelong elevated risk of sudden blood clotting, kidney failure, other severe complications and premature death. Historically, treatment options for aHUS were limited to plasma exchange or plasma infusion (PE/PI) therapy, which carries significant risks and has not been proven effective in any controlled trials. People with aHUS and ESRD have also had to undergo lifelong dialysis, which has a 5-year survival rate of 34–38%. Shiga-toxin producing E. coli (STEC) HUS occurs after ingestion of a strain of bacteria expressing Shiga toxin such as enterohemorrhagic Escherichia coli (EHEC), of which E. coli O157:H7 is the most common serotype . Atypical HUS (aHUS) represents 5–10% of HUS cases and is largely due to one or several genetic mutations that cause chronic, uncontrolled, and excessive activation of the complement system , which is a group of immune signaling factors that promote inflammation, enhance the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the body, and directly attack the pathogen's cell membrane. This results in platelet activation, endothelial cell damage, and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count, hemolysis (breakdown of red blood cells), damage to multiple organs, and ultimately death. Early signs of systemic complement-mediated TMA include thrombocytopenia (platelet count below 150,000 or a decrease from baseline of at least 25%) and evidence of microangiopathic hemolysis, which is characterized by elevated LDH levels, decreased haptoglobin, decreased hemoglobin (the oxygen-containing component of blood), and/or the presence of schistocytes. Despite the use of supportive care, an estimated 33–40% of patients will die or have end-stage renal disease (ESRD) with the first clinical manifestation of aHUS, and 65% of patients will die, require dialysis, or have permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI) therapy. Patients who survive the presenting signs and symptoms of aHUS endure a chronic thrombotic and inflammatory state, which puts them at lifelong elevated risk of sudden blood clotting, kidney failure, other severe complications and premature death. Historically, treatment options for aHUS were limited to plasma exchange or plasma infusion (PE/PI) therapy, which carries significant risks and has not been proven effective in any controlled trials. People with aHUS and ESRD have also had to undergo lifelong dialysis, which has a 5-year survival rate of 34–38%. HUS is caused by ingestion of bacteria that produce Shiga toxins , with Shiga-toxin producing E. coli (STEC) being the most common type. E. coli can produce shigatoxin-1, shigatoxin-2, or both; with shigatoxin-2 producing organisms being more virulent and being much more likely to cause HUS. Once ingested, the bacteria move to the intestines where they produce the Shiga toxins. The bacteria and toxins damage the mucosal lining of the intestines, and thus are able to gain entry into the circulation. Shiga toxin enters the mesenteric microvasculature lining the intestines where it releases inflammatory cytokines including IL-6 , IL-8 , TNFα , and IL-1β . These inflammatory mediators lead to inflammation and vascular injury with microthrombi that are seen with HUS. It also further damages the intestinal barrier leading to diarrhea (usually bloody) and further entry of Shiga toxin from the intestines to the bloodstream as the intestinal barrier is compromised. Once Shiga toxin enters the circulation it can travel throughout the body and cause the wide array of end organ damage and the multitude of symptoms seen with HUS. Shiga toxin gains entry to cells by binding to globotriaosylceramide (Gb3) which is a globoside found on cell membranes, it is found throughout the body including the surface of the glomerular endothelium of the kidney. Shiga toxin gains entry to the cell via Gb3 and endocytosis , it then is transported to the Golgi apparatus where furin cleaves the A subunit of the Shiga toxin. It is then transported to the endoplasmic reticulum where it is further cleaved, leaving the A1 subunit of Shiga toxin free. The A1 subunit of Shiga toxin inhibits the 28s subunit of the ribosomal rRNA , this leads to inhibited protein production by the ribosomes. With the cell's protein synthesis inhibited by Shiga toxin, the cell is destroyed. This leads to vascular injury (including in the kidneys where Gb3 is concentrated). The vascular injury facilitates the formation of vascular microthrombi which are characteristic of TTP. The TTP leads to platelet trapping (and thrombocytopenia), red blood cell destruction (and anemia), and end organ damage that is characteristically seen with HUS and TTP. HUS is one of the thrombotic microangiopathies , a category of disorders that includes STEC-HUS, aHUS, and thrombotic thrombocytopenic purpura (TTP). The release of cytokines and chemokines (IL-6, IL-8, TNF-α, IL-1β) that are commonly released by Shiga toxin are implicated in platelet activation and TTP. The presence of schistocytes is a key finding that helps to diagnose HUS. Shiga-toxin directly activates the alternative complement pathway and also interferes with complement regulation by binding to complement factor H, an inhibitor of the complement cascade. Shiga-toxin causes complement-mediated platelet, leukocyte, and endothelial cell activation, resulting in systemic hemolysis, inflammation and thrombosis. Severe clinical complications of TMA have been reported in patients from 2 weeks to more than 44 days after presentation with STEC-HUS, with improvements in clinical condition extending beyond this time frame, suggesting that complement activation persists beyond the acute clinical presentation and for at least 4 months. The consumption of platelets as they adhere to the thrombi lodged in the small vessels typically leads to mild or moderate thrombocytopenia with a platelet count of less than 60,000 per microliter. As in the related condition TTP, reduced blood flow through the narrowed blood vessels of the microvasculature leads to reduced blood flow to vital organs, and ischemia may develop. The kidneys and the central nervous system (brain and spinal cord) are the parts of the body most critically dependent on high blood flow, and are thus the most likely organs to be affected. However, in comparison to TTP, the kidneys tend to be more severely affected in HUS, and the central nervous system is less commonly affected. In contrast with typical disseminated intravascular coagulation seen with other causes of sepsis and occasionally with advanced cancer, coagulation factors are not consumed in HUS (or TTP) and the coagulation screen , fibrinogen level, and assays for fibrin degradation products such as "D-Dimers", are generally normal despite the low platelet count (thrombocytopenia). HUS occurs after 3–7% of all sporadic E. coli O157:H7 infections and up to approximately 20% or more of epidemic infections. Children and adolescents are commonly affected. One reason could be that children have more Gb3 receptors than adults which may be why children are more susceptible to HUS. Cattle, swine, deer, and other mammals do not have GB3 receptors, but can be asymptomatic carriers of Shiga toxin-producing bacteria. Some humans can also be asymptomatic carriers. Once the bacteria colonizes, diarrhea followed by bloody diarrhea , hemorrhagic colitis, typically follows. Other serotypes of STEC also cause disease, inlduding HUS, as occurred with E. coli O104:H4, which triggered a 2011 epidemic of STEC-HUS in Germany . Grossly, the kidneys may show patchy or diffuse renal cortical necrosis . Histologically , the glomeruli show thickened and sometimes split capillary walls due largely to endothelial swelling. Large deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the mesangium are also found along with mesangiolysis. Interlobular and afferent arterioles show fibrinoid necrosis and intimal hyperplasia and are often occluded by thrombi. STEC-HUS most often affects infants and young children, but also occurs in adults. The most common form of transmission is ingestion of undercooked meat, unpasteurized fruits and juices, contaminated produce, contact with unchlorinated water, and person-to-person transmission in daycare or long-term care facilities. Unlike typical HUS, aHUS does not follow STEC infection and is thought to result from one or several genetic mutations that cause chronic, uncontrolled, and excessive activation of complement. This leads to platelet activation, endothelial cell damage, and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count, hemolysis , damage to multiple organs, and ultimately, death. Early signs of systemic complement-mediated TMA include thrombocytopenia (platelet count below 150,000 or a decrease from baseline of at least 25%) and evidence of microangiopathic hemolysis, which is characterized by elevated LDH levels, decreased haptoglobin, decreased hemoglobin , and/or the presence of schistocytes. The similarities between HUS, aHUS, and TTP make differential diagnosis essential. All three of these systemic TMA-causing diseases are characterized by thrombocytopenia and microangiopathic hemolysis, plus one or more of the following: neurological symptoms (e.g., confusion, cerebral convulsions, seizures ); renal impairment (e.g., elevated creatinine, decreased estimated glomerular filtration rate [eGFR], abnormal urinalysis ); and gastrointestinal (GI) symptoms (e.g., diarrhea, nausea/vomiting, abdominal pain, gastroenteritis ).The presence of diarrhea does not exclude aHUS as the cause of TMA, as 28% of patients with aHUS present with diarrhea and/or gastroenteritis. First diagnosis of aHUS is often made in the context of an initial, complement-triggering infection, and Shiga-toxin has also been implicated as a trigger that identifies patients with aHUS. Additionally, in one study, mutations of genes encoding several complement regulatory proteins were detected in 8 of 36 (22%) patients diagnosed with STEC-HUS. However, the absence of an identified complement regulatory gene mutation does not preclude aHUS as the cause of the TMA, as approximately 50% of patients with aHUS lack an identifiable mutation in complement regulatory genes. Diagnostic work-up supports the differential diagnosis of TMA-causing diseases. A positive Shiga-toxin/EHEC test confirms a cause for STEC-HUS, and severe ADAMTS13 deficiency (i.e., ≤5% of normal ADAMTS13 levels) confirms a diagnosis of TTP. The effect of antibiotics in shiga toxin producing E. coli is unclear. While some early studies raised concerns more recent studies show either no effect or a benefit. Treatment involves supportive care and may include dialysis , steroids , blood transfusions , and plasmapheresis . Early IV fluid hydration is associated with better outcomes including shorter hospital stays and reducing the risk of dialysis. Empiric antibiotics are not indicated in those who are immunocompetent, and may worsen the HUS. Antidiarrheals and narcotic medications to slow the gut are not recommended as they are associated with worsening symptoms, increased risk of HUS in those with STEC infection, and adverse neurologic reactions. Platelet transfusions should not be used as the may drive the process of microangiopathy leading to worsening TTP. While eculizumab is being used to treat atypical hemolytic uremic syndrome, no evidence as of 2018 supports its use in the main forms of HUS. Scientists are trying to understand how useful it would be to immunize humans or cattle. Acute renal failure occurs in 55–70% of people with STEC-HUS, although up to 70–85% recover renal function. With aggressive treatment, more than 90% of patients survive the acute phase of HUS, and only about 9% may develop ESRD. Roughly one-third of persons with HUS have abnormal kidney function many years later, and a few require long-term dialysis. Another 8% of persons with HUS have other lifelong complications, such as high blood pressure, seizures, blindness, paralysis, and the effects of having part of their colon removed. STEC-HUS is associated with a 3% mortality rate among young children and a 20% mortality rate in middle age or older adults. 15-20% of children infected with STEC develop HUS, with the highest risk being in children younger than 5 years old. Patients with aHUS generally have poor outcomes, with up to 50% progressing to end-stage renal disease (ESRD) or irreversible brain damage; as many as 25% die during the acute phase. HUS is now considered as a part of the broader group of Thrombotic microangiopathies (TMA). Thrombotic thrombocytopenic purpura (TTP), a TMA, was first described by the Hungarian born, American pathologist and physician Eli Moschcowitz (1879 – 1964). In 1924, Moschcowitz first described TTP as a distinct clinicopathologic condition that can mimic the clinical characteristics of Hemolytic–uremic syndrome (HUS). That was in a 16-year-old girl who died 2 weeks after the abrupt onset and progression of petechial bleeding, pallor, fever, paralysis, hematuria and coma; and called "Moschcowitz disease". Moreover, Moschcowitz was among the first to work in psychosomatic medicine, and he presented a paper in 1935 on the psychological origins of physical disease. HUS was first described by Conrad Gasser in 1955, and the systemic character of HUS was subsequently defined. Bernard Kaplan identified several distinct entities that can manifest as HUS and emphasized that HUS was a syndrome with a common pathologic outcome. Kaplan is a Canadian professor and director of Pediatric Nephrology. He has an international reputation for his studies, over the past 34 years, on the hemolytic uremic syndromes. The discovery that endothelial cell injury underlies this broad spectrum of TMA disorders has come into focus during the last two decades. In the 1980s, Mohamed Karmali (1945-2016) was the first to make the association between Stx, diarrheal E. coli infection and the idiopathic hemolytic uremic syndrome of infancy and childhood. Karmali's work showed that the hemolytic uremic syndrome the children in Canada was caused by this particular bacteria. Karmali also developed the system of classifying strains of E.coli and determining which cause disease in humans. He defined the presence of microvascular injury in diarrhea-associated HUS and the critical role of a verotoxin produced by specific strains of Escherichia coli. This verotoxin was subsequently found to be a member of a family of toxins first identified with Shigella and known as Shiga toxin (Stx). This relationship and the eventual link of TTP to abnormally high levels of ultra-large Von Willebrand factor (vWF) multimers caused by congenital or acquired reductions in ADAMTS13 activity was established at approximately the same time. In 1924, a Finnish physician Erik Adolf von Willebrand (1870-1949) was consulted about a young girl with a bleeding disorder. Von Willebrand described this disorder in 1926, distinguishing it from hemophilia. The disorder was named after him, becoming known as von Willebrand disease. The cause of the disease was later discovered to be a deficiency of a protein, now known as von Willebrand factor, that enables hemostasis. Paul Warwicker is an English nephrologist, whilst in Newcastle in the mid 1990s his research in molecular genetics with Professors Tim and Judith Goodship led to the genetic mapping of the familial form of atypical HUS and the descriptions of the first HUS-related mutations and polymorphisms in the factor H gene in both familial and sporadic HUS. He was awarded an MD in molecular genetics in 2000, and elected fellow of the Royal College of Physicians in the same year. Paul Warwicker confirmed the association of atypical HUS (aHUS) to defects in a region on chromosome 1 that contains the genes for several complement regulatory proteins. Later, mutations in complement factor H, complement factor I, membrane cofactor protein, factor B, C3, and thrombomodulin have now been found to cause many of the familial cases of aHUS. These discoveries have allowed a more comprehensive understanding of the pathogenesis, evaluation, and treatment of the entire spectrum of TMA disorders and provide a more rational and effective approach to the care of these children with complicated disease. Prior to the use of monoclonal antibodies patients with aHUS had an extremely poor prognosis. Eculizumab (Soliris®, Alexion Pharmaceuticals, Inc., Boston, MA, USA) is a humanized monoclonal complement inhibitor that is the first and only approved treatment for patients with aHUS by FDA in September 2011. Eculizumab binds with high affinity to C5, inhibiting C5 cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9, thus inhibiting complement-mediated TMA. Eculizumab was proven to be effective in patients with aHUS in which it resolved and prevented complement-mediated TMA, improving renal function and hematologic outcomes. Alexion head of R&D 'John Orloff, M.D. "The results met the high bar of complete TMA response, defined by hematologic normalization and improved kidney function," said Alexion R&D head John Orloff, M.D., who reckons the drug can become the "new standard of care for patients with aHUS." "We are preparing regulatory submissions for Ultomiris in aHUS in the U.S., European Union and Japan as quickly as possible," he added. The country with the highest incidence of HUS is Argentina and it performs a key role in the research of this condition. In the United States, the overall incidence of HUS is estimated at 2.1 cases per 100,000 persons/year, with a peak incidence between six months and four years of age. HUS and the E. coli infections that cause it have been the source of much negative publicity for the FDA, meat industries, and fast-food restaurants since the 1990s, especially in the contaminations linked to Jack in the Box restaurants. In 2006, an epidemic of harmful E. coli emerged in the United States due to contaminated spinach. In June 2009, Nestlé Toll House cookie dough was linked to an outbreak of E. coli O157:H7 in the United States, which sickened 70 people in 30 states. In May 2011 an epidemic of bloody diarrhea caused by E. coli O104:H4-contaminated fenugreek seeds hit Germany. Tracing the epidemic revealed more than 3,800 cases, with HUS developing in more than 800 of the cases, including 36 fatal cases. Nearly 90% of the HUS cases were in adults.

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Acute hemorrhagic fever syndrome

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Bleeding

Bleeding , hemorrhage , haemorrhage or blood loss is blood escaping from the circulatory system from damaged blood vessels . Bleeding can occur internally , or externally either through a natural opening such as the mouth , nose , ear , urethra , vagina or anus , or through a puncture in the skin . Hypovolemia is a massive decrease in blood volume, and death by excessive loss of blood is referred to as exsanguination . Typically, a healthy person can endure a loss of 10–15% of the total blood volume without serious medical difficulties (by comparison, blood donation typically takes 8–10% of the donor's blood volume). The stopping or controlling of bleeding is called hemostasis and is an important part of both first aid and surgery . Epistaxis – nosebleed Ruptured aneurysm Aortic transection Iatrogenic injuryBleeding arises due to either traumatic injury, underlying medical condition, or a combination. Traumatic bleeding is caused by some type of injury. There are different types of wounds which may cause traumatic bleeding. These include: [ citation needed ] The pattern of injury, evaluation and treatment will vary with the mechanism of the injury. Blunt trauma causes injury via a shock effect; delivering energy over an area. Wounds are often not straight and unbroken skin may hide significant injury. Penetrating trauma follows the course of the injurious device. As the energy is applied in a more focused fashion, it requires less energy to cause significant injury. Any body organ, including bone and brain, can be injured and bleed. Bleeding may not be readily apparent; internal organs such as the liver, kidney and spleen may bleed into the abdominal cavity. The only apparent signs may come with blood loss. Bleeding from a bodily orifice, such as the rectum, nose, or ears may signal internal bleeding, but cannot be relied upon. Bleeding from a medical procedure also falls into this category. [ citation needed ] "Medical bleeding" denotes hemorrhage as a result of an underlying medical condition (i.e. causes of bleeding that are not directly due to trauma). Blood can escape from blood vessels as a result of 3 basic patterns of injury: [ citation needed ] The underlying scientific basis for blood clotting and hemostasis is discussed in detail in the articles, coagulation , hemostasis and related articles. The discussion here is limited to the common practical aspects of blood clot formation which manifest as bleeding. Some medical conditions can also make patients susceptible to bleeding. These are conditions that affect the normal hemostatic (bleeding-control) functions of the body. Such conditions either are, or cause, bleeding diatheses . Hemostasis involves several components. The main components of the hemostatic system include platelets and the coagulation system. Platelets are small blood components that form a plug in the blood vessel wall that stops bleeding. Platelets also produce a variety of substances that stimulate the production of a blood clot. One of the most common causes of increased bleeding risk is exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). The prototype for these drugs is aspirin, which inhibits the production of thromboxane. NSAIDs (for example Ibuprofen) inhibit the activation of platelets , and thereby increase the risk of bleeding. The effect of aspirin is irreversible; therefore, the inhibitory effect of aspirin is present until the platelets have been replaced (about ten days). Other NSAIDs, such as "ibuprofen" (Motrin) and related drugs, are reversible and therefore, the effect on platelets is not as long-lived. [ citation needed ] There are several named coagulation factors that interact in a complex way to form blood clots, as discussed in the article on coagulation . Deficiencies of coagulation factors are associated with clinical bleeding. For instance, deficiency of Factor VIII causes classic hemophilia A while deficiencies of Factor IX cause "Christmas disease"( hemophilia B ). Antibodies to Factor VIII can also inactivate the Factor VII and precipitate bleeding that is very difficult to control. This is a rare condition that is most likely to occur in older patients and in those with autoimmune diseases. Another common bleeding disorder is Von Willebrand disease . It is caused by a deficiency or abnormal function of the "Von Willebrand" factor, which is involved in platelet activation. Deficiencies in other factors, such as factor XIII or factor VII are occasionally seen, but may not be associated with severe bleeding and are not as commonly diagnosed. In addition to NSAID-related bleeding, another common cause of bleeding is that related to the medication, warfarin ("Coumadin" and others). This medication needs to be closely monitored as the bleeding risk can be markedly increased by interactions with other medications. Warfarin acts by inhibiting the production of Vitamin K in the gut. Vitamin K is required for the production of the clotting factors, II, VII, IX, and X in the liver. One of the most common causes of warfarin-related bleeding is taking antibiotics. The gut bacteria make vitamin K and are killed by antibiotics. This decreases vitamin K levels and therefore the production of these clotting factors. Deficiencies of platelet function may require platelet transfusion while deficiencies of clotting factors may require transfusion of either fresh frozen plasma or specific clotting factors, such as Factor VIII for patients with hemophilia. Infectious diseases such as Ebola , Marburg virus disease and yellow fever can cause bleeding. [ citation needed ]Traumatic bleeding is caused by some type of injury. There are different types of wounds which may cause traumatic bleeding. These include: [ citation needed ] The pattern of injury, evaluation and treatment will vary with the mechanism of the injury. Blunt trauma causes injury via a shock effect; delivering energy over an area. Wounds are often not straight and unbroken skin may hide significant injury. Penetrating trauma follows the course of the injurious device. As the energy is applied in a more focused fashion, it requires less energy to cause significant injury. Any body organ, including bone and brain, can be injured and bleed. Bleeding may not be readily apparent; internal organs such as the liver, kidney and spleen may bleed into the abdominal cavity. The only apparent signs may come with blood loss. Bleeding from a bodily orifice, such as the rectum, nose, or ears may signal internal bleeding, but cannot be relied upon. Bleeding from a medical procedure also falls into this category. [ citation needed ]"Medical bleeding" denotes hemorrhage as a result of an underlying medical condition (i.e. causes of bleeding that are not directly due to trauma). Blood can escape from blood vessels as a result of 3 basic patterns of injury: [ citation needed ] The underlying scientific basis for blood clotting and hemostasis is discussed in detail in the articles, coagulation , hemostasis and related articles. The discussion here is limited to the common practical aspects of blood clot formation which manifest as bleeding. Some medical conditions can also make patients susceptible to bleeding. These are conditions that affect the normal hemostatic (bleeding-control) functions of the body. Such conditions either are, or cause, bleeding diatheses . Hemostasis involves several components. The main components of the hemostatic system include platelets and the coagulation system. Platelets are small blood components that form a plug in the blood vessel wall that stops bleeding. Platelets also produce a variety of substances that stimulate the production of a blood clot. One of the most common causes of increased bleeding risk is exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). The prototype for these drugs is aspirin, which inhibits the production of thromboxane. NSAIDs (for example Ibuprofen) inhibit the activation of platelets , and thereby increase the risk of bleeding. The effect of aspirin is irreversible; therefore, the inhibitory effect of aspirin is present until the platelets have been replaced (about ten days). Other NSAIDs, such as "ibuprofen" (Motrin) and related drugs, are reversible and therefore, the effect on platelets is not as long-lived. [ citation needed ] There are several named coagulation factors that interact in a complex way to form blood clots, as discussed in the article on coagulation . Deficiencies of coagulation factors are associated with clinical bleeding. For instance, deficiency of Factor VIII causes classic hemophilia A while deficiencies of Factor IX cause "Christmas disease"( hemophilia B ). Antibodies to Factor VIII can also inactivate the Factor VII and precipitate bleeding that is very difficult to control. This is a rare condition that is most likely to occur in older patients and in those with autoimmune diseases. Another common bleeding disorder is Von Willebrand disease . It is caused by a deficiency or abnormal function of the "Von Willebrand" factor, which is involved in platelet activation. Deficiencies in other factors, such as factor XIII or factor VII are occasionally seen, but may not be associated with severe bleeding and are not as commonly diagnosed. In addition to NSAID-related bleeding, another common cause of bleeding is that related to the medication, warfarin ("Coumadin" and others). This medication needs to be closely monitored as the bleeding risk can be markedly increased by interactions with other medications. Warfarin acts by inhibiting the production of Vitamin K in the gut. Vitamin K is required for the production of the clotting factors, II, VII, IX, and X in the liver. One of the most common causes of warfarin-related bleeding is taking antibiotics. The gut bacteria make vitamin K and are killed by antibiotics. This decreases vitamin K levels and therefore the production of these clotting factors. Deficiencies of platelet function may require platelet transfusion while deficiencies of clotting factors may require transfusion of either fresh frozen plasma or specific clotting factors, such as Factor VIII for patients with hemophilia.Infectious diseases such as Ebola , Marburg virus disease and yellow fever can cause bleeding. [ citation needed ]Dioxaborolane chemistry enables radioactive fluoride ( 18 F ) labeling of red blood cells , which allows for positron emission tomography (PET) imaging of intracerebral hemorrhages. Hemorrhaging is broken down into four classes by the American College of Surgeons' advanced trauma life support (ATLS). This system is basically the same as used in the staging of hypovolemic shock . Individuals in excellent physical and cardiovascular shape may have more effective compensatory mechanisms before experiencing cardiovascular collapse. These patients may look deceptively stable, with minimal derangements in vital signs, while having poor peripheral perfusion. Elderly patients or those with chronic medical conditions may have less tolerance to blood loss, less ability to compensate, and may take medications such as betablockers that can potentially blunt the cardiovascular response. Care must be taken in the assessment. [ citation needed ] Although there is no universally accepted definition of massive hemorrhage, the following can be used to identify the condition: "(i) blood loss exceeding circulating blood volume within a 24-hour period, (ii) blood loss of 50% of circulating blood volume within a 3-hour period, (iii) blood loss exceeding 150 ml/min, or (iv) blood loss that necessitates plasma and platelet transfusion." The World Health Organization made a standardized grading scale to measure the severity of bleeding. Hemorrhaging is broken down into four classes by the American College of Surgeons' advanced trauma life support (ATLS). This system is basically the same as used in the staging of hypovolemic shock . Individuals in excellent physical and cardiovascular shape may have more effective compensatory mechanisms before experiencing cardiovascular collapse. These patients may look deceptively stable, with minimal derangements in vital signs, while having poor peripheral perfusion. Elderly patients or those with chronic medical conditions may have less tolerance to blood loss, less ability to compensate, and may take medications such as betablockers that can potentially blunt the cardiovascular response. Care must be taken in the assessment. [ citation needed ] Although there is no universally accepted definition of massive hemorrhage, the following can be used to identify the condition: "(i) blood loss exceeding circulating blood volume within a 24-hour period, (ii) blood loss of 50% of circulating blood volume within a 3-hour period, (iii) blood loss exceeding 150 ml/min, or (iv) blood loss that necessitates plasma and platelet transfusion." The World Health Organization made a standardized grading scale to measure the severity of bleeding. Hemorrhaging is broken down into four classes by the American College of Surgeons' advanced trauma life support (ATLS). This system is basically the same as used in the staging of hypovolemic shock . Individuals in excellent physical and cardiovascular shape may have more effective compensatory mechanisms before experiencing cardiovascular collapse. These patients may look deceptively stable, with minimal derangements in vital signs, while having poor peripheral perfusion. Elderly patients or those with chronic medical conditions may have less tolerance to blood loss, less ability to compensate, and may take medications such as betablockers that can potentially blunt the cardiovascular response. Care must be taken in the assessment. [ citation needed ]Although there is no universally accepted definition of massive hemorrhage, the following can be used to identify the condition: "(i) blood loss exceeding circulating blood volume within a 24-hour period, (ii) blood loss of 50% of circulating blood volume within a 3-hour period, (iii) blood loss exceeding 150 ml/min, or (iv) blood loss that necessitates plasma and platelet transfusion." The World Health Organization made a standardized grading scale to measure the severity of bleeding. Acute bleeding from an injury to the skin is often treated by the application of direct pressure. For severely injured patients, tourniquets are helpful in preventing complications of shock . Anticoagulant medications may need to be discontinued and possibly reversed in patients with clinically significant bleeding. Patients that have lost excessive amounts of blood may require a blood transfusion . The use of cyanoacrylate glue to prevent bleeding and seal battle wounds was designed and first used in the Vietnam War . Skin glue, a medical version of "super glue", is sometimes used instead of using traditional stitches used for small wounds that need to be closed at the skin level. The word "Haemorrhage" (or hæmorrhage ; using the æ ligature ) comes from Latin haemorrhagia, from Ancient Greek αἱμορραγία ( haimorrhagía , "a violent bleeding"), from αἱμορραγής ( haimorrhagḗs , "bleeding violently"), from αἷμα ( haîma , "blood") + -ραγία ( -ragía ), from ῥηγνύναι ( rhēgnúnai , "to break, burst").

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Acute hemorrhagic fever syndrome

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Kidney failure

Kidney failure , also known as end-stage kidney disease , is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as either acute kidney failure , which develops rapidly and may resolve; and chronic kidney failure , which develops slowly and can often be irreversible. Symptoms may include leg swelling , feeling tired, vomiting , loss of appetite, and confusion . Complications of acute and chronic failure include uremia , hyperkalaemia, and volume overload . Complications of chronic failure also include heart disease , high blood pressure , and anaemia . Causes of acute kidney failure include low blood pressure , blockage of the urinary tract , certain medications, muscle breakdown , and hemolytic uremic syndrome . Causes of chronic kidney failure include diabetes , high blood pressure , nephrotic syndrome , and polycystic kidney disease . Diagnosis of acute failure is often based on a combination of factors such as decreased urine production or increased serum creatinine . Diagnosis of chronic failure is based on a glomerular filtration rate (GFR) of less than 15 or the need for renal replacement therapy . It is also equivalent to stage 5 chronic kidney disease . Treatment of acute failure depends on the underlying cause. Treatment of chronic failure may include hemodialysis , peritoneal dialysis , or a kidney transplant . Hemodialysis uses a machine to filter the blood outside the body. In peritoneal dialysis specific fluid is placed into the abdominal cavity and then drained, with this process being repeated multiple times per day. Kidney transplantation involves surgically placing a kidney from someone else and then taking immunosuppressant medication to prevent rejection . Other recommended measures from chronic disease include staying active and specific dietary changes. Depression is also common among patients with kidney failure, and is associated with poor outcomes including higher risk of kidney function decline, hospitalization, and death. A recent PCORI -funded study of patients with kidney failure receiving outpatient hemodialysis found similar effectiveness between nonpharmacological and pharmacological treatments for depression. In the United States, acute failure affects about 3 per 1,000 people a year. Chronic failure affects about 1 in 1,000 people with 3 per 10,000 people newly developing the condition each year. Acute failure is often reversible while chronic failure often is not. With appropriate treatment many with chronic disease can continue working. Kidney failure can be divided into two categories: acute kidney failure or chronic kidney failure . The type of renal failure is differentiated by the trend in the serum creatinine ; other factors that may help differentiate acute kidney failure from chronic kidney failure include anemia and the kidney size on sonography as chronic kidney disease generally leads to anemia and small kidney size. [ citation needed ] Acute kidney injury (AKI), previously called acute renal failure (ARF), is a rapidly progressive loss of renal function , generally characterized by oliguria (decreased urine production, quantified as less than 400 mL per day in adults, less than 0.5 mL/kg/h in children or less than 1 mL/kg/h in infants); and fluid and electrolyte imbalance . AKI can result from a variety of causes, generally classified as prerenal , intrinsic , and postrenal . Many people diagnosed with paraquat intoxication experience AKI, sometimes requiring hemodialysis . [ citation needed ] The underlying cause must be identified and treated to arrest the progress, and dialysis may be necessary to bridge the time gap required for treating these fundamental causes. [ citation needed ] Chronic kidney disease (CKD) can also develop slowly and, initially, show few symptoms. CKD can be the long term consequence of irreversible acute disease or part of a disease progression. [ citation needed ] CKD is divided into 5 different stages (1-5) according to the estimated glomerular filtration rate (eGFR). In CKD1 eGFR is normal and in CKD5 eGFR has decreased to less than 15 ml/min. Acute kidney injuries can be present on top of chronic kidney disease, a condition called acute-on-chronic kidney failure (AoCRF). The acute part of AoCRF may be reversible, and the goal of treatment, as with AKI, is to return the person to baseline kidney function, typically measured by serum creatinine . Like AKI, AoCRF can be difficult to distinguish from chronic kidney disease if the person has not been monitored by a physician and no baseline (i.e., past) blood work is available for comparison. [ citation needed ]Acute kidney injury (AKI), previously called acute renal failure (ARF), is a rapidly progressive loss of renal function , generally characterized by oliguria (decreased urine production, quantified as less than 400 mL per day in adults, less than 0.5 mL/kg/h in children or less than 1 mL/kg/h in infants); and fluid and electrolyte imbalance . AKI can result from a variety of causes, generally classified as prerenal , intrinsic , and postrenal . Many people diagnosed with paraquat intoxication experience AKI, sometimes requiring hemodialysis . [ citation needed ] The underlying cause must be identified and treated to arrest the progress, and dialysis may be necessary to bridge the time gap required for treating these fundamental causes. [ citation needed ]Chronic kidney disease (CKD) can also develop slowly and, initially, show few symptoms. CKD can be the long term consequence of irreversible acute disease or part of a disease progression. [ citation needed ] CKD is divided into 5 different stages (1-5) according to the estimated glomerular filtration rate (eGFR). In CKD1 eGFR is normal and in CKD5 eGFR has decreased to less than 15 ml/min. Acute kidney injuries can be present on top of chronic kidney disease, a condition called acute-on-chronic kidney failure (AoCRF). The acute part of AoCRF may be reversible, and the goal of treatment, as with AKI, is to return the person to baseline kidney function, typically measured by serum creatinine . Like AKI, AoCRF can be difficult to distinguish from chronic kidney disease if the person has not been monitored by a physician and no baseline (i.e., past) blood work is available for comparison. [ citation needed ]Symptoms can vary from person to person. Someone in early stage kidney disease may not feel sick or notice symptoms as they occur. When the kidneys fail to filter properly, waste accumulates in the blood and the body, a condition called azotemia . Very low levels of azotaemia may produce few, if any, symptoms. If the disease progresses, symptoms become noticeable (if the failure is of sufficient degree to cause symptoms). Kidney failure accompanied by noticeable symptoms is termed uraemia . Symptoms of kidney failure include the following: Abnormal heart rhythms Muscle paralysis Swelling of the hands, legs, ankles, feet, or face Shortness of breath due to extra fluid on the lungs (may also be caused by anemia) Pain in the back or side Feeling tired or weak Memory problems Difficulty concentrating Dizziness Low blood pressure Foamy or bubbly urine Swelling in the hands, feet, abdomen, and faceAcute kidney injury (previously known as acute renal failure) – or AKI – usually occurs when the blood supply to the kidneys is suddenly interrupted or when the kidneys become overloaded with toxins. Causes of acute kidney injury include accidents, injuries, or complications from surgeries in which the kidneys are deprived of normal blood flow for extended periods of time. Heart-bypass surgery is an example of one such procedure. [ citation needed ] Drug overdoses, accidental or from chemical overloads of drugs such as antibiotics or chemotherapy, along with bee stings may also cause the onset of acute kidney injury. Unlike chronic kidney disease, however, the kidneys can often recover from acute kidney injury, allowing the person with AKI to resume a normal life. People with acute kidney injury require supportive treatment until their kidneys recover function, and they often remain at increased risk of developing future kidney failure. Among the accidental causes of renal failure is the crush syndrome , when large amounts of toxins are suddenly released in the blood circulation after a long compressed limb is suddenly relieved from the pressure obstructing the blood flow through its tissues, causing ischemia . The resulting overload can lead to the clogging and the destruction of the kidneys. It is a reperfusion injury that appears after the release of the crushing pressure. The mechanism is believed to be the release into the bloodstream of muscle breakdown products – notably myoglobin , potassium , and phosphorus – that are the products of rhabdomyolysis (the breakdown of skeletal muscle damaged by ischemic conditions). The specific action on the kidneys is not fully understood, but may be due in part to nephrotoxic metabolites of myoglobin. [ citation needed ] Chronic kidney failure has numerous causes. The most common causes of chronic failure are diabetes mellitus and long-term, uncontrolled hypertension . Polycystic kidney disease is another well-known cause of chronic failure. The majority of people affected with polycystic kidney disease have a family history of the disease. Systemic lupus erythematosus (SLE) is also a known cause of chronic kidney failure. Other genetic illnesses cause kidney failure, as well. [ citation needed ] Overuse of common drugs such as ibuprofen , and acetaminophen (paracetamol) can also cause chronic kidney failure. Some infectious disease agents, such as hantavirus , can attack the kidneys, causing kidney failure. The APOL1 gene has been proposed as a major genetic risk locus for a spectrum of nondiabetic renal failure in individuals of African origin, these include HIV-associated nephropathy (HIVAN), primary nonmonogenic forms of focal segmental glomerulosclerosis , and hypertension affiliated chronic kidney disease not attributed to other etiologies. Two western African variants in APOL1 have been shown to be associated with end stage kidney disease in African Americans and Hispanic Americans. Acute kidney injury (previously known as acute renal failure) – or AKI – usually occurs when the blood supply to the kidneys is suddenly interrupted or when the kidneys become overloaded with toxins. Causes of acute kidney injury include accidents, injuries, or complications from surgeries in which the kidneys are deprived of normal blood flow for extended periods of time. Heart-bypass surgery is an example of one such procedure. [ citation needed ] Drug overdoses, accidental or from chemical overloads of drugs such as antibiotics or chemotherapy, along with bee stings may also cause the onset of acute kidney injury. Unlike chronic kidney disease, however, the kidneys can often recover from acute kidney injury, allowing the person with AKI to resume a normal life. People with acute kidney injury require supportive treatment until their kidneys recover function, and they often remain at increased risk of developing future kidney failure. Among the accidental causes of renal failure is the crush syndrome , when large amounts of toxins are suddenly released in the blood circulation after a long compressed limb is suddenly relieved from the pressure obstructing the blood flow through its tissues, causing ischemia . The resulting overload can lead to the clogging and the destruction of the kidneys. It is a reperfusion injury that appears after the release of the crushing pressure. The mechanism is believed to be the release into the bloodstream of muscle breakdown products – notably myoglobin , potassium , and phosphorus – that are the products of rhabdomyolysis (the breakdown of skeletal muscle damaged by ischemic conditions). The specific action on the kidneys is not fully understood, but may be due in part to nephrotoxic metabolites of myoglobin. [ citation needed ]Chronic kidney failure has numerous causes. The most common causes of chronic failure are diabetes mellitus and long-term, uncontrolled hypertension . Polycystic kidney disease is another well-known cause of chronic failure. The majority of people affected with polycystic kidney disease have a family history of the disease. Systemic lupus erythematosus (SLE) is also a known cause of chronic kidney failure. Other genetic illnesses cause kidney failure, as well. [ citation needed ] Overuse of common drugs such as ibuprofen , and acetaminophen (paracetamol) can also cause chronic kidney failure. Some infectious disease agents, such as hantavirus , can attack the kidneys, causing kidney failure. The APOL1 gene has been proposed as a major genetic risk locus for a spectrum of nondiabetic renal failure in individuals of African origin, these include HIV-associated nephropathy (HIVAN), primary nonmonogenic forms of focal segmental glomerulosclerosis , and hypertension affiliated chronic kidney disease not attributed to other etiologies. Two western African variants in APOL1 have been shown to be associated with end stage kidney disease in African Americans and Hispanic Americans. Chronic kidney failure is measured in five stages, which are calculated using the person's GFR, or glomerular filtration rate . Stage 1 CKD is mildly diminished renal function, with few overt symptoms. Stages 2 and 3 need increasing levels of supportive care from their medical providers to slow and treat their renal dysfunction. People with stage 4 and 5 kidney failure usually require preparation towards active treatment in order to survive. Stage 5 CKD is considered a severe illness and requires some form of renal replacement therapy ( dialysis ) or kidney transplant whenever feasible. [ citation needed ] A normal GFR varies according to many factors, including sex, age, body size and ethnic background. Renal professionals consider the glomerular filtration rate (GFR) to be the best overall index of kidney function. The National Kidney Foundation offers an easy to use on-line GFR calculator for anyone who is interested in knowing their glomerular filtration rate. (A serum creatinine level, a simple blood test, is needed to use the calculator.) Before the advancement of modern medicine, renal failure was often referred to as uremic poisoning. Uremia was the term for the contamination of the blood with urea. It is the presence of an excessive amount of urea in blood. Starting around 1847, this included reduced urine output, which was thought to be caused by the urine mixing with the blood instead of being voided through the urethra. [ citation needed ] The term uremia is now used for the illness accompanying kidney failure. Two other urinary indices, are the fractional sodium excretion (FENa) index and the renal failure index (RFI). The renal failure index is equal to urine sodium times plasma creatinine divided by urine creatinine . A FENa score greater than 3% or a renal failure index (RFI) greater than 3 are helpful in confirming acute renal failure. Chronic kidney failure is measured in five stages, which are calculated using the person's GFR, or glomerular filtration rate . Stage 1 CKD is mildly diminished renal function, with few overt symptoms. Stages 2 and 3 need increasing levels of supportive care from their medical providers to slow and treat their renal dysfunction. People with stage 4 and 5 kidney failure usually require preparation towards active treatment in order to survive. Stage 5 CKD is considered a severe illness and requires some form of renal replacement therapy ( dialysis ) or kidney transplant whenever feasible. [ citation needed ] A normal GFR varies according to many factors, including sex, age, body size and ethnic background. Renal professionals consider the glomerular filtration rate (GFR) to be the best overall index of kidney function. The National Kidney Foundation offers an easy to use on-line GFR calculator for anyone who is interested in knowing their glomerular filtration rate. (A serum creatinine level, a simple blood test, is needed to use the calculator.)Before the advancement of modern medicine, renal failure was often referred to as uremic poisoning. Uremia was the term for the contamination of the blood with urea. It is the presence of an excessive amount of urea in blood. Starting around 1847, this included reduced urine output, which was thought to be caused by the urine mixing with the blood instead of being voided through the urethra. [ citation needed ] The term uremia is now used for the illness accompanying kidney failure. Two other urinary indices, are the fractional sodium excretion (FENa) index and the renal failure index (RFI). The renal failure index is equal to urine sodium times plasma creatinine divided by urine creatinine . A FENa score greater than 3% or a renal failure index (RFI) greater than 3 are helpful in confirming acute renal failure. Those with end stage renal failure who undergo haemodialysis have higher risk of spontaneous intra-abdominal bleeding than the general population (21.2%) and non-occlusive mesenteric ischemia (18.1%). Meanwhile, those undergoing peritoneal dialysis have a higher chance of developing peritonitis and gastrointestinal perforation . However, the rate of acute pancreatitis does not differ from the general population. The treatment of acute kidney injury depends on the cause. The treatment of chronic kidney failure may include renal replacement therapy: hemodialysis , peritoneal dialysis , or kidney transplant . In non-diabetics and people with type 1 diabetes , a low protein diet is found to have a preventive effect on progression of chronic kidney disease. However, this effect does not apply to people with type 2 diabetes . A whole food, plant-based diet may help some people with kidney disease. A high protein diet from either animal or plant sources appears to have negative effects on kidney function at least in the short term. People who receive earlier referrals to a nephrology specialist, meaning a longer time before they must start dialysis, have a shorter initial hospitalization and reduced risk of death after the start of dialysis. Other methods of reducing disease progression include minimizing exposure to nephrotoxins such as NSAIDs and intravenous contrast . In non-diabetics and people with type 1 diabetes , a low protein diet is found to have a preventive effect on progression of chronic kidney disease. However, this effect does not apply to people with type 2 diabetes . A whole food, plant-based diet may help some people with kidney disease. A high protein diet from either animal or plant sources appears to have negative effects on kidney function at least in the short term. People who receive earlier referrals to a nephrology specialist, meaning a longer time before they must start dialysis, have a shorter initial hospitalization and reduced risk of death after the start of dialysis. Other methods of reducing disease progression include minimizing exposure to nephrotoxins such as NSAIDs and intravenous contrast .

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Acute hemorrhagic fever syndrome

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Bleeding diathesis

In medicine ( hematology ), bleeding diathesis is an unusual susceptibility to bleed ( hemorrhage ) mostly due to hypocoagulability (a condition of irregular and slow blood clotting), in turn caused by a coagulopathy (a defect in the system of coagulation ). Therefore, this may result in the reduction of platelets being produced and leads to excessive bleeding. Several types of coagulopathy are distinguished, ranging from mild to lethal. Coagulopathy can be caused by thinning of the skin ( Cushing's syndrome ), such that the skin is weakened and is bruised easily and frequently without any trauma or injury to the body. Also, coagulopathy can be contributed by impaired wound healing or impaired clot formation. Following are some complications of coagulopathies, some of them caused by their treatments:Following are some complications of coagulopathies, some of them caused by their treatments:While there are several possible causes, they generally result in excessive bleeding and a lack of clotting. [ citation needed ] Acquired causes of coagulopathy include anticoagulation with warfarin , liver failure , vitamin K deficiency and disseminated intravascular coagulation . Additionally, the hemotoxic venom from certain species of snakes can cause this condition, for example Bothrops , rattlesnakes and other species of viper . Viral hemorrhagic fevers include dengue hemorrhagic fever and dengue shock syndrome. Leukemia may also cause coagulopathy. Furthermore, cystic fibrosis has been known to cause bleeding diathesis, especially in undiagnosed infants, due to malabsorption of fat soluble vitamins like vitamin K. [ citation needed ] There are autoimmune causes of coagulation disorders. They include acquired antibodies to coagulation factors, termed inhibitors of coagulation. The main inhibitor is directed against clotting factor VIII. Another example is antiphospholipid syndrome , an autoimmune, hypercoagulable state. [ citation needed ] Bleeding diathesis may also be caused by impaired wound healing (as in scurvy ), or by thinning of the skin, such as in Cushing's syndrome . [ citation needed ]Acquired causes of coagulopathy include anticoagulation with warfarin , liver failure , vitamin K deficiency and disseminated intravascular coagulation . Additionally, the hemotoxic venom from certain species of snakes can cause this condition, for example Bothrops , rattlesnakes and other species of viper . Viral hemorrhagic fevers include dengue hemorrhagic fever and dengue shock syndrome. Leukemia may also cause coagulopathy. Furthermore, cystic fibrosis has been known to cause bleeding diathesis, especially in undiagnosed infants, due to malabsorption of fat soluble vitamins like vitamin K. [ citation needed ]There are autoimmune causes of coagulation disorders. They include acquired antibodies to coagulation factors, termed inhibitors of coagulation. The main inhibitor is directed against clotting factor VIII. Another example is antiphospholipid syndrome , an autoimmune, hypercoagulable state. [ citation needed ]Bleeding diathesis may also be caused by impaired wound healing (as in scurvy ), or by thinning of the skin, such as in Cushing's syndrome . [ citation needed ]Some people lack genes that typically produce the protein coagulation factors that allow normal clotting. Various types of hemophilia and von Willebrand disease are the major genetic disorders associated with coagulopathy. Rare examples are Bernard–Soulier syndrome , Wiskott–Aldrich syndrome and Glanzmann's thrombasthenia . Gene therapy treatments may be a solution as they involve in the insertion of normal genes to replace defective genes causing for the genetic disorder. Gene therapy is a source of active research that hold promise for the future. Consult a hematologist and have a regular blood check ups. Have an early diagnostic test for any blood disorders or blood diseases including hemophilia, hemorrhage, and sickle-cell anemia. Prothrombin time and partial thromboplastin time blood tests are useful to investigate the reason behind the excessive bleeding. The PT evaluates coagulation factors I, II, V, VII and X , while the PTT evaluates coagulation factors I, II, V, VIII, IX, X, XI and XII . The analysis of both tests thus helps to diagnose certain disorders. Blood transfusion involves the transfer of plasma containing all the necessary coagulating factors ( fibrinogen , prothrombin , thromboplastin ) to help restore them and to improve the immune defense of the patient after excessive blood loss. Blood transfusion also caused the transfer of platelets that can work along with coagulating factors for blood clotting to commence. Different drugs can be prescribed depending on the type of disease. Vitamins (K, P and C) are essential in case of obstruction to walls of blood vessels. Also, vitamin K is required for the production of blood clotting factors, hence the injection of vitamin K ( phytomenadione ) is recommended to boost blood clotting.

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Acute hemorrhagic fever syndrome

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Chikungunya

Chikungunya is an infection caused by the Chikungunya virus ( CHIKV ). The disease was first identified in 1952 in Tanzania and named based on the Kimakonde words for "to become contorted". Symptoms include fever and joint pain . These typically occur two to twelve days after exposure. Other symptoms may include headache , muscle pain , joint swelling , and a rash . Symptoms usually improve within a week; however, occasionally the joint pain may last for months or years. The risk of death is around 1 in 1,000. The very young, old, and those with other health problems are at risk of more severe disease. The virus is spread between people by two types of mosquitos : Aedes albopictus and Aedes aegypti . They mainly bite during the day. The virus may circulate within a number of animals including birds and rodents . Diagnosis is by either testing the blood for viral RNA or antibodies to the virus. The symptoms can be mistaken for those of dengue fever and Zika fever . It is believed most people become immune after a single infection. The best means of prevention are overall mosquito control and the avoidance of bites in areas where the disease is common. This may be partly achieved by decreasing mosquitos' access to water and by the use of insect repellent and mosquito nets . In November 2023 the USFDA approved an adults-only vaccine ( Ixchiq ) for prevention of the disease. Once infected and symptomatic, recommendations to patients should include rest, fluids, and medications to help with fever and joint pain. In 2014, more than a million suspected cases occurred globally. While the disease is endemic in Africa and Asia, outbreaks have been reported in Europe and the Americas since the 2000s; in 2014, an outbreak was reported in Florida in the continental United States , but as of 2016 there were no further locally-acquired cases. Around 85% of people infected with Chikungunya virus experience symptoms, typically beginning with a sudden high fever above 39 °C (102 °F) . The fever is soon followed by severe muscle and joint pain . Pain usually affects multiple joints in the arms and legs, and is symmetric – i.e. if one elbow is affected, the other is as well. People with Chikungunya also frequently experience headache , back pain, nausea , and fatigue . Around half of those affected develop a rash , with reddening and sometimes small bumps on the palms, foot soles, torso, and face. For some, the rash remains constrained to a small part of the body; for others, the rash can be extensive, covering more than 90% of the skin. Some people experience gastrointestinal issues, with abdominal pain and vomiting. Others experience eye problems, namely sensitivity to light , conjunctivitis , and pain behind the eye. This first set of symptoms – called the "acute phase" of Chikungunya – lasts around a week, after which most symptoms resolve on their own. Many people continue to have symptoms after the "acute phase" resolves, termed the "post-acute phase" for symptoms lasting three weeks to three months, and the "chronic stage" for symptoms lasting longer than three months. In both cases, the lasting symptoms tend to be joint pains: arthritis , tenosynovitis , and/or bursitis . If the affected person had pre-existing joint issues, these tend to worsen. Overuse of a joint can result in painful swelling, stiffness, nerve damage, and neuropathic pain . Typically the joint pain improves with time; however, the chronic stage can last anywhere from a few months to several years. Joint pain is reported in 87–98% of cases, and nearly always occurs in more than one joint, though joint swelling is uncommon. Typically the affected joints are located in both arms and legs. Joints are more likely to be affected if they have previously been damaged by disorders such as arthritis . Pain most commonly occurs in peripheral joints, such as the wrists, ankles, and joints of the hands and feet as well as some of the larger joints, typically the shoulders, elbows and knees. Pain may also occur in the muscles or ligaments . In more than half of cases, normal activity is limited by significant fatigue and pain. Infrequently, inflammation of the eyes may occur in the form of iridocyclitis , or uveitis , and retinal lesions may occur. Temporary damage to the liver may occur. People with Chikungunya occasionally develop neurologic disorders, most frequently swelling or degeneration of the brain, inflammation or degeneration of the myelin sheaths around neurons, Guillain–Barré syndrome , acute disseminated encephalomyelitis , hypotonia (in newborns), and issues with visual processing. In particularly rare cases, people may develop behavioral changes, seizures, irritation of the cerebellum or meninges , oculomotor nerve palsy , or paralysis of the eye muscles . Newborns are susceptible to particularly severe effects of Chikungunya infection. Signs of infection typically begin with fever, rash, and swelling in the extremities. Around half of newborns have a mild case of the disease that resolves on its own; the other half have severe disease with inflammation of the brain and seizures . In severe cases, affected newborns may also have issues with bleeding and bloodflow, and problems with heart function. In addition to newborns, the elderly, and those with diabetes , heart disease , liver and kidney diseases, and human immunodeficiency virus infection tend to have more severe cases of Chikungunya. Around 1 to 5 in 1,000 people with symptomatic Chikungunya die of the disease. Chikungunya virus (CHIKV), is a member of the genus Alphavirus , and family Togaviridae . It was first isolated in 1953 in Tanzania and is an RNA virus with a positive-sense single-stranded genome of about 11.6kb. It is a member of the Semliki Forest virus complex and is closely related to Ross River virus , O'nyong'nyong virus , and Semliki Forest virus . Because it is transmitted by arthropods , namely mosquitoes, it can also be referred to as an arbovirus ( ar thropod- bo rne virus). In the United States, it is classified as a category B priority pathogen , and work requires biosafety level III precautions. Chikungunya is generally transmitted from mosquitoes to humans. Less common modes of transmission include vertical transmission , which is transmission from mother to child during pregnancy or at birth. Transmission via infected blood products and through organ donation is also theoretically possible during times of outbreak, though no cases have yet been documented. The incubation period ranges from one to twelve days, and is most typically three to seven. Chikungunya is related to mosquitoes , their environments, and human behavior. The adaptation of mosquitoes to the changing climate of North Africa around 5,000 years ago made them seek out environments where humans stored water. Human habitation and the mosquitoes' environments were then very closely connected. During periods of epidemics humans are the reservoir of the virus. Because high amounts of virus are present in the blood in the beginning of acute infection, the virus can be spread from a viremic human to a mosquito, and back to a human. During other times, monkeys, birds and other vertebrates have served as reservoirs. Three genotypes of this virus have been described, each with a distinct genotype and antigenic character: West African, East/Central/South African, and Asian genotypes. The Asian lineage originated in 1952 and has subsequently split into two lineages – India (Indian Ocean Lineage) and South East Asian clades. This virus was first reported in the Americas in 2014. Phylogenetic investigations have shown that there are two strains in Brazil – the Asian and East/Central/South African types – and that the Asian strain arrived in the Caribbean (most likely from Oceania) in about March 2013. The rate of molecular evolution was estimated to have a mean rate of 5 × 10 −4 substitutions per site per year (95% higher probability density 2.9–7.9 × 10 −4 ). Chikungunya is spread through bites from Aedes mosquitoes, and the species A. aegypti was identified as the most common vector, though the virus has recently been associated with many other species, including A. albopictus . Research by the Pasteur Institute in Paris has suggested Chikungunya virus strains in the 2005-2006 Reunion Island outbreak incurred a mutation that facilitated transmission by the Asian tiger mosquito ( A. albopictus ). Other species potentially able to transmit Chikungunya virus include Ae. furcifer-taylori , Ae. africanus , and Ae. luteocephalus . Chikungunya virus (CHIKV), is a member of the genus Alphavirus , and family Togaviridae . It was first isolated in 1953 in Tanzania and is an RNA virus with a positive-sense single-stranded genome of about 11.6kb. It is a member of the Semliki Forest virus complex and is closely related to Ross River virus , O'nyong'nyong virus , and Semliki Forest virus . Because it is transmitted by arthropods , namely mosquitoes, it can also be referred to as an arbovirus ( ar thropod- bo rne virus). In the United States, it is classified as a category B priority pathogen , and work requires biosafety level III precautions. Chikungunya is generally transmitted from mosquitoes to humans. Less common modes of transmission include vertical transmission , which is transmission from mother to child during pregnancy or at birth. Transmission via infected blood products and through organ donation is also theoretically possible during times of outbreak, though no cases have yet been documented. The incubation period ranges from one to twelve days, and is most typically three to seven. Chikungunya is related to mosquitoes , their environments, and human behavior. The adaptation of mosquitoes to the changing climate of North Africa around 5,000 years ago made them seek out environments where humans stored water. Human habitation and the mosquitoes' environments were then very closely connected. During periods of epidemics humans are the reservoir of the virus. Because high amounts of virus are present in the blood in the beginning of acute infection, the virus can be spread from a viremic human to a mosquito, and back to a human. During other times, monkeys, birds and other vertebrates have served as reservoirs. Three genotypes of this virus have been described, each with a distinct genotype and antigenic character: West African, East/Central/South African, and Asian genotypes. The Asian lineage originated in 1952 and has subsequently split into two lineages – India (Indian Ocean Lineage) and South East Asian clades. This virus was first reported in the Americas in 2014. Phylogenetic investigations have shown that there are two strains in Brazil – the Asian and East/Central/South African types – and that the Asian strain arrived in the Caribbean (most likely from Oceania) in about March 2013. The rate of molecular evolution was estimated to have a mean rate of 5 × 10 −4 substitutions per site per year (95% higher probability density 2.9–7.9 × 10 −4 ). Chikungunya is spread through bites from Aedes mosquitoes, and the species A. aegypti was identified as the most common vector, though the virus has recently been associated with many other species, including A. albopictus . Research by the Pasteur Institute in Paris has suggested Chikungunya virus strains in the 2005-2006 Reunion Island outbreak incurred a mutation that facilitated transmission by the Asian tiger mosquito ( A. albopictus ). Other species potentially able to transmit Chikungunya virus include Ae. furcifer-taylori , Ae. africanus , and Ae. luteocephalus . Chikungunya virus is passed to humans when a bite from an infected mosquito breaks the skin and introduces the virus into the body. The pathogenesis of chikungunya infection in humans is still poorly understood, despite recent outbreaks. It appears that in vitro , Chikungunya virus is able to replicate in human epithelial and endothelial cells , primary fibroblasts , and monocyte-derived macrophages . Viral replication is highly cytopathic , but susceptible to type-I and -II interferon . In vivo , in studies using living cells, chikungunya virus appears to replicate in fibroblasts, skeletal muscle progenitor cells, and myofibers. The type-1 interferon response seems to play an important role in the host's response to chikungunya infection. Upon infection with chikungunya, the host's fibroblasts produce type-1 alpha and beta interferon ( IFN-α and IFN-β ). In mouse studies, deficiencies in INF-1 in mice exposed to the virus cause increased morbidity and mortality. The chikungunya-specific upstream components of the type-1 interferon pathway involved in the host's response to chikungunya infection are still unknown. Nonetheless, mouse studies suggest that IPS-1 is an important factor, and that IRF3 and IRF7 are important in an age-dependent manner. Mouse studies also suggest that chikungunya evades host defenses and counters the type-I interferon response by producing NS2, a nonstructural protein that degrades RBP1 and turns off the host cell's ability to transcribe DNA. NS2 interferes with the JAK-STAT signaling pathway and prevents STAT from becoming phosphorylated . In the acute phase of chikungunya, the virus is typically present in the areas where symptoms present, specifically skeletal muscles, and joints . In the chronic phase, it is suggested that viral persistence (the inability of the body to entirely rid itself of the virus), lack of clearance of the antigen , or both, contribute to joint pain. The inflammation response during both the acute and chronic phase of the disease results in part from interactions between the virus and monocytes and macrophages. Chikungunya virus disease in humans is associated with elevated serum levels of specific cytokines and chemokines . High levels of specific cytokines have been linked to more severe acute disease: interleukin-6 (IL-6), IL-1β , RANTES , monocyte chemoattractant protein 1 (MCP-1), monokine induced by gamma interferon (MIG), and interferon gamma-induced protein 10 (IP-10). Cytokines may also contribute to chronic Chikungunya virus disease, as persistent joint pain has been associated with elevated levels of IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF). In those with chronic symptoms, a mild elevation of C-reactive protein (CRP) has been observed, suggesting ongoing chronic inflammation. However, there is little evidence linking chronic Chikungunya virus disease and the development of autoimmunity . [ citation needed ] The virus consists of four nonstructural proteins and three structural proteins. The structural proteins are the capsid and two envelope glycoproteins: E1 and E2, which form heterodimeric spikes on the viron surface. E2 binds to cellular receptors in order to enter the host cell through receptor-mediated endocytosis . E1 contains a fusion peptide which, when exposed to the acidity of the endosome in eukaryotic cells , dissociates from E2 and initiates membrane fusion that allows the release of nucleocapsids into the host cytoplasm, promoting infection. The mature virion contains 240 heterodimeric spikes of E2/E1, which after release, bud on the surface of the infected cell, where they are released by exocytosis to infect other cells. The virus consists of four nonstructural proteins and three structural proteins. The structural proteins are the capsid and two envelope glycoproteins: E1 and E2, which form heterodimeric spikes on the viron surface. E2 binds to cellular receptors in order to enter the host cell through receptor-mediated endocytosis . E1 contains a fusion peptide which, when exposed to the acidity of the endosome in eukaryotic cells , dissociates from E2 and initiates membrane fusion that allows the release of nucleocapsids into the host cytoplasm, promoting infection. The mature virion contains 240 heterodimeric spikes of E2/E1, which after release, bud on the surface of the infected cell, where they are released by exocytosis to infect other cells. Chikungunya is diagnosed on the basis of clinical, epidemiological, and laboratory criteria. Clinically, acute onset of high fever and severe joint pain would lead to suspicion of chikungunya. Epidemiological criteria consist of whether the individual has traveled to or spent time in an area in which chikungunya is present within the last twelve days (i.e.) the potential incubation period). Laboratory criteria include a decreased lymphocyte count consistent with viremia . However a definitive laboratory diagnosis can be accomplished through viral isolation, RT-PCR, or serological diagnosis. The differential diagnosis may include other mosquito-borne diseases , such as dengue or malaria , or other infections such as influenza . Chronic recurrent polyarthralgia occurs in at least 20% of chikungunya patients one year after infection, whereas such symptoms are uncommon in dengue. Virus isolation provides the most definitive diagnosis, but takes one to two weeks for completion and must be carried out in biosafety level III laboratories . The technique involves exposing specific cell lines to samples from whole blood and identifying Chikungunya virus -specific responses. RT-PCR using nested primer pairs is used to amplify several chikungunya-specific genes from whole blood, generating thousands to millions of copies of the genes in order to identify them. RT-PCR can also be used to quantify the viral load in the blood. Using RT-PCR, diagnostic results can be available in one to two days. Serological diagnosis requires a larger amount of blood than the other methods, and uses an ELISA assay to measure chikungunya-specific IgM levels in the blood serum. One advantage offered by serological diagnosis is that serum IgM is detectable from 5 days to months after the onset of symptoms, but drawbacks are that results may require two to three days, and false positives can occur with infection due to other related viruses, such as o'nyong'nyong virus and Semliki Forest virus . Presently, there is no specific way to test for chronic signs and symptoms associated with Chikungunya fever although nonspecific laboratory findings such as C reactive protein and elevated cytokines can correlate with disease activity. Because no approved vaccine exists, the most effective means of prevention are protection against contact with the disease-carrying mosquitoes and controlling mosquito populations by limiting their habitat . Mosquito control focuses on eliminating the standing water where mosquitos lay eggs and develop as larva; if elimination of the standing water is not possible, insecticides or biological control agents can be added. Methods of protection against contact with mosquitos include using insect repellents with substances such as DEET , icaridin , PMD ( p-menthane-3,8-diol , a substance derived from the lemon eucalyptus tree), or ethyl butylacetylaminopropionate (IR3535). However, increasing insecticide resistance presents a challenge to chemical control methods. [ citation needed ] Wearing bite-proof long sleeves and trousers also offers protection, and garments can be treated with pyrethroids , a class of insecticides that often has repellent properties. Vaporized pyrethroids (for example in mosquito coils) are also insect repellents. As infected mosquitoes often feed and rest inside homes, securing screens on windows and doors will help to keep mosquitoes out of the house. In the case of the day-active A. aegypti and A. albopictus , however, this will have only a limited effect, since many contacts between the mosquitoes and humans occur outdoors. [ citation needed ] A Chikungunya vaccine is a vaccine intended to provide acquired immunity against the chikungunya virus . The most commonly reported side effects include headache, fatigue, muscle pain, joint pain, fever, nausea and tenderness at the injection site. A Chikungunya vaccine is a vaccine intended to provide acquired immunity against the chikungunya virus . The most commonly reported side effects include headache, fatigue, muscle pain, joint pain, fever, nausea and tenderness at the injection site. Currently, no specific treatment for chikungunya is available. Supportive care is recommended, and symptomatic treatment of fever and joint swelling includes the use of nonsteroidal anti-inflammatory drugs such as naproxen , non-aspirin analgesics such as paracetamol (acetaminophen) and fluids. Aspirin is not recommended due to the increased risk of bleeding. Despite anti-inflammatory effects, corticosteroids are not recommended during the acute phase of disease, as they may cause immunosuppression and worsen infection. Passive immunotherapy has potential benefit in treatment of chikungunya. Studies in animals using passive immunotherapy have been effective, and clinical studies using passive immunotherapy in those particularly vulnerable to severe infection are currently in progress. Passive immunotherapy involves administration of anti-CHIKV hyperimmune human intravenous antibodies (immunoglobulins) to those exposed to a high risk of chikungunya infection. No antiviral treatment for Chikungunya virus is currently available, though testing has shown several medications to be effective in vitro . In those who have more than two weeks of arthritis, ribavirin may be useful. The effect of chloroquine is not clear. It does not appear to help acute disease, but tentative evidence indicates it might help those with chronic arthritis. Steroids do not appear to be an effective treatment. NSAIDs and simple analgesics can be used to provide partial symptom relief in most cases. Methotrexate , a drug used in the treatment of rheumatoid arthritis , has been shown to have benefit in treating inflammatory polyarthritis resulting from chikungunya, though the drug mechanism for improving viral arthritis is unclear. In those who have more than two weeks of arthritis, ribavirin may be useful. The effect of chloroquine is not clear. It does not appear to help acute disease, but tentative evidence indicates it might help those with chronic arthritis. Steroids do not appear to be an effective treatment. NSAIDs and simple analgesics can be used to provide partial symptom relief in most cases. Methotrexate , a drug used in the treatment of rheumatoid arthritis , has been shown to have benefit in treating inflammatory polyarthritis resulting from chikungunya, though the drug mechanism for improving viral arthritis is unclear. The mortality rate of chikungunya is slightly less than 1 in 1000. Those over the age of 65, neonates, and those with underlying chronic medical problems are most likely to have severe complications. Neonates are vulnerable as it is possible to vertically transmit chikungunya from mother to infant during delivery, which results in high rates of morbidity, as infants lack fully developed immune systems . The likelihood of prolonged symptoms or chronic joint pain is increased with increased age and prior rheumatological disease. Historically, chikungunya has been present mostly in the developing world . The disease causes an estimated 3 million infections each year. Epidemics in the Indian Ocean, Pacific Islands, and in the Americas, continue to change the distribution of the disease. In Africa, chikungunya is spread by a sylvatic cycle in which the virus largely cycles between other non-human primates , small mammals, and mosquitos between human outbreaks. During outbreaks, due to the high concentration of virus in the blood of those in the acute phase of infection, the virus can circulate from humans to mosquitoes and back to humans. The transmission of the pathogen between humans and mosquitoes that exist in urban environments was established on multiple occasions from strains occurring on the eastern half of Africa in non-human primate hosts. This emergence and spread beyond Africa may have started as early as the 18th century. Currently, available data does not indicate whether the introduction of chikungunya into Asia occurred in the 19th century or more recently, but this epidemic Asian strain causes outbreaks in India and continues to circulate in Southeast Asia. In Africa, outbreaks were typically tied to heavy rainfall causing increased mosquito population. In recent outbreaks in urban centers, the virus has spread by circulating between humans and mosquitoes. Global rates of chikungunya infection are variable, depending on outbreaks. When chikungunya was first identified in 1952, it had a low-level circulation in West Africa, with infection rates linked to rainfall. Beginning in the 1960s, periodic outbreaks were documented in Asia and Africa. However, since 2005, following several decades of relative inactivity, chikungunya has re-emerged and caused large outbreaks in Africa, Asia, and the Americas. In India, for instance, chikungunya re-appeared following 32 years of absence of viral activity. Outbreaks have occurred in Europe, the Caribbean, and South America, areas in which chikungunya was not previously transmitted. Local transmission has also occurred in the United States and Australia, countries in which the virus was previously unknown. In 2005, an outbreak on the island of Réunion was the largest then documented, with an estimated 266,000 cases on an island with a population of approximately 770,000. In a 2006 outbreak, India reported 1.25 million suspected cases. Chikungunya was introduced to the Americas in 2013, first detected on the French island of Saint Martin , and for the next two years in the Americas, 1,118,763 suspected cases and 24,682 confirmed cases were reported by the PAHO . An analysis of the genetic code of Chikungunya virus suggests that the increased severity of the 2005–present outbreak may be due to a change in the genetic sequence which altered the E1 segment of the virus' viral coat protein, a variant called E1-A226V. This mutation potentially allows the virus to multiply more easily in mosquito cells. The change allows the virus to use the Asian tiger mosquito (an invasive species ) as a vector in addition to the more strictly tropical main vector, Aedes aegypti . Enhanced transmission of Chikungunya virus by A. albopictus could mean an increased risk for outbreaks in other areas where the Asian tiger mosquito is present. A albopictus is an invasive species which has spread through Europe, the Americas, the Caribbean, Africa and the Middle East. [ citation needed ] After the detection of zika virus in Brazil in April 2015, the first ever in the Western Hemisphere, it is now thought some chikungunya and dengue cases could in fact be zika virus cases or coinfections .The disease was first described by Marion Robinson and W.H.R. Lumsden in a pair of 1955 papers, following an outbreak in 1952 on the Makonde Plateau , along the border between Mozambique and Tanganyika (the mainland part of modern-day Tanzania ). Since then outbreaks have occurred occasionally in Africa, South Asia, and Southeast Asia; recent outbreaks have spread the disease over a wider range. [ citation needed ] The first recorded outbreak may have been in 1779. This is in agreement with the molecular genetics evidence that suggests it evolved around the year 1700. According to the original paper by Lumsden, the term 'chikungunya' is derived from the Makonde root verb kungunyala , meaning to dry up or become contorted. In concurrent research, Robinson [ citation needed ] glossed the Makonde term more specifically as "that which bends up". It is understood to refer to the contorted posture of people affected with the severe joint pain and arthritic symptoms associated with this disease. Subsequent authors apparently overlooked the references to the Makonde language and assumed the term to have been derived from Swahili , the lingua franca of the region. The erroneous attribution to Swahili has been repeated in numerous print sources. Erroneous spellings of the name of the disease are also in common use. [ citation needed ]Chikungunya is one of more than a dozen agents researched as a potential biological weapon . This disease is part of the group of neglected tropical diseases .

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Acute hemorrhagic fever syndrome

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Orthohantavirus

Hantavirus Orthohantavirus is a genus of single-stranded, enveloped, negative-sense RNA viruses in the family Hantaviridae within the order Bunyavirales . Members of this genus may be called orthohantaviruses or simply hantaviruses . Orthohantaviruses typically cause chronic asymptomatic infection in rodents . Humans may become infected with hantaviruses through contact with rodent urine, saliva, or feces. Some strains cause potentially fatal diseases in humans, such as hantavirus hemorrhagic fever with renal syndrome (HFRS), or hantavirus pulmonary syndrome (HPS), also known as hantavirus cardiopulmonary syndrome (HCPS), while others have not been associated with known human disease (e.g. Prospect Hill virus ). HPS (HCPS) is a "rare respiratory illness associated with the inhalation of aerosolized rodent excreta (urine and feces) contaminated by hantavirus particles". Human infections of hantaviruses have almost entirely been linked to human contact with rodent excrement; however, in 2005 and 2019, human-to-human transmission of the Andes virus was reported in South America. Orthohantaviruses are named for the Greek word ortho - meaning "straight" or "true" and for the Hantan River in South Korea , where the first member species ( Hantaan virus ) was identified and isolated in 1976 by Ho Wang Lee . Hantavirus infections in humans are associated with two diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), caused by Old World and New World hantaviruses, respectively. A common feature of the two diseases is increased vascular permeability, which causes hypotension , thrombocytopenia , and leukocytosis . The pulmonary illness is the more fatal of the two, whereas the hemorrhagic fever is much more common. Treatment for both is primarily supportive as there is no specific treatment for hantavirus infections. While many hantaviruses cause either of the two diseases, some are not known to cause illness, such as the Prospect Hill orthohantavirus . Hemorrhagic fever with renal syndrome (HFRS) is caused chiefly by hantaviruses in Asia and Europe. Clinical presentation varies from subclinical to fatal, depending on the virus. After an incubation period of 2–4 weeks, the typical illness starts with non-specific symptoms such as high fever, chills, headache, backache, abdominal pains, nausea, and vomiting. After the initial period, bleeding under the skin begins, often paired with low blood pressure, followed by further internal bleeding throughout the body. Renal dysfunction leading to further health issues begins thereafter, which may cause death. A more mild form of HFRS that occurs in Europe is called "nephropathia epidemica" (NE). Trench nephritis during World War I is now thought to have been HFRS. [ citation needed ] Hantavirus pulmonary syndrome (HPS), also called hantavirus cardiopulmonary syndrome (HCPS), is usually caused by hantaviruses in the Americas. Its incubation period ranges from 16 to 24 days. Illness initially shows similar symptoms as HFRS. After a few days of non-specific symptoms, sudden onset of progressive, or productive, coughing, shortness of breath, and elevated heart rate occur due to fluid buildup in the lungs . These symptoms are accompanied by impairment of lymphoid organs . Death from cardiovascular shock may occur rapidly after the appearance of severe symptoms. While HCPS is typically associated with New World hantaviruses, the Puumala orthohantavirus in Europe has also caused the syndrome on rare occasions. Hantaviruses are transmitted by contact with the bodily fluids of rodents, particularly from saliva from bites and especially from inhalation of viral particles from urine and feces in aerosols . The manner of transmission is the same for both diseases caused by hantaviruses. Among the HCPS-causing hantaviruses is the Andes orthohantavirus , which is the only hantavirus confirmed to be capable of spreading from person to person, though this is rare. Hemorrhagic fever with renal syndrome (HFRS) is caused chiefly by hantaviruses in Asia and Europe. Clinical presentation varies from subclinical to fatal, depending on the virus. After an incubation period of 2–4 weeks, the typical illness starts with non-specific symptoms such as high fever, chills, headache, backache, abdominal pains, nausea, and vomiting. After the initial period, bleeding under the skin begins, often paired with low blood pressure, followed by further internal bleeding throughout the body. Renal dysfunction leading to further health issues begins thereafter, which may cause death. A more mild form of HFRS that occurs in Europe is called "nephropathia epidemica" (NE). Trench nephritis during World War I is now thought to have been HFRS. [ citation needed ]Hantavirus pulmonary syndrome (HPS), also called hantavirus cardiopulmonary syndrome (HCPS), is usually caused by hantaviruses in the Americas. Its incubation period ranges from 16 to 24 days. Illness initially shows similar symptoms as HFRS. After a few days of non-specific symptoms, sudden onset of progressive, or productive, coughing, shortness of breath, and elevated heart rate occur due to fluid buildup in the lungs . These symptoms are accompanied by impairment of lymphoid organs . Death from cardiovascular shock may occur rapidly after the appearance of severe symptoms. While HCPS is typically associated with New World hantaviruses, the Puumala orthohantavirus in Europe has also caused the syndrome on rare occasions. Hantaviruses are transmitted by contact with the bodily fluids of rodents, particularly from saliva from bites and especially from inhalation of viral particles from urine and feces in aerosols . The manner of transmission is the same for both diseases caused by hantaviruses. Among the HCPS-causing hantaviruses is the Andes orthohantavirus , which is the only hantavirus confirmed to be capable of spreading from person to person, though this is rare. Hantavirus virions are about 80–120 nm in diameter. The lipid bilayer of the viral envelope is about 5 nm thick and is embedded with viral surface proteins to which sugar residues are attached. These glycoproteins, known as Gn and Gc, are encoded by the M segment of the viral genome. They tend to associate ( heterodimerize ) with each other and have both an interior tail and an exterior domain that extends to about 6 nm beyond the envelope surface. [ citation needed ] Inside the envelope are the nucleocapsids. These are composed of many copies of the nucleocapsid protein N, which interact with the three segments of the viral genome to form helical structures. The virally encoded RNA polymerase is also found in the interior. By mass, the virion is greater than 50% protein, 20–30% lipid, and 2–7% carbohydrate. The density of the virions is 1.18 g/cm 3 . These features are common to all members of the family Hantaviridae . [ citation needed ] The genome of hantaviruses is negative-sense, single-stranded RNA . Their genomes are composed of three segments: the small (S), medium (M), and large (L) segments. The S segment, 1–3 kilobases (kb) in length, encodes for the nucleocapsid (N) protein. The M segment, 3.2–4.9 kb in length, encodes a glycoprotein precursor polyprotein that is co-translationally cleaved into the envelope glycoproteins Gn and Gc, alternatively called G1 and G2. The L segment, 6.8–12 kb in length, encodes the L protein which functions primarily as the viral RNA-dependent RNA polymerase used for transcription and replication. Within virions , the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, the RNA component of which circularizes due to sequence complementarity between the 5′ and 3′ terminal sequences of genomic segments. [ citation needed ] As with other Bunyavirales , each of the three segments has a consensus 3′-terminal nucleotide sequence (AUCAUCAUC), which is complementary to the 5′-terminal sequence and is distinct from those of the other four genera in the family. These sequences appear to form panhandle structure which seem likely to play a role in replication and encapsidation facilitated by binding with the viral nucleocapsid (N) protein. The large segment is 6530–6550 nucleotides (nt) in length, the medium is 3613–3707 nt in length and the small is 1696–2083 nt in length. [ citation needed ] No nonstructural proteins are known, unlike the other genera in this family. At the 5′ and 3′ of each segment are short noncoding sequences: the noncoding segment in all sequences at the 5′ end is 37–51 nt. The 3′ noncoding regions differ: L segment 38–43 nt; M segment 168–229 nt; and S segment 370–730 nt. The 3′ end of the S segment is conserved between the genera suggesting a functional role. [ citation needed ] Viral entry into host cells initiates by binding to surface cell receptors. Integrins are considered to be the main receptors for hantaviruses in vitro , but complement decay-accelerating factor (DAF) and globular heads of complement C1q receptor (gC1qR) have mediated attachment in cultured cells too. Entry may proceed through a number of possible routes, including clathrin -dependent endocytosis , clathrin-independent receptor-mediated endocytosis, and micro pinocytosis . Viral particles are then transported to late endosomes . Gc-mediated membrane fusion with the endosomal membrane , triggered by low pH , releases the nucleocapsid into the cytoplasm . After the release of the nucleocapsids into cytoplasm, the complexes are targeted to the endoplasmic reticulum–Golgi intermediate compartments (ERGIC) through microtubular -associated movement resulting in the formation of viral factories at ERGIC. [ citation needed ] These factories then facilitate transcription and subsequent translation of the viral proteins. Transcription of viral genes must be initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this cap snatching , the mRNAs of hantaviruses are capped and contain nontemplated 5′-terminal extensions. The G1 (or Gn) and G2 (Gc) glycoproteins form hetero-oligomers and are then transported from the endoplasmic reticulum to the Golgi complex , where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirus virions are believed to assemble by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae . Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis . [ citation needed ] The pathogenesis of hantavirus infections is unclear as there is a lack of animal models to describe it (rats and mice do not seem to acquire severe disease). While the primary site of viral replication in the body is not known, in HFRS the main effect is in the blood vessels while in HPS most symptoms are associated with the lungs. In HFRS, there are increased vascular permeability and decreased blood pressure due to endothelial dysfunction and the most dramatic damage is seen in the kidneys, whereas in HPS, the lungs, spleen, and gall bladder are most affected. Early symptoms of HPS tend to present similarly to the flu (muscle aches, fever and fatigue) and usually appear around 2 to 3 weeks after exposure. Later stages of the disease (about 4 to 10 days after symptoms start) include difficulty breathing, shortness of breath and coughing. Findings of significant congruence between phylogenies of hantaviruses and phylogenies of their rodent reservoirs have led to the theory that rodents, although infected by the virus, are not harmed by it because of long-standing hantavirus–rodent host coevolution , although findings in 2008 led to new hypotheses regarding hantavirus evolution. Various hantaviruses have been found to infect multiple rodent species, and cases of cross-species transmission ( host switching ) have been recorded. Additionally, rates of substitution based on nucleotide sequence data reveal that hantavirus clades and rodent subfamilies may not have diverged at the same time. Furthermore, as of 2007 hantaviruses have been found in multiple species of non-rodent shrews and moles. Taking into account the inconsistencies in the theory of coevolution, it was proposed in 2009 that the patterns seen in hantaviruses in relation to their reservoirs could be attributed to preferential host switching directed by geographical proximity and adaptation to specific host types. Another proposal from 2010 is that geographical clustering of hantavirus sequences may have been caused by an isolation-by-distance mechanism. Upon comparison of the hantaviruses found in hosts of orders Rodentia and Eulipotyphla , it was proposed in 2011 that the hantavirus evolutionary history is a mix of both host switching and codivergence and that ancestral shrews or moles, rather than rodents, may have been the early original hosts of ancient hantaviruses. A Bayesian analysis in 2014 suggested a common origin for these viruses ~2000 years ago. The association with particular rodent families appears to have been more recent. The viruses carried by the subfamilies Arvicolinae and Murinae originated in Asia 500–700 years ago. These subsequently spread to Africa , Europe , North America and Siberia possibly carried by their hosts. The species infecting the subfamily Neotominae evolved 500–600 years ago in Central America and then spread toward North America. The species infecting Sigmodontinae evolved in Brazil 400 years ago. Their ancestors may have been a Neotominae-associated virus from northern South America. The evolution of shrew -borne hantaviruses appears to have involved natural occurrences of homologous recombination events and the reassortment of genome segments. The evolution of Tula orthohantavirus carried by the European common vole also appears to have involved homologous recombination events. Hantavirus virions are about 80–120 nm in diameter. The lipid bilayer of the viral envelope is about 5 nm thick and is embedded with viral surface proteins to which sugar residues are attached. These glycoproteins, known as Gn and Gc, are encoded by the M segment of the viral genome. They tend to associate ( heterodimerize ) with each other and have both an interior tail and an exterior domain that extends to about 6 nm beyond the envelope surface. [ citation needed ] Inside the envelope are the nucleocapsids. These are composed of many copies of the nucleocapsid protein N, which interact with the three segments of the viral genome to form helical structures. The virally encoded RNA polymerase is also found in the interior. By mass, the virion is greater than 50% protein, 20–30% lipid, and 2–7% carbohydrate. The density of the virions is 1.18 g/cm 3 . These features are common to all members of the family Hantaviridae . [ citation needed ]The genome of hantaviruses is negative-sense, single-stranded RNA . Their genomes are composed of three segments: the small (S), medium (M), and large (L) segments. The S segment, 1–3 kilobases (kb) in length, encodes for the nucleocapsid (N) protein. The M segment, 3.2–4.9 kb in length, encodes a glycoprotein precursor polyprotein that is co-translationally cleaved into the envelope glycoproteins Gn and Gc, alternatively called G1 and G2. The L segment, 6.8–12 kb in length, encodes the L protein which functions primarily as the viral RNA-dependent RNA polymerase used for transcription and replication. Within virions , the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, the RNA component of which circularizes due to sequence complementarity between the 5′ and 3′ terminal sequences of genomic segments. [ citation needed ] As with other Bunyavirales , each of the three segments has a consensus 3′-terminal nucleotide sequence (AUCAUCAUC), which is complementary to the 5′-terminal sequence and is distinct from those of the other four genera in the family. These sequences appear to form panhandle structure which seem likely to play a role in replication and encapsidation facilitated by binding with the viral nucleocapsid (N) protein. The large segment is 6530–6550 nucleotides (nt) in length, the medium is 3613–3707 nt in length and the small is 1696–2083 nt in length. [ citation needed ] No nonstructural proteins are known, unlike the other genera in this family. At the 5′ and 3′ of each segment are short noncoding sequences: the noncoding segment in all sequences at the 5′ end is 37–51 nt. The 3′ noncoding regions differ: L segment 38–43 nt; M segment 168–229 nt; and S segment 370–730 nt. The 3′ end of the S segment is conserved between the genera suggesting a functional role. [ citation needed ]Viral entry into host cells initiates by binding to surface cell receptors. Integrins are considered to be the main receptors for hantaviruses in vitro , but complement decay-accelerating factor (DAF) and globular heads of complement C1q receptor (gC1qR) have mediated attachment in cultured cells too. Entry may proceed through a number of possible routes, including clathrin -dependent endocytosis , clathrin-independent receptor-mediated endocytosis, and micro pinocytosis . Viral particles are then transported to late endosomes . Gc-mediated membrane fusion with the endosomal membrane , triggered by low pH , releases the nucleocapsid into the cytoplasm . After the release of the nucleocapsids into cytoplasm, the complexes are targeted to the endoplasmic reticulum–Golgi intermediate compartments (ERGIC) through microtubular -associated movement resulting in the formation of viral factories at ERGIC. [ citation needed ] These factories then facilitate transcription and subsequent translation of the viral proteins. Transcription of viral genes must be initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this cap snatching , the mRNAs of hantaviruses are capped and contain nontemplated 5′-terminal extensions. The G1 (or Gn) and G2 (Gc) glycoproteins form hetero-oligomers and are then transported from the endoplasmic reticulum to the Golgi complex , where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirus virions are believed to assemble by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae . Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis . [ citation needed ]The pathogenesis of hantavirus infections is unclear as there is a lack of animal models to describe it (rats and mice do not seem to acquire severe disease). While the primary site of viral replication in the body is not known, in HFRS the main effect is in the blood vessels while in HPS most symptoms are associated with the lungs. In HFRS, there are increased vascular permeability and decreased blood pressure due to endothelial dysfunction and the most dramatic damage is seen in the kidneys, whereas in HPS, the lungs, spleen, and gall bladder are most affected. Early symptoms of HPS tend to present similarly to the flu (muscle aches, fever and fatigue) and usually appear around 2 to 3 weeks after exposure. Later stages of the disease (about 4 to 10 days after symptoms start) include difficulty breathing, shortness of breath and coughing. Findings of significant congruence between phylogenies of hantaviruses and phylogenies of their rodent reservoirs have led to the theory that rodents, although infected by the virus, are not harmed by it because of long-standing hantavirus–rodent host coevolution , although findings in 2008 led to new hypotheses regarding hantavirus evolution. Various hantaviruses have been found to infect multiple rodent species, and cases of cross-species transmission ( host switching ) have been recorded. Additionally, rates of substitution based on nucleotide sequence data reveal that hantavirus clades and rodent subfamilies may not have diverged at the same time. Furthermore, as of 2007 hantaviruses have been found in multiple species of non-rodent shrews and moles. Taking into account the inconsistencies in the theory of coevolution, it was proposed in 2009 that the patterns seen in hantaviruses in relation to their reservoirs could be attributed to preferential host switching directed by geographical proximity and adaptation to specific host types. Another proposal from 2010 is that geographical clustering of hantavirus sequences may have been caused by an isolation-by-distance mechanism. Upon comparison of the hantaviruses found in hosts of orders Rodentia and Eulipotyphla , it was proposed in 2011 that the hantavirus evolutionary history is a mix of both host switching and codivergence and that ancestral shrews or moles, rather than rodents, may have been the early original hosts of ancient hantaviruses. A Bayesian analysis in 2014 suggested a common origin for these viruses ~2000 years ago. The association with particular rodent families appears to have been more recent. The viruses carried by the subfamilies Arvicolinae and Murinae originated in Asia 500–700 years ago. These subsequently spread to Africa , Europe , North America and Siberia possibly carried by their hosts. The species infecting the subfamily Neotominae evolved 500–600 years ago in Central America and then spread toward North America. The species infecting Sigmodontinae evolved in Brazil 400 years ago. Their ancestors may have been a Neotominae-associated virus from northern South America. The evolution of shrew -borne hantaviruses appears to have involved natural occurrences of homologous recombination events and the reassortment of genome segments. The evolution of Tula orthohantavirus carried by the European common vole also appears to have involved homologous recombination events. Orthohantaviruses belong to the family Hantaviridae and members of both the genus and the family are called hantaviruses. The genus also belongs to the subfamily Mammantavirinae , the mammalian hantaviruses, with three other genera. Orthohantaviruses specifically are mammalian hantaviruses that are transmitted among rodents. The genus contains these 38 species: Hantaviruses that were formerly classified as species in this genus and which were not reassigned as member viruses of any existing species include: Isla Vista hantavirus , also called Isla Vista virus Muleshoe hantavirus , also called Muleshoe virus Rio Segundo hantavirus , also called Rio Segundo virusAccording to the U.S. CDC, the best prevention against contracting hantavirus is to eliminate or minimize contact with rodents in the home, workplace, or campsite. As the virus can be transmitted by rodent saliva, excretions, and bites, control of rats and mice in areas frequented by humans is key for disease prevention. General prevention can be accomplished by disposing of rodent nests, sealing any cracks and holes in homes where mice or rats could enter, setting traps, or laying down poisons or using natural predators such as cats in the home. The duration that hantaviruses remain infectious in the environment varies based on factors such as the rodent's diet, temperature, humidity, and whether indoors or outdoors. The viruses have been demonstrated to remain active for 2–3 days at normal room temperature, while ultraviolet rays in direct sunlight kill them within a few hours. Rodent droppings or urine of indeterminate age, though, should always be treated as infectious. As of 2021 [ update ] , no vaccines against hantaviruses have been approved by the U.S. FDA, but whole virus inactivated bivalent vaccines against Hantaan virus and Seoul virus are available in China and South Korea. In both countries, the use of the vaccine, combined with other preventive measures, has significantly reduced the incidence of hantavirus infections. Apart from these vaccines, four types of vaccines have been researched: DNA vaccines targeting the M genome segment and the S genome segment, subunit vaccines that use recombinant Gn, Gc, and N proteins of the virus, virus vector vaccines that have recombinant hantavirus proteins inserted in them, and virus-like particle vaccines that contain viral proteins, but lack genetic material. Of these, only DNA vaccines have entered into clinical trials. As of 2021 [ update ] , no vaccines against hantaviruses have been approved by the U.S. FDA, but whole virus inactivated bivalent vaccines against Hantaan virus and Seoul virus are available in China and South Korea. In both countries, the use of the vaccine, combined with other preventive measures, has significantly reduced the incidence of hantavirus infections. Apart from these vaccines, four types of vaccines have been researched: DNA vaccines targeting the M genome segment and the S genome segment, subunit vaccines that use recombinant Gn, Gc, and N proteins of the virus, virus vector vaccines that have recombinant hantavirus proteins inserted in them, and virus-like particle vaccines that contain viral proteins, but lack genetic material. Of these, only DNA vaccines have entered into clinical trials. Ribavirin may be a drug for HPS and HFRS, but its effectiveness remains unknown; still, spontaneous recovery is possible with supportive treatment. People with suspected hantavirus infection may be admitted to a hospital, and given oxygen and mechanical ventilation support to help them breathe during the acute pulmonary stage with severe respiratory distress. Immunotherapy, administration of human neutralizing antibodies during acute phases of hantavirus, has been studied only in mice, hamsters, and rats. No controlled clinical trials have been reported. Hantavirus infections have been reported from all continents except Australia. Regions especially affected by HFRS include China , the Korean Peninsula , Russia (Hantaan, Puumala, and Seoul viruses), and Northern and Western Europe ( Puumala and Dobrava virus). Regions with the highest incidences of hantavirus pulmonary syndrome include Argentina , Chile , Brazil , the United States , Canada , and Panama . [ citation needed ] In 2010, a novel hantavirus, Sangassou virus , was isolated in Africa, which causes HFRS. In China, Hong Kong, the Korean Peninsula, and Russia, HFRS is caused by Hantaan, Puumala, and Seoul viruses. In March 2020, a man from Yunnan tested positive for hantavirus. He died while travelling to Shandong for work on a chartered bus. According to the Global Times reports, around 32 other people have been tested for the virus. As of 2005 [ update ] , no human infections have been reported in Australia, though rodents were found to carry antibodies. In Europe, two hantaviruses – Puumala and Dobrava-Belgrade viruses – are known to cause HFRS. Puumala usually causes a generally mild disease, nephropathia epidemica , which typically presents with fever, headache, gastrointestinal symptoms, impaired renal function, and blurred vision. Dobrava infections are similar, except that they often also have hemorrhagic complications. [ citation needed ] Puumala virus is carried by its rodent host, the bank vole ( Clethrionomys glareolus ), and is present throughout most of Europe, except for the Mediterranean region. Four Dobrava virus genotypes are known, each carried by a different rodent species. Genotype Dobrava is found in the yellow-necked mouse ( Apodemus flavicollis ), genotypes Saaremaa and Kurkino in the striped field mouse ( Apodemus agrarius ), and genotype Sochi in the Black Sea field mouse ( Apodemus ponticus ). [ citation needed ] In 2017 alone, the Robert Koch Institute (RKI) in Germany received 1,713 notifications of hantavirus infections. The primary cause of the disease in Canada is Sin Nombre virus-infected deer mice. Between 1989 and 2014, 109 confirmed cases were reported, with the death rate estimated at 29%. The virus exists in deer mice nationwide, but cases were concentrated in western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) with only one case in eastern Canada. In Canada, "[a]ll cases occurred in rural settings and approximately 70% of the cases have been associated with domestic and farming activities." In the United States, minor cases of HPS include Sin Nombre orthohantavirus , New York orthohantavirus , Bayou orthohantavirus , and possibly Black Creek Canal orthohantavirus . [ citation needed ] As of January 2017 [ update ] , 728 cases of hantavirus had been reported in the United States cumulatively since 1995, across 36 states, not including cases with presumed exposure outside the United States. More than 96% of cases have occurred in states west of the Mississippi River . The top 10 states by number of cases reported (which differs slightly from a count ordered by the state of original exposure ) were New Mexico (109), Colorado (104), Arizona (78), California (61), Washington (50), Texas (45), Montana (43), Utah (38), Idaho (21), and Oregon (21); 36% of the total reported cases have resulted in death. In Mexico, rodents have been found to carry hantaviruses include Thomas's giant deer mouse (Megadontomys thomasi) , the pack rat Neotoma picta , Orizaba deer mouse (Peromyscus beatae) , Western harvest mouse (Reithrodontomys megalotis) and Sumichrast's harvest mouse (Reithrodontomys sumichrasti) . Agents of HPS found in South America include the Andes virus (also called Oran, Castelo de Sonhos – Portuguese for "Castle of Dreams", Lechiguanas, Juquitiba, Araraquara, and Bermejo virus, among many other synonyms), which is the only hantavirus that has shown an interpersonal form of transmission, and the Laguna Negra virus , an extremely close relative of the previously known Rio Mamore virus. [ citation needed ] Rodents that have been shown to carry hantaviruses include Abrothrix longipilis and Oligoryzomys longicaudatus . In 2010, a novel hantavirus, Sangassou virus , was isolated in Africa, which causes HFRS. In China, Hong Kong, the Korean Peninsula, and Russia, HFRS is caused by Hantaan, Puumala, and Seoul viruses. In March 2020, a man from Yunnan tested positive for hantavirus. He died while travelling to Shandong for work on a chartered bus. According to the Global Times reports, around 32 other people have been tested for the virus. In March 2020, a man from Yunnan tested positive for hantavirus. He died while travelling to Shandong for work on a chartered bus. According to the Global Times reports, around 32 other people have been tested for the virus. As of 2005 [ update ] , no human infections have been reported in Australia, though rodents were found to carry antibodies. In Europe, two hantaviruses – Puumala and Dobrava-Belgrade viruses – are known to cause HFRS. Puumala usually causes a generally mild disease, nephropathia epidemica , which typically presents with fever, headache, gastrointestinal symptoms, impaired renal function, and blurred vision. Dobrava infections are similar, except that they often also have hemorrhagic complications. [ citation needed ] Puumala virus is carried by its rodent host, the bank vole ( Clethrionomys glareolus ), and is present throughout most of Europe, except for the Mediterranean region. Four Dobrava virus genotypes are known, each carried by a different rodent species. Genotype Dobrava is found in the yellow-necked mouse ( Apodemus flavicollis ), genotypes Saaremaa and Kurkino in the striped field mouse ( Apodemus agrarius ), and genotype Sochi in the Black Sea field mouse ( Apodemus ponticus ). [ citation needed ] In 2017 alone, the Robert Koch Institute (RKI) in Germany received 1,713 notifications of hantavirus infections. The primary cause of the disease in Canada is Sin Nombre virus-infected deer mice. Between 1989 and 2014, 109 confirmed cases were reported, with the death rate estimated at 29%. The virus exists in deer mice nationwide, but cases were concentrated in western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) with only one case in eastern Canada. In Canada, "[a]ll cases occurred in rural settings and approximately 70% of the cases have been associated with domestic and farming activities." In the United States, minor cases of HPS include Sin Nombre orthohantavirus , New York orthohantavirus , Bayou orthohantavirus , and possibly Black Creek Canal orthohantavirus . [ citation needed ] As of January 2017 [ update ] , 728 cases of hantavirus had been reported in the United States cumulatively since 1995, across 36 states, not including cases with presumed exposure outside the United States. More than 96% of cases have occurred in states west of the Mississippi River . The top 10 states by number of cases reported (which differs slightly from a count ordered by the state of original exposure ) were New Mexico (109), Colorado (104), Arizona (78), California (61), Washington (50), Texas (45), Montana (43), Utah (38), Idaho (21), and Oregon (21); 36% of the total reported cases have resulted in death. In Mexico, rodents have been found to carry hantaviruses include Thomas's giant deer mouse (Megadontomys thomasi) , the pack rat Neotoma picta , Orizaba deer mouse (Peromyscus beatae) , Western harvest mouse (Reithrodontomys megalotis) and Sumichrast's harvest mouse (Reithrodontomys sumichrasti) . The primary cause of the disease in Canada is Sin Nombre virus-infected deer mice. Between 1989 and 2014, 109 confirmed cases were reported, with the death rate estimated at 29%. The virus exists in deer mice nationwide, but cases were concentrated in western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) with only one case in eastern Canada. In Canada, "[a]ll cases occurred in rural settings and approximately 70% of the cases have been associated with domestic and farming activities." In the United States, minor cases of HPS include Sin Nombre orthohantavirus , New York orthohantavirus , Bayou orthohantavirus , and possibly Black Creek Canal orthohantavirus . [ citation needed ] As of January 2017 [ update ] , 728 cases of hantavirus had been reported in the United States cumulatively since 1995, across 36 states, not including cases with presumed exposure outside the United States. More than 96% of cases have occurred in states west of the Mississippi River . The top 10 states by number of cases reported (which differs slightly from a count ordered by the state of original exposure ) were New Mexico (109), Colorado (104), Arizona (78), California (61), Washington (50), Texas (45), Montana (43), Utah (38), Idaho (21), and Oregon (21); 36% of the total reported cases have resulted in death. In Mexico, rodents have been found to carry hantaviruses include Thomas's giant deer mouse (Megadontomys thomasi) , the pack rat Neotoma picta , Orizaba deer mouse (Peromyscus beatae) , Western harvest mouse (Reithrodontomys megalotis) and Sumichrast's harvest mouse (Reithrodontomys sumichrasti) . Agents of HPS found in South America include the Andes virus (also called Oran, Castelo de Sonhos – Portuguese for "Castle of Dreams", Lechiguanas, Juquitiba, Araraquara, and Bermejo virus, among many other synonyms), which is the only hantavirus that has shown an interpersonal form of transmission, and the Laguna Negra virus , an extremely close relative of the previously known Rio Mamore virus. [ citation needed ] Rodents that have been shown to carry hantaviruses include Abrothrix longipilis and Oligoryzomys longicaudatus . Hantavirus HFRS was likely first referenced in China in the 12th century. The first clinical recognition was in 1931 in northeast China. Around the same time in the 1930s, NE was identified in Sweden. HFRS came to the recognition of western physicians during the Korean War between 1951 and 1954 when more than 3,000 United Nations soldiers fell ill in an outbreak. In 1976, the first pathogenic hantavirus, the Hantaan orthohantavirus , was isolated from rodents near the Hantan River in South Korea . Other prominent hantaviruses that cause HFRS, including the Dobrava-Belgrade orthohantavirus , Puumala orthohantavirus , and Seoul orthohantavirus , were identified in the years after then and are collectively referred to as the Old World hantaviruses. In 1993, an outbreak of HCPS , then unrecognized, occurred in the Four Corners region of the United States and led to the discovery of the Sin Nombre orthohantavirus . Since then, approximately 43 hantavirus strains, of which 20 are pathogenic, have been found in the Americas and are referred to as the New World hantaviruses. This includes the Andes orthohantavirus , one of the primary causes of HCPS in South America and the only hantavirus known to be capable of person-to-person transmission. In late medieval England a mysterious sweating sickness swept through the country in 1485 just before the Battle of Bosworth Field . Noting that the symptoms overlap with hantavirus pulmonary syndrome, several scientists have theorized that the virus may have been the cause of the disease. The hypothesis was criticized because sweating sickness was recorded as being transmitted from human to human, whereas hantaviruses were not known to spread in this way.

Wiki

Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/Subconjunctival_bleeding/html

Subconjunctival bleeding

Subconjunctival bleeding , also known as subconjunctival hemorrhage or subconjunctival haemorrhage , is bleeding from a small blood vessel over the whites of the eye . It results in a red spot in the white of the eye. There is generally little to no pain and vision is not affected. Generally only one eye is affected. Causes can include coughing, vomiting, heavy lifting, straining during acute constipation or the act of "bearing down" during childbirth, as these activities can increase the blood pressure in the vascular systems supplying the conjunctiva. Other causes include blunt or penetrating trauma to the eye. Risk factors include hypertension, diabetes, old age, and blood thinners . Subconjunctival bleeding occurs in about 2% of newborns following a vaginal delivery . The blood accumulates between the conjunctiva and the episclera . Diagnosis is generally based on the appearance of the conjunctiva. The condition is relatively common, and both sexes are affected equally. Spontaneous bleeding occurs more commonly over the age of 50 while the traumatic type occurs more often in young males. Generally no specific treatment is required and the condition resolves over two to three weeks. Artificial tears may be used to alleviate irritation. Subconjunctival bleeding initially appears bright red underneath the transparent bulbar conjunctiva. Later, the bleeding may spread and become green or yellow as the hemoglobin is metabolized. It usually disappears within two weeks. The affected eye may feel dry, rough, or scratchy, but the condition is not usually painful.Atmospheric pressure changes due to aircraft altitude changes Mask squeeze from scuba diving without equalizing mask pressure during descent Subconjunctival bleeding in infants may be associated with scurvy (a vitamin C deficiency), abuse or traumatic asphyxia syndrome. Diagnosis is by visual inspection, by noting the typical finding of bright red discoloration confined to the white portion (sclera) of the eye. In rare cases blood may drip from the eye.A subconjunctival bleeding is typically a self-limiting condition that requires no treatment unless there is evidence of an eye infection or there has been significant eye trauma. Artificial tears may be applied four to six times a day if the eye feels dry or scratchy. The elective use of aspirin is typically discouraged.

Wiki

Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/Chickenpox/html

Chickenpox

Chickenpox , or chicken pox , also known as varicella , [ pronunciation? ] is a highly contagious , vaccine-preventable disease caused by the initial infection with varicella zoster virus (VZV), a member of the herpesvirus family. The disease results in a characteristic skin rash that forms small, itchy blisters , which eventually scab over. It usually starts on the chest, back, and face. It then spreads to the rest of the body. The rash and other symptoms, such as fever , tiredness , and headaches , usually last five to seven days. Complications may occasionally include pneumonia , inflammation of the brain , and bacterial skin infections. The disease is usually more severe in adults than in children. Chickenpox is an airborne disease which easily spreads via human-to-human transmission , typically through the coughs and sneezes of an infected person. The incubation period is 10–21 days, after which the characteristic rash appears. It may be spread from one to two days before the rash appears until all lesions have crusted over. It may also spread through contact with the blisters. Those with shingles may spread chickenpox to those who are not immune through contact with the blisters. The disease can usually be diagnosed based on the presenting symptom; however, in unusual cases it may be confirmed by polymerase chain reaction (PCR) testing of the blister fluid or scabs. Testing for antibodies may be done to determine if a person is immune. People usually only get chickenpox once. Although reinfections by the virus occur, these reinfections usually do not cause any symptoms. Since its introduction in 1995 in the United States, the varicella vaccine has resulted in a decrease in the number of cases and complications from the disease. It protects about 70–90 percent of people from disease with a greater benefit for severe disease. Routine immunization of children is recommended in many countries. Immunization within three days of exposure may improve outcomes in children. Treatment of those infected may include calamine lotion to help with itching, keeping the fingernails short to decrease injury from scratching, and the use of paracetamol (acetaminophen) to help with fevers. For those at increased risk of complications, antiviral medication such as aciclovir is recommended. Chickenpox occurs in all parts of the world. In 2013, there were 140 million cases of chickenpox and shingles worldwide. Before routine immunization the number of cases occurring each year was similar to the number of people born. Since immunization the number of infections in the United States has decreased nearly 90%. In 2015 chickenpox resulted in 6,400 deaths globally – down from 8,900 in 1990. Death occurs in about 1 per 60,000 cases. Chickenpox was not separated from smallpox until the late 19th century. In 1888 its connection to shingles was determined. The first documented use of the term chicken pox was in 1658. Various explanations have been suggested for the use of "chicken" in the name, one being the relative mildness of the disease. The early ( prodromal ) symptoms in adolescents and adults are nausea, loss of appetite, aching muscles, and headache. This is followed by the characteristic rash or oral sores, malaise , and a low-grade fever that signal the presence of the disease. Oral manifestations of the disease (enanthem) not uncommonly may precede the external rash (exanthem). In children the illness is not usually preceded by prodromal symptoms, and the first sign is the rash or the spots in the oral cavity. The rash begins as small red dots on the face, scalp, torso, upper arms and legs; progressing over 10–12 hours to small bumps, blisters and pustules ; followed by umbilication and the formation of scabs. At the blister stage, intense itching is usually present. Blisters may also occur on the palms, soles, and genital area. Commonly, visible evidence of the disease develops in the oral cavity and tonsil areas in the form of small ulcers which can be painful or itchy or both; this enanthem (internal rash) can precede the exanthem (external rash) by 1 to 3 days or can be concurrent. These symptoms of chickenpox appear 10 to 21 days after exposure to a contagious person. Adults may have a more widespread rash and longer fever, and they are more likely to experience complications, such as varicella pneumonia . Because watery nasal discharge containing live virus usually precedes both exanthem (external rash) and enanthem (oral ulcers) by 1 to 2 days, the infected person actually becomes contagious one to two days before recognition of the disease. Contagiousness persists until all vesicular lesions have become dry crusts (scabs), which usually entails four or five days, by which time nasal shedding of live virus ceases. The condition usually resolves by itself within a week or two. The rash may, however, last for up to one month. [ medical citation needed ] Chickenpox is rarely fatal, although it is generally more severe in adult men than in women or children. Non-immune pregnant women and those with a suppressed immune system are at highest risk of serious complications. Arterial ischemic stroke (AIS) associated with chickenpox in the previous year accounts for nearly one third of childhood AIS. The most common late complication of chickenpox is shingles (herpes zoster), caused by reactivation of the varicella zoster virus decades after the initial, often childhood, chickenpox infection. During pregnancy the dangers to the fetus associated with a primary VZV infection are greater in the first six months. In the third trimester, the mother is more likely to have severe symptoms. For pregnant women, antibodies produced as a result of immunization or previous infection are transferred via the placenta to the fetus . Varicella infection in pregnant women could lead to spread via the placenta and infection of the fetus. If infection occurs during the first 28 weeks of gestation , this can lead to fetal varicella syndrome (also known as congenital varicella syndrome ). Effects on the fetus can range in severity from underdeveloped toes and fingers to severe anal and bladder malformation. Possible problems include: Infection late in gestation or immediately following birth is referred to as " neonatal varicella ". Maternal infection is associated with premature delivery. The risk of the baby developing the disease is greatest following exposure to infection in the period 7 days before delivery and up to 8 days following the birth. The baby may also be exposed to the virus via infectious siblings or other contacts, but this is of less concern if the mother is immune. Newborns who develop symptoms are at a high risk of pneumonia and other serious complications of the disease. During pregnancy the dangers to the fetus associated with a primary VZV infection are greater in the first six months. In the third trimester, the mother is more likely to have severe symptoms. For pregnant women, antibodies produced as a result of immunization or previous infection are transferred via the placenta to the fetus . Varicella infection in pregnant women could lead to spread via the placenta and infection of the fetus. If infection occurs during the first 28 weeks of gestation , this can lead to fetal varicella syndrome (also known as congenital varicella syndrome ). Effects on the fetus can range in severity from underdeveloped toes and fingers to severe anal and bladder malformation. Possible problems include: Infection late in gestation or immediately following birth is referred to as " neonatal varicella ". Maternal infection is associated with premature delivery. The risk of the baby developing the disease is greatest following exposure to infection in the period 7 days before delivery and up to 8 days following the birth. The baby may also be exposed to the virus via infectious siblings or other contacts, but this is of less concern if the mother is immune. Newborns who develop symptoms are at a high risk of pneumonia and other serious complications of the disease. Exposure to VZV in a healthy child initiates the production of host immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) antibodies; IgG antibodies persist for life and confer immunity. Cell-mediated immune responses are also important in limiting the scope and the duration of primary varicella infection. After primary infection, VZV is hypothesized to spread from mucosal and epidermal lesions to local sensory nerves . VZV then remains latent in the dorsal ganglion cells of the sensory nerves. Reactivation of VZV results in the clinically distinct syndrome of herpes zoster (i.e., shingles ), postherpetic neuralgia , and sometimes Ramsay Hunt syndrome type II . Varicella zoster can affect the arteries in the neck and head, producing stroke, either during childhood, or after a latency period of many years. After a chickenpox infection, the virus remains dormant in the body's nerve tissues for about 50 years. This, however, does not mean that VZV cannot be contracted later in life. The immune system usually keeps the virus at bay, but it can still manifest itself at any given age causing a different form of the viral infection called shingles (also known as herpes zoster). Since the efficacy of the human immune system decreases with age, the United States Advisory Committee on Immunization Practices (ACIP) suggests that every adult over the age of 50 years get the herpes zoster vaccine. Shingles affects one in five adults infected with chickenpox as children, especially those who are immune-suppressed, particularly from cancer, HIV, or other conditions. Stress can bring on shingles as well, although scientists are still researching the connection. Adults over the age of 60 who had chickenpox but not shingles are the most prone age demographic. After a chickenpox infection, the virus remains dormant in the body's nerve tissues for about 50 years. This, however, does not mean that VZV cannot be contracted later in life. The immune system usually keeps the virus at bay, but it can still manifest itself at any given age causing a different form of the viral infection called shingles (also known as herpes zoster). Since the efficacy of the human immune system decreases with age, the United States Advisory Committee on Immunization Practices (ACIP) suggests that every adult over the age of 50 years get the herpes zoster vaccine. Shingles affects one in five adults infected with chickenpox as children, especially those who are immune-suppressed, particularly from cancer, HIV, or other conditions. Stress can bring on shingles as well, although scientists are still researching the connection. Adults over the age of 60 who had chickenpox but not shingles are the most prone age demographic. The diagnosis of chickenpox is primarily based on the signs and symptoms, with typical early symptoms followed by a characteristic rash . Confirmation of the diagnosis is by examination of the fluid within the vesicles of the rash, or by testing blood for evidence of an acute immunologic response. Vesicular fluid can be examined with a Tzanck smear , or by testing for direct fluorescent antibody . The fluid can also be "cultured", whereby attempts are made to grow the virus from a fluid sample. Blood tests can be used to identify a response to acute infection (IgM) or previous infection and subsequent immunity (IgG). Prenatal diagnosis of fetal varicella infection can be performed using ultrasound , though a delay of 5 weeks following primary maternal infection is advised. A PCR (DNA) test of the mother's amniotic fluid can also be performed, though the risk of spontaneous abortion due to the amniocentesis procedure is higher than the risk of the baby's developing fetal varicella syndrome. The spread of chickenpox can be prevented by isolating affected individuals. Contagion is by exposure to respiratory droplets, or direct contact with lesions, within a period lasting from three days before the onset of the rash, to four days after the onset of the rash. As with all respiratory pathogens once presumed to transmit via respiratory droplets, it is highly likely to be carried by the aerosols generated during routine breathing, talking, and even singing. The chickenpox virus is susceptible to disinfectants, notably chlorine bleach (i.e., sodium hypochlorite ). Like all enveloped viruses , it is sensitive to drying, heat and detergents. Chickenpox can be prevented by vaccination. The side effects are usually mild, such as some pain or swelling at the injection site . A live attenuated varicella vaccine, the Oka strain, was developed by Michiaki Takahashi and his colleagues in Japan in the early 1970s. In 1995, Merck & Co. licensed the "Oka" strain of the varicella virus in the United States , and Maurice Hilleman 's team at Merck invented a varicella vaccine in the same year. The varicella vaccine is recommended in many countries. Some countries require the varicella vaccination or an exemption before entering elementary school. A second dose is recommended five years after the initial immunization. A vaccinated person is likely to have a milder case of chickenpox if they become infected. Immunization within three days following household contact reduces infection rates and severity in children. Being exposed to chickenpox as an adult (for example, through contact with infected children) may boost immunity to shingles. Therefore, it was thought that when the majority of children were vaccinated against chickenpox, adults might lose this natural boosting, so immunity would drop and more shingles cases would occur. On the other hand, current observations suggest that exposure to children with varicella is not a critical factor in the maintenance of immunity. Multiple subclinical reactivations of varicella zoster virus may occur spontaneously and, despite not causing clinical disease, may still provide an endogenous boost to immunity against zoster. The vaccine is part of the routine immunization schedule in the US. Some European countries include it as part of universal vaccinations in children, but not all countries provide the vaccine. In the UK as of 2014, the vaccine is only recommended in people who are particularly vulnerable to chickenpox. This is to keep the virus in circulation, thereby exposing the population to the virus at an early age, when it is less harmful, and to reduce the occurrence of shingles through repeated exposure to the virus later in life. In November 2023, the UK Joint Committee on Vaccination and Immunisation recommended all children be given the vaccine at ages 12 months and 18 months; however, this has not yet been implemented. In populations that have not been immunized or if immunity is questionable, a clinician may order an enzyme immunoassay . An immunoassay measures the levels of antibodies against the virus that give immunity to a person. If the levels of antibodies are low (low titer) or questionable, reimmunization may be done. The spread of chickenpox can be prevented by isolating affected individuals. Contagion is by exposure to respiratory droplets, or direct contact with lesions, within a period lasting from three days before the onset of the rash, to four days after the onset of the rash. As with all respiratory pathogens once presumed to transmit via respiratory droplets, it is highly likely to be carried by the aerosols generated during routine breathing, talking, and even singing. The chickenpox virus is susceptible to disinfectants, notably chlorine bleach (i.e., sodium hypochlorite ). Like all enveloped viruses , it is sensitive to drying, heat and detergents. Chickenpox can be prevented by vaccination. The side effects are usually mild, such as some pain or swelling at the injection site . A live attenuated varicella vaccine, the Oka strain, was developed by Michiaki Takahashi and his colleagues in Japan in the early 1970s. In 1995, Merck & Co. licensed the "Oka" strain of the varicella virus in the United States , and Maurice Hilleman 's team at Merck invented a varicella vaccine in the same year. The varicella vaccine is recommended in many countries. Some countries require the varicella vaccination or an exemption before entering elementary school. A second dose is recommended five years after the initial immunization. A vaccinated person is likely to have a milder case of chickenpox if they become infected. Immunization within three days following household contact reduces infection rates and severity in children. Being exposed to chickenpox as an adult (for example, through contact with infected children) may boost immunity to shingles. Therefore, it was thought that when the majority of children were vaccinated against chickenpox, adults might lose this natural boosting, so immunity would drop and more shingles cases would occur. On the other hand, current observations suggest that exposure to children with varicella is not a critical factor in the maintenance of immunity. Multiple subclinical reactivations of varicella zoster virus may occur spontaneously and, despite not causing clinical disease, may still provide an endogenous boost to immunity against zoster. The vaccine is part of the routine immunization schedule in the US. Some European countries include it as part of universal vaccinations in children, but not all countries provide the vaccine. In the UK as of 2014, the vaccine is only recommended in people who are particularly vulnerable to chickenpox. This is to keep the virus in circulation, thereby exposing the population to the virus at an early age, when it is less harmful, and to reduce the occurrence of shingles through repeated exposure to the virus later in life. In November 2023, the UK Joint Committee on Vaccination and Immunisation recommended all children be given the vaccine at ages 12 months and 18 months; however, this has not yet been implemented. In populations that have not been immunized or if immunity is questionable, a clinician may order an enzyme immunoassay . An immunoassay measures the levels of antibodies against the virus that give immunity to a person. If the levels of antibodies are low (low titer) or questionable, reimmunization may be done. Treatment mainly consists of easing the symptoms. As a protective measure, people are usually required to stay at home while they are infectious to avoid spreading the disease to others. Cutting the fingernails short or wearing gloves may prevent scratching and minimize the risk of secondary infections . Although there have been no formal clinical studies evaluating the effectiveness of topical application of calamine lotion (a topical barrier preparation containing zinc oxide , and one of the most commonly used interventions), it has an excellent safety profile. Maintaining good hygiene and daily cleaning of skin with warm water can help to avoid secondary bacterial infection ; scratching may increase the risk of secondary infection. Paracetamol (acetaminophen) but not aspirin may be used to reduce fever. Aspirin use by someone with chickenpox may cause serious, sometimes fatal disease of the liver and brain, Reye syndrome . People at risk of developing severe complications who have had significant exposure to the virus may be given intra-muscular varicella zoster immune globulin (VZIG), a preparation containing high titres of antibodies to varicella zoster virus, to ward off the disease. Antivirals are sometimes used. If aciclovir by mouth is started within 24 hours of rash onset, it decreases symptoms by one day but has no effect on complication rates. Use of aciclovir therefore is not currently recommended for individuals with normal immune function. Children younger than 12 years old and older than one month are not meant to receive antiviral drugs unless they have another medical condition which puts them at risk of developing complications. Treatment of chickenpox in children is aimed at symptoms while the immune system deals with the virus. With children younger than 12 years, cutting fingernails and keeping them clean is an important part of treatment as they are more likely to scratch their blisters more deeply than adults. Aspirin is highly contraindicated in children younger than 16 years, as it has been related to Reye syndrome. Infection in otherwise healthy adults tends to be more severe. Treatment with antiviral drugs (e.g. aciclovir or valaciclovir ) is generally advised, as long as it is started within 24–48 hours from rash onset. Remedies to ease the symptoms of chickenpox in adults are basically the same as those used for children. Adults are more often prescribed antiviral medication, as it is effective in reducing the severity of the condition and the likelihood of developing complications. Adults are advised to increase water intake to reduce dehydration and to relieve headaches. Painkillers such as paracetamol (acetaminophen) are recommended, as they are effective in relieving itching and other symptoms such as fever or pains. Antihistamines relieve itching and may be used in cases where the itching prevents sleep, because they also act as a sedative . As with children, antiviral medication is considered more useful for those adults who are more prone to develop complications. These include pregnant women or people who have a weakened immune system. If aciclovir by mouth is started within 24 hours of rash onset, it decreases symptoms by one day but has no effect on complication rates. Use of aciclovir therefore is not currently recommended for individuals with normal immune function. Children younger than 12 years old and older than one month are not meant to receive antiviral drugs unless they have another medical condition which puts them at risk of developing complications. Treatment of chickenpox in children is aimed at symptoms while the immune system deals with the virus. With children younger than 12 years, cutting fingernails and keeping them clean is an important part of treatment as they are more likely to scratch their blisters more deeply than adults. Aspirin is highly contraindicated in children younger than 16 years, as it has been related to Reye syndrome. Infection in otherwise healthy adults tends to be more severe. Treatment with antiviral drugs (e.g. aciclovir or valaciclovir ) is generally advised, as long as it is started within 24–48 hours from rash onset. Remedies to ease the symptoms of chickenpox in adults are basically the same as those used for children. Adults are more often prescribed antiviral medication, as it is effective in reducing the severity of the condition and the likelihood of developing complications. Adults are advised to increase water intake to reduce dehydration and to relieve headaches. Painkillers such as paracetamol (acetaminophen) are recommended, as they are effective in relieving itching and other symptoms such as fever or pains. Antihistamines relieve itching and may be used in cases where the itching prevents sleep, because they also act as a sedative . As with children, antiviral medication is considered more useful for those adults who are more prone to develop complications. These include pregnant women or people who have a weakened immune system. The duration of the visible blistering caused by varicella zoster virus varies in children usually from four to seven days, and the appearance of new blisters begins to subside after the fifth day. Chickenpox infection is milder in young children, and symptomatic treatment, with sodium bicarbonate baths or antihistamine medication may ease itching. In adults, the disease is more severe, though the incidence is much less common. Infection in adults is associated with greater morbidity and mortality due to pneumonia (either direct viral pneumonia or secondary bacterial pneumonia ), bronchitis (either viral bronchitis or secondary bacterial bronchitis), hepatitis, and encephalitis. In particular, up to 10% of pregnant women with chickenpox develop pneumonia, the severity of which increases with onset later in gestation. In England and Wales, 75% of deaths due to chickenpox are in adults. Inflammation of the brain, encephalitis, can occur in immunocompromised individuals, although the risk is higher with herpes zoster. Necrotizing fasciitis is also a rare complication. Varicella can be lethal to individuals with impaired immunity. The number of people in this high-risk group has increased, due to the HIV epidemic and the increased use of immunosuppressive therapies. Varicella is a particular problem in hospitals when there are patients with immune systems weakened by drugs (e.g., high-dose steroids) or HIV . Secondary bacterial infection of skin lesions, manifesting as impetigo , cellulitis , and erysipelas , is the most common complication in healthy children. Disseminated primary varicella infection usually seen in the immunocompromised may have high morbidity. Ninety percent of cases of varicella pneumonia occur in the adult population. Rarer complications of disseminated chickenpox include myocarditis , hepatitis , and glomerulonephritis . Hemorrhagic complications are more common in the immunocompromised or immunosuppressed populations, although healthy children and adults have been affected. Five major clinical syndromes have been described: febrile purpura, malignant chickenpox with purpura , postinfectious purpura, purpura fulminans , and anaphylactoid purpura . These syndromes have variable courses, with febrile purpura being the most benign of the syndromes and having an uncomplicated outcome. In contrast, malignant chickenpox with purpura is a grave clinical condition that has a mortality rate of greater than 70%. The cause of these hemorrhagic chickenpox syndromes is not known. Primary varicella occurs in all countries worldwide. In 2015 chickenpox resulted in 6,400 deaths globally – down from 8,900 in 1990. There were 7,000 deaths in 2013. Varicella is highly transmissible, with an infection rate of 90% in close contacts. In temperate countries, chickenpox is primarily a disease of children, with most cases occurring during the winter and spring, most likely due to school contact. In such countries it is one of the classic diseases of childhood , with most cases occurring in children up to age 15; most people become infected before adulthood, and 10% of young adults remain susceptible. In the United States, a temperate country, the Centers for Disease Control and Prevention (CDC) do not require state health departments to report infections of chickenpox, and only 31 states volunteered this information as of 2013 [ update ] . A 2013 study conducted by the social media disease surveillance tool called Sickweather used anecdotal reports of chickenpox infections on social media systems Facebook and Twitter to measure and rank states with the most infections per capita, with Maryland, Tennessee and Illinois in the top three. In the tropics, chickenpox often occurs in older people and may cause more serious disease. In adults, the pock marks are darker and the scars more prominent than in children. How the term chickenpox originated is not clear but it may be due to it being a relatively mild disease. It has been said to be derived from chickpeas , based on resemblance of the vesicles to chickpeas, or to come from the rash resembling chicken pecks. Other suggestions include the designation chicken for a child (i.e., literally 'child pox'), a corruption of itching-pox , or the idea that the disease may have originated in chickens. Samuel Johnson explained the designation as "from its being of no very great danger". Because chickenpox is usually more severe in adults than it is in children, some parents deliberately expose their children to the virus, for example by taking them to " chickenpox parties ". Doctors say that children are safer getting the vaccine, which is a weakened form of the virus, than getting the disease, which can be fatal or lead to shingles later in life. Repeated exposure to chickenpox may protect against zoster. How the term chickenpox originated is not clear but it may be due to it being a relatively mild disease. It has been said to be derived from chickpeas , based on resemblance of the vesicles to chickpeas, or to come from the rash resembling chicken pecks. Other suggestions include the designation chicken for a child (i.e., literally 'child pox'), a corruption of itching-pox , or the idea that the disease may have originated in chickens. Samuel Johnson explained the designation as "from its being of no very great danger". Because chickenpox is usually more severe in adults than it is in children, some parents deliberately expose their children to the virus, for example by taking them to " chickenpox parties ". Doctors say that children are safer getting the vaccine, which is a weakened form of the virus, than getting the disease, which can be fatal or lead to shingles later in life. Repeated exposure to chickenpox may protect against zoster. Humans are the only known species that the disease affects naturally. However, chickenpox has been caused in animals, including chimpanzees and gorillas . Sorivudine , a nucleoside analog, has been reported to be effective in the treatment of primary varicella in healthy adults (case reports only), but large-scale clinical trials are still needed to demonstrate its efficacy. There was speculation in 2005 that continuous dosing of aciclovir by mouth for a period of time could eradicate VZV from the host, although further trials were required to discern whether eradication was actually viable.

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Acute hemorrhagic fever syndrome

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SARS-CoV-2

2019-nCoV Severe acute respiratory syndrome coronavirus 2 ( SARS‑CoV‑2 ) is a strain of coronavirus that causes COVID-19 , the respiratory illness responsible for the COVID-19 pandemic . The virus previously had the provisional name 2019 novel coronavirus ( 2019-nCoV ), and has also been called human coronavirus 2019 ( HCoV-19 or hCoV-19 ). First identified in the city of Wuhan , Hubei, China, the World Health Organization designated the outbreak a public health emergency of international concern from January 30, 2020, to May 5, 2023. SARS‑CoV‑2 is a positive-sense single-stranded RNA virus that is contagious in humans. SARS‑CoV‑2 is a strain of the species severe-acute-respiratory-syndrome-related coronavirus (SARSr-CoV), as is SARS-CoV-1 , the virus that caused the 2002–2004 SARS outbreak . There are animal-borne coronavirus strains more closely related to SARS-CoV-2, the most closely known relative being the BANAL-52 bat coronavirus. SARS-CoV-2 is of zoonotic origin; its close genetic similarity to bat coronaviruses suggests it emerged from such a bat-borne virus . Research is ongoing as to whether SARS‑CoV‑2 came directly from bats or indirectly through any intermediate hosts. The virus shows little genetic diversity , indicating that the spillover event introducing SARS‑CoV‑2 to humans is likely to have occurred in late 2019. Epidemiological studies estimate that in the period between December 2019 and September 2020 each infection resulted in an average of 2.4–3.4 new infections when no members of the community were immune and no preventive measures were taken. However, some subsequent variants have become more infectious. The virus is airborne and primarily spreads between people through close contact and via aerosols and respiratory droplets that are exhaled when talking, breathing, or otherwise exhaling, as well as those produced from coughs and sneezes. It enters human cells by binding to angiotensin-converting enzyme 2 (ACE2), a membrane protein that regulates the renin–angiotensin system. During the initial outbreak in Wuhan , China, various names were used for the virus; some names used by different sources included "the coronavirus" or "Wuhan coronavirus". In January 2020, the World Health Organization (WHO) recommended "2019 novel coronavirus" (2019-nCoV) as the provisional name for the virus. This was in accordance with WHO's 2015 guidance against using geographical locations, animal species, or groups of people in disease and virus names. On 11 February 2020, the International Committee on Taxonomy of Viruses adopted the official name "severe acute respiratory syndrome coronavirus 2" (SARS‑CoV‑2). To avoid confusion with the disease SARS , the WHO sometimes refers to SARS‑CoV‑2 as "the COVID-19 virus" in public health communications and the name HCoV-19 was included in some research articles. Referring to COVID-19 as the "Wuhan virus" has been described as dangerous by WHO officials, and as xenophobic by many journalists and academics. Human-to-human transmission of SARS‑CoV‑2 was confirmed on 20 January 2020 during the COVID-19 pandemic . Transmission was initially assumed to occur primarily via respiratory droplets from coughs and sneezes within a range of about 1.8 metres (6 ft) . Laser light scattering experiments suggest that speaking is an additional mode of transmission and a far-reaching one, indoors, with little air flow. Other studies have suggested that the virus may be airborne as well, with aerosols potentially being able to transmit the virus. During human-to-human transmission, between 200 and 800 infectious SARS‑CoV‑2 virions are thought to initiate a new infection. If confirmed, aerosol transmission has biosafety implications because a major concern associated with the risk of working with emerging viruses in the laboratory is the generation of aerosols from various laboratory activities which are not immediately recognizable and may affect other scientific personnel. Indirect contact via contaminated surfaces is another possible cause of infection. Preliminary research indicates that the virus may remain viable on plastic ( polypropylene ) and stainless steel ( AISI 304 ) for up to three days, but it does not survive on cardboard for more than one day or on copper for more than four hours. The virus is inactivated by soap, which destabilizes its lipid bilayer . Viral RNA has also been found in stool samples and semen from infected individuals. The degree to which the virus is infectious during the incubation period is uncertain, but research has indicated that the pharynx reaches peak viral load approximately four days after infection or in the first week of symptoms and declines thereafter. The duration of SARS-CoV-2 RNA shedding is generally between 3 and 46 days after symptom onset. A study by a team of researchers from the University of North Carolina found that the nasal cavity is seemingly the dominant initial site of infection, with subsequent aspiration -mediated virus-seeding into the lungs in SARS‑CoV‑2 pathogenesis. They found that there was an infection gradient from high in proximal towards low in distal pulmonary epithelial cultures, with a focal infection in ciliated cells and type 2 pneumocytes in the airway and alveolar regions respectively. Studies have identified a range of animals—such as cats, ferrets, hamsters, non-human primates, minks, tree shrews, raccoon dogs, fruit bats, and rabbits—that are susceptible and permissive to SARS-CoV-2 infection. Some institutions have advised that those infected with SARS‑CoV‑2 restrict their contact with animals. On 1 February 2020, the World Health Organization (WHO) indicated that "transmission from asymptomatic cases is likely not a major driver of transmission". One meta-analysis found that 17% of infections are asymptomatic, and asymptomatic individuals were 42% less likely to transmit the virus. However, an epidemiological model of the beginning of the outbreak in China suggested that "pre-symptomatic shedding may be typical among documented infections" and that subclinical infections may have been the source of a majority of infections. That may explain how out of 217 on board a cruise liner that docked at Montevideo , only 24 of 128 who tested positive for viral RNA showed symptoms. Similarly, a study of ninety-four patients hospitalized in January and February 2020 estimated patients began shedding virus two to three days before symptoms appear and that "a substantial proportion of transmission probably occurred before first symptoms in the index case ". The authors later published a correction that showed that shedding began earlier than first estimated, four to five days before symptoms appear. There is uncertainty about reinfection and long-term immunity. It is not known how common reinfection is, but reports have indicated that it is occurring with variable severity. The first reported case of reinfection was a 33-year-old man from Hong Kong who first tested positive on 26 March 2020, was discharged on 15 April 2020 after two negative tests, and tested positive again on 15 August 2020 (142 days later), which was confirmed by whole-genome sequencing showing that the viral genomes between the episodes belong to different clades . The findings had the implications that herd immunity may not eliminate the virus if reinfection is not an uncommon occurrence and that vaccines may not be able to provide lifelong protection against the virus. Another case study described a 25-year-old man from Nevada who tested positive for SARS‑CoV‑2 on 18 April 2020 and on 5 June 2020 (separated by two negative tests). Since genomic analyses showed significant genetic differences between the SARS‑CoV‑2 variant sampled on those two dates, the case study authors determined this was a reinfection. The man's second infection was symptomatically more severe than the first infection, but the mechanisms that could account for this are not known. On 1 February 2020, the World Health Organization (WHO) indicated that "transmission from asymptomatic cases is likely not a major driver of transmission". One meta-analysis found that 17% of infections are asymptomatic, and asymptomatic individuals were 42% less likely to transmit the virus. However, an epidemiological model of the beginning of the outbreak in China suggested that "pre-symptomatic shedding may be typical among documented infections" and that subclinical infections may have been the source of a majority of infections. That may explain how out of 217 on board a cruise liner that docked at Montevideo , only 24 of 128 who tested positive for viral RNA showed symptoms. Similarly, a study of ninety-four patients hospitalized in January and February 2020 estimated patients began shedding virus two to three days before symptoms appear and that "a substantial proportion of transmission probably occurred before first symptoms in the index case ". The authors later published a correction that showed that shedding began earlier than first estimated, four to five days before symptoms appear. There is uncertainty about reinfection and long-term immunity. It is not known how common reinfection is, but reports have indicated that it is occurring with variable severity. The first reported case of reinfection was a 33-year-old man from Hong Kong who first tested positive on 26 March 2020, was discharged on 15 April 2020 after two negative tests, and tested positive again on 15 August 2020 (142 days later), which was confirmed by whole-genome sequencing showing that the viral genomes between the episodes belong to different clades . The findings had the implications that herd immunity may not eliminate the virus if reinfection is not an uncommon occurrence and that vaccines may not be able to provide lifelong protection against the virus. Another case study described a 25-year-old man from Nevada who tested positive for SARS‑CoV‑2 on 18 April 2020 and on 5 June 2020 (separated by two negative tests). Since genomic analyses showed significant genetic differences between the SARS‑CoV‑2 variant sampled on those two dates, the case study authors determined this was a reinfection. The man's second infection was symptomatically more severe than the first infection, but the mechanisms that could account for this are not known. No natural reservoir for SARS-CoV-2 has been identified. Prior to the emergence of SARS-CoV-2 as a pathogen infecting humans, there had been two previous zoonosis -based coronavirus epidemics, those caused by SARS-CoV-1 and MERS-CoV . The first known infections from SARS‑CoV‑2 were discovered in Wuhan, China. The original source of viral transmission to humans remains unclear, as does whether the virus became pathogenic before or after the spillover event . Because many of the early infectees were workers at the Huanan Seafood Market , it has been suggested that the virus might have originated from the market. However, other research indicates that visitors may have introduced the virus to the market, which then facilitated rapid expansion of the infections. A March 2021 WHO-convened report stated that human spillover via an intermediate animal host was the most likely explanation, with direct spillover from bats next most likely. Introduction through the food supply chain and the Huanan Seafood Market was considered another possible, but less likely, explanation. An analysis in November 2021, however, said that the earliest-known case had been misidentified and that the preponderance of early cases linked to the Huanan Market argued for it being the source. For a virus recently acquired through a cross-species transmission, rapid evolution is expected. The mutation rate estimated from early cases of SARS-CoV-2 was of 6.54 × 10 −4 per site per year. Coronaviruses in general have high genetic plasticity , but SARS-CoV-2's viral evolution is slowed by the RNA proofreading capability of its replication machinery. For comparison, the viral mutation rate in vivo of SARS-CoV-2 has been found to be lower than that of influenza. Research into the natural reservoir of the virus that caused the 2002–2004 SARS outbreak has resulted in the discovery of many SARS-like bat coronaviruses , most originating in horseshoe bats . The closest match by far, published in Nature (journal) in February 2022, were viruses BANAL-52 (96.8% resemblance to SARS‑CoV‑2), BANAL-103 and BANAL-236, collected in three different species of bats in Feuang , Laos. An earlier source published in February 2020 identified the virus RaTG13 , collected in bats in Mojiang , Yunnan, China to be the closest to SARS‑CoV‑2, with 96.1% resemblance. None of the above are its direct ancestor. Bats are considered the most likely natural reservoir of SARS‑CoV‑2. Differences between the bat coronavirus and SARS‑CoV‑2 suggest that humans may have been infected via an intermediate host; although the source of introduction into humans remains unknown. Although the role of pangolins as an intermediate host was initially posited (a study published in July 2020 suggested that pangolins are an intermediate host of SARS‑CoV‑2-like coronaviruses ), subsequent studies have not substantiated their contribution to the spillover. Evidence against this hypothesis includes the fact that pangolin virus samples are too distant to SARS-CoV-2: isolates obtained from pangolins seized in Guangdong were only 92% identical in sequence to the SARS‑CoV‑2 genome (matches above 90 percent may sound high, but in genomic terms it is a wide evolutionary gap ). In addition, despite similarities in a few critical amino acids, pangolin virus samples exhibit poor binding to the human ACE2 receptor. SARS‑CoV‑2 belongs to the broad family of viruses known as coronaviruses . It is a positive-sense single-stranded RNA (+ssRNA) virus, with a single linear RNA segment. Coronaviruses infect humans, other mammals, including livestock and companion animals, and avian species. Human coronaviruses are capable of causing illnesses ranging from the common cold to more severe diseases such as Middle East respiratory syndrome (MERS, fatality rate ~34%). SARS-CoV-2 is the seventh known coronavirus to infect people, after 229E , NL63 , OC43 , HKU1 , MERS-CoV , and the original SARS-CoV . Like the SARS-related coronavirus implicated in the 2003 SARS outbreak, SARS‑CoV‑2 is a member of the subgenus Sarbecovirus ( beta-CoV lineage B). Coronaviruses undergo frequent recombination. The mechanism of recombination in unsegmented RNA viruses such as SARS-CoV-2 is generally by copy-choice replication, in which gene material switches from one RNA template molecule to another during replication. The SARS-CoV-2 RNA sequence is approximately 30,000 bases in length, relatively long for a coronavirus—which in turn carry the largest genomes among all RNA families. Its genome consists nearly entirely of protein-coding sequences, a trait shared with other coronaviruses. A distinguishing feature of SARS‑CoV‑2 is its incorporation of a polybasic site cleaved by furin , which appears to be an important element enhancing its virulence. It was suggested that the acquisition of the furin-cleavage site in the SARS-CoV-2 S protein was essential for zoonotic transfer to humans. The furin protease recognizes the canonical peptide sequence R X[ R / K ] R ↓X where the cleavage site is indicated by a down arrow and X is any amino acid . In SARS-CoV-2 the recognition site is formed by the incorporated 12 codon nucleotide sequence CCT CGG CGG GCA which corresponds to the amino acid sequence P RR A . This sequence is upstream of an arginine and serine which forms the S1/S2 cleavage site ( P RR A R ↓ S ) of the spike protein. Although such sites are a common naturally-occurring feature of other viruses within the Subfamily Orthocoronavirinae, it appears in few other viruses from the Beta-CoV genus, and it is unique among members of its subgenus for such a site. The furin cleavage site PRRAR↓ is highly similar to that of the feline coronavirus , an alphacoronavirus 1 strain. Viral genetic sequence data can provide critical information about whether viruses separated by time and space are likely to be epidemiologically linked. With a sufficient number of sequenced genomes , it is possible to reconstruct a phylogenetic tree of the mutation history of a family of viruses. By 12 January 2020, five genomes of SARS‑CoV‑2 had been isolated from Wuhan and reported by the Chinese Center for Disease Control and Prevention (CCDC) and other institutions; the number of genomes increased to 42 by 30 January 2020. A phylogenetic analysis of those samples showed they were "highly related with at most seven mutations relative to a common ancestor ", implying that the first human infection occurred in November or December 2019. Examination of the topology of the phylogenetic tree at the start of the pandemic also found high similarities between human isolates. As of 21 August 2021 , [ update ] 3,422 SARS‑CoV‑2 genomes, belonging to 19 strains, sampled on all continents except Antarctica were publicly available. On 11 February 2020, the International Committee on Taxonomy of Viruses announced that according to existing rules that compute hierarchical relationships among coronaviruses based on five conserved sequences of nucleic acids, the differences between what was then called 2019-nCoV and the virus from the 2003 SARS outbreak were insufficient to make them separate viral species . Therefore, they identified 2019-nCoV as a virus of Severe acute respiratory syndrome–related coronavirus . In July 2020, scientists reported that a more infectious SARS‑CoV‑2 variant with spike protein variant G614 has replaced D614 as the dominant form in the pandemic. Coronavirus genomes and subgenomes encode six open reading frames (ORFs). In October 2020, researchers discovered a possible overlapping gene named ORF3d , in the SARS‑CoV‑2 genome . It is unknown if the protein produced by ORF3d has any function, but it provokes a strong immune response. ORF3d has been identified before, in a variant of coronavirus that infects pangolins . A phylogenetic tree based on whole-genome sequences of SARS-CoV-2 and related coronaviruses is: ( Bat ) Rc-o319 , 81% to SARS-CoV-2, Rhinolophus cornutus , Iwate , Japan Bat SL-ZXC21 , 88% to SARS-CoV-2, Rhinolophus pusillus , Zhoushan , Zhejiang Bat SL-ZC45 , 88% to SARS-CoV-2, Rhinolophus pusillus , Zhoushan, Zhejiang Pangolin SARSr-CoV-GX, 85.3% to SARS-CoV-2, Manis javanica , smuggled from Southeast Asia Pangolin SARSr-CoV-GD, 90.1% to SARS-CoV-2, Manis javanica , smuggled from Southeast Asia Bat RshSTT182, 92.6% to SARS-CoV-2, Rhinolophus shameli , Steung Treng , Cambodia Bat RshSTT200, 92.6% to SARS-CoV-2, Rhinolophus shameli , Steung Treng, Cambodia (Bat) RacCS203 , 91.5% to SARS-CoV-2, Rhinolophus acuminatus , Chachoengsao , Thailand (Bat) RmYN02 , 93.3% to SARS-CoV-2, Rhinolophus malayanus , Mengla , Yunnan (Bat) RpYN06 , 94.4% to SARS-CoV-2, Rhinolophus pusillus , Xishuangbanna , Yunnan (Bat) RaTG13 , 96.1% to SARS-CoV-2, Rhinolophus affinis , Mojiang , Yunnan (Bat) BANAL-52 , 96.8% to SARS-CoV-2, Rhinolophus malayanus , Vientiane , Laos SARS-CoV-2 SARS-CoV-1 , 79% to SARS-CoV-2 There are many thousands of variants of SARS-CoV-2, which can be grouped into the much larger clades . Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR). Several notable variants of SARS-CoV-2 emerged in late 2020. The World Health Organization has currently declared five variants of concern , which are as follows: Other notable variants include 6 other WHO-designated variants under investigation and Cluster 5 , which emerged among mink in Denmark and resulted in a mink euthanasia campaign rendering it virtually extinct. A phylogenetic tree based on whole-genome sequences of SARS-CoV-2 and related coronaviruses is: ( Bat ) Rc-o319 , 81% to SARS-CoV-2, Rhinolophus cornutus , Iwate , Japan Bat SL-ZXC21 , 88% to SARS-CoV-2, Rhinolophus pusillus , Zhoushan , Zhejiang Bat SL-ZC45 , 88% to SARS-CoV-2, Rhinolophus pusillus , Zhoushan, Zhejiang Pangolin SARSr-CoV-GX, 85.3% to SARS-CoV-2, Manis javanica , smuggled from Southeast Asia Pangolin SARSr-CoV-GD, 90.1% to SARS-CoV-2, Manis javanica , smuggled from Southeast Asia Bat RshSTT182, 92.6% to SARS-CoV-2, Rhinolophus shameli , Steung Treng , Cambodia Bat RshSTT200, 92.6% to SARS-CoV-2, Rhinolophus shameli , Steung Treng, Cambodia (Bat) RacCS203 , 91.5% to SARS-CoV-2, Rhinolophus acuminatus , Chachoengsao , Thailand (Bat) RmYN02 , 93.3% to SARS-CoV-2, Rhinolophus malayanus , Mengla , Yunnan (Bat) RpYN06 , 94.4% to SARS-CoV-2, Rhinolophus pusillus , Xishuangbanna , Yunnan (Bat) RaTG13 , 96.1% to SARS-CoV-2, Rhinolophus affinis , Mojiang , Yunnan (Bat) BANAL-52 , 96.8% to SARS-CoV-2, Rhinolophus malayanus , Vientiane , Laos SARS-CoV-2 SARS-CoV-1 , 79% to SARS-CoV-2 There are many thousands of variants of SARS-CoV-2, which can be grouped into the much larger clades . Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR). Several notable variants of SARS-CoV-2 emerged in late 2020. The World Health Organization has currently declared five variants of concern , which are as follows: Other notable variants include 6 other WHO-designated variants under investigation and Cluster 5 , which emerged among mink in Denmark and resulted in a mink euthanasia campaign rendering it virtually extinct. There are many thousands of variants of SARS-CoV-2, which can be grouped into the much larger clades . Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR). Several notable variants of SARS-CoV-2 emerged in late 2020. The World Health Organization has currently declared five variants of concern , which are as follows: Other notable variants include 6 other WHO-designated variants under investigation and Cluster 5 , which emerged among mink in Denmark and resulted in a mink euthanasia campaign rendering it virtually extinct. Each SARS-CoV-2 virion is 60–140 nanometres (2.4 × 10 −6 –5.5 × 10 −6 in) in diameter; its mass within the global human populace has been estimated as being between 0.1 and 10 kilograms. Like other coronaviruses, SARS-CoV-2 has four structural proteins, known as the S ( spike ), E ( envelope ), M ( membrane ), and N ( nucleocapsid ) proteins; the N protein holds the RNA genome, and the S, E, and M proteins together create the viral envelope . Coronavirus S proteins are glycoproteins and also type I membrane proteins (membranes containing a single transmembrane domain oriented on the extracellular side). They are divided into two functional parts (S1 and S2). In SARS-CoV-2, the spike protein, which has been imaged at the atomic level using cryogenic electron microscopy , is the protein responsible for allowing the virus to attach to and fuse with the membrane of a host cell; specifically, its S1 subunit catalyzes attachment, the S2 subunit fusion. As of early 2022, about 7 million SARS-CoV-2 genomes had been sequenced and deposited into public databases and another 800,000 or so were added each month. By September 2023, the GISAID EpiCoV database contained more than 16 million genome sequences. SARS-CoV-2 has a linear, positive-sense , single-stranded RNA genome about 30,000 bases long. Its genome has a bias against cytosine (C) and guanine (G) nucleotides , like other coronaviruses. The genome has the highest composition of U (32.2%), followed by A (29.9%), and a similar composition of G (19.6%) and C (18.3%). The nucleotide bias arises from the mutation of guanines and cytosines to adenosines and uracils , respectively. The mutation of CG dinucleotides is thought to arise to avoid the zinc finger antiviral protein related defense mechanism of cells, and to lower the energy to unbind the genome during replication and translation (adenosine and uracil base pair via two hydrogen bonds , cytosine and guanine via three). The depletion of CG dinucleotides in its genome has led the virus to have a noticeable codon usage bias . For instance, arginine's six different codons have a relative synonymous codon usage of AGA (2.67), CGU (1.46), AGG (.81), CGC (.58), CGA (.29), and CGG (.19). A similar codon usage bias trend is seen in other SARS–related coronaviruses. Virus infections start when viral particles bind to host surface cellular receptors. Protein modeling experiments on the spike protein of the virus soon suggested that SARS‑CoV‑2 has sufficient affinity to the receptor angiotensin converting enzyme 2 (ACE2) on human cells to use them as a mechanism of cell entry . By 22 January 2020, a group in China working with the full virus genome and a group in the United States using reverse genetics methods independently and experimentally demonstrated that ACE2 could act as the receptor for SARS‑CoV‑2. Studies have shown that SARS‑CoV‑2 has a higher affinity to human ACE2 than the original SARS virus. SARS‑CoV‑2 may also use basigin to assist in cell entry. Initial spike protein priming by transmembrane protease, serine 2 (TMPRSS2) is essential for entry of SARS‑CoV‑2. The host protein neuropilin 1 (NRP1) may aid the virus in host cell entry using ACE2. After a SARS‑CoV‑2 virion attaches to a target cell, the cell's TMPRSS2 cuts open the spike protein of the virus, exposing a fusion peptide in the S2 subunit, and the host receptor ACE2. After fusion, an endosome forms around the virion, separating it from the rest of the host cell. The virion escapes when the pH of the endosome drops or when cathepsin , a host cysteine protease, cleaves it. The virion then releases RNA into the cell and forces the cell to produce and disseminate copies of the virus , which infect more cells. SARS‑CoV‑2 produces at least three virulence factors that promote shedding of new virions from host cells and inhibit immune response . Whether they include downregulation of ACE2, as seen in similar coronaviruses, remains under investigation (as of May 2020). Each SARS-CoV-2 virion is 60–140 nanometres (2.4 × 10 −6 –5.5 × 10 −6 in) in diameter; its mass within the global human populace has been estimated as being between 0.1 and 10 kilograms. Like other coronaviruses, SARS-CoV-2 has four structural proteins, known as the S ( spike ), E ( envelope ), M ( membrane ), and N ( nucleocapsid ) proteins; the N protein holds the RNA genome, and the S, E, and M proteins together create the viral envelope . Coronavirus S proteins are glycoproteins and also type I membrane proteins (membranes containing a single transmembrane domain oriented on the extracellular side). They are divided into two functional parts (S1 and S2). In SARS-CoV-2, the spike protein, which has been imaged at the atomic level using cryogenic electron microscopy , is the protein responsible for allowing the virus to attach to and fuse with the membrane of a host cell; specifically, its S1 subunit catalyzes attachment, the S2 subunit fusion. As of early 2022, about 7 million SARS-CoV-2 genomes had been sequenced and deposited into public databases and another 800,000 or so were added each month. By September 2023, the GISAID EpiCoV database contained more than 16 million genome sequences. SARS-CoV-2 has a linear, positive-sense , single-stranded RNA genome about 30,000 bases long. Its genome has a bias against cytosine (C) and guanine (G) nucleotides , like other coronaviruses. The genome has the highest composition of U (32.2%), followed by A (29.9%), and a similar composition of G (19.6%) and C (18.3%). The nucleotide bias arises from the mutation of guanines and cytosines to adenosines and uracils , respectively. The mutation of CG dinucleotides is thought to arise to avoid the zinc finger antiviral protein related defense mechanism of cells, and to lower the energy to unbind the genome during replication and translation (adenosine and uracil base pair via two hydrogen bonds , cytosine and guanine via three). The depletion of CG dinucleotides in its genome has led the virus to have a noticeable codon usage bias . For instance, arginine's six different codons have a relative synonymous codon usage of AGA (2.67), CGU (1.46), AGG (.81), CGC (.58), CGA (.29), and CGG (.19). A similar codon usage bias trend is seen in other SARS–related coronaviruses. Virus infections start when viral particles bind to host surface cellular receptors. Protein modeling experiments on the spike protein of the virus soon suggested that SARS‑CoV‑2 has sufficient affinity to the receptor angiotensin converting enzyme 2 (ACE2) on human cells to use them as a mechanism of cell entry . By 22 January 2020, a group in China working with the full virus genome and a group in the United States using reverse genetics methods independently and experimentally demonstrated that ACE2 could act as the receptor for SARS‑CoV‑2. Studies have shown that SARS‑CoV‑2 has a higher affinity to human ACE2 than the original SARS virus. SARS‑CoV‑2 may also use basigin to assist in cell entry. Initial spike protein priming by transmembrane protease, serine 2 (TMPRSS2) is essential for entry of SARS‑CoV‑2. The host protein neuropilin 1 (NRP1) may aid the virus in host cell entry using ACE2. After a SARS‑CoV‑2 virion attaches to a target cell, the cell's TMPRSS2 cuts open the spike protein of the virus, exposing a fusion peptide in the S2 subunit, and the host receptor ACE2. After fusion, an endosome forms around the virion, separating it from the rest of the host cell. The virion escapes when the pH of the endosome drops or when cathepsin , a host cysteine protease, cleaves it. The virion then releases RNA into the cell and forces the cell to produce and disseminate copies of the virus , which infect more cells. SARS‑CoV‑2 produces at least three virulence factors that promote shedding of new virions from host cells and inhibit immune response . Whether they include downregulation of ACE2, as seen in similar coronaviruses, remains under investigation (as of May 2020). Very few drugs are known to effectively inhibit SARS‑CoV‑2. Masitinib is a clinically safe drug and was recently found to inhibit its main protease , 3CLpro and showed >200-fold reduction in viral titers in the lungs and nose in mice. However, it is not approved for the treatment of COVID-19 in humans as of August 2021. [ needs update ] In December 2021, the United States granted emergency use authorization to Nirmatrelvir/ritonavir for the treatment of the virus; the European Union , United Kingdom , and Canada followed suit with full authorization soon after. One study found that Nirmatrelvir/ritonavir reduced the risk of hospitalization and death by 88%. COVID Moonshot is an international collaborative open-science project started in March 2020 with the goal of developing an un- patented oral antiviral drug for treatment of SARS-CoV-2. Retrospective tests collected within the Chinese surveillance system revealed no clear indication of substantial unrecognized circulation of SARS‑CoV‑2 in Wuhan during the latter part of 2019. A meta-analysis from November 2020 estimated the basic reproduction number ( R 0 {\displaystyle R_{0}} ) of the virus to be between 2.39 and 3.44. This means each infection from the virus is expected to result in 2.39 to 3.44 new infections when no members of the community are immune and no preventive measures are taken. The reproduction number may be higher in densely populated conditions such as those found on cruise ships . Human behavior affects the R0 value and hence estimates of R0 differ between different countries, cultures, and social norms. For instance, one study found relatively low R0 (~3.5) in Sweden, Belgium and the Netherlands, while Spain and the US had significantly higher R0 values (5.9 to 6.4, respectively). There have been about 96,000 confirmed cases of infection in mainland China. While the proportion of infections that result in confirmed cases or progress to diagnosable disease remains unclear, one mathematical model estimated that 75,815 people were infected on 25 January 2020 in Wuhan alone, at a time when the number of confirmed cases worldwide was only 2,015. Before 24 February 2020, over 95% of all deaths from COVID-19 worldwide had occurred in Hubei province , where Wuhan is located. As of 10 March 2023 , the percentage had decreased to 0.047% . As of 10 March 2023 , there were 676,609,955 total confirmed cases of SARS‑CoV‑2 infection. The total number of deaths attributed to the virus was 6,881,955 .

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Acute hemorrhagic fever syndrome

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Syndrome of inappropriate antidiuretic hormone secretion

The syndrome of inappropriate antidiuretic hormone secretion ( SIADH ), also known as the syndrome of inappropriate antidiuresis (SIAD), is characterized by a physiologically inappropriate release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source. Unsuppressed ADH causes a physiologically inappropriate increase in solute-free water being reabsorbed by the tubules of the kidney to the venous circulation leading to hypotonic hyponatremia (a low plasma osmolality and low sodium levels). The causes of SIADH are commonly grouped into categories including: central nervous system diseases that directly stimulate the hypothalamus to release ADH, various cancers that synthesize and secrete ectopic ADH, various lung diseases, numerous drugs that may stimulate the release of ADH, enhance ADH effects, act as ADH analogues in the body, or stimulate the vasopressin receptor 2 at the kidney (the site of ADH action); or inherited mutations leading to a gain of function of the vasopressin-2 receptor (a very rare occurrence). Inappropriate antidiuresis may also be due to acute stressors such as exercise, pain, severe nausea or during the post-operative state. In 17-60% of people, the cause of inappropriate antidiuresis is never found. ADH is derived from a preprohormone precursor that is synthesized in cells in the hypothalamus and stored in vesicles in the posterior pituitary. Appropriate ADH secretion is regulated by osmoreceptors on the hypothalamic cells that synthesize and store ADH: plasma hypertonicity activates these receptors, ADH is released into the blood stream, the kidney increases solute-free water reabsorption and return to the circulation, and the hypertonicity is alleviated. A decrease in the effective circulating volume of blood (the volume of arterial blood effectively perfusing tissues) also stimulates an appropriate, physiologic release of ADH. Inappropriate (increased) ADH secretion causes a physiologically inappropriate water reabsorption by the kidneys . This causes the extracellular fluid (ECF) space to become hypo-osmolar, including a low sodium concentration (hyponatremia). In the intracellular space , cells swell as intracellular volume increases as water moves from an area of low solute concentration (extracellular space) to an area of high solute concentration (the cells' interior). In severe or acute hypoosmolar hyponatremia, swelling of brain cells causes various neurological abnormalities, which in severe or acute cases can result in convulsions , coma , and death . The symptoms of chronic syndrome of inappropriate antidiuresis are more vague, and may include cognitive impairment , gait abnormalities , or osteoporosis . The main treatment of inappropriate antidiuresis is to identify and treat the underlying cause, if possible. This usually causes plasma osmolality and sodium levels to return to normal in several days. In those in which an underlying cause cannot be found, or is untreatable, treatments are targeted to alleviating correcting the hypoosmolality and hyponatremia. These include restriction of fluid intake, using salt tablets (sometimes with diuretics ), urea supplements, or increasing the protein intake. The vasopressin receptor 2 blocker tolvaptan may also be used. The presence of cerebral edema , or other moderate to severe symptoms, may necessitate intravenous hypertonic saline administration with close monitoring of the serum sodium levels to avoid overcorrection. SIADH was originally described in 1957 in two people with small-cell carcinoma of the lung. Muscle aches Generalized muscle weakness Muscle aches Generalized muscle weakness Causes of SIADH include conditions that dysregulate ADH secretion in the central nervous system, tumors that secrete ADH, drugs that increase ADH secretion, among other causes. Cancer accounts for an estimated 24% of cases of SIADH, with 25% of those causes due to small cell lung cancer . Medications or drugs are responsible for 18% of cases of SIADH. This is due to a variety of mechanisms including: stimulation of ADH release ( opiates , ifosfamide , vincristine , platinum-based antineoplastics and MDMA (also known as ecstasy); enhancers of ADH effect ( Non-steroidal anti-inflammatories ); ADH analogues ( desmopressin , oxytocin ); and vasopressin receptor 2 activators ( selective serotonin reuptake inhibitors (SSRIs), haloperidol , carbamazepine , cyclophosphamide , and chlorpropamide ). Of the causes of medication induced syndrome of inappropriate antidiuresis, antidepressants (especially SSRIs) are the most common culprit. Central nervous system (CNS) disorders or conditions may cause SIADH in 9% of cases, this includes subarachnoid hemorrhage (56% of CNS causes), pituitary surgery (35% of CNS causes), brain cancer, infections, stroke and head trauma. No cause of inappropriate antidiuresis is initially found in 17-60% of cases. A list of common causes is below: Endurance exercise General anesthesiaNormally there are homeostatic processes in the body which maintain the concentration of body solutes within a narrow range, both inside and outside cells. The process occurs as follows: in some hypothalamic cells there are osmoreceptors which respond to hyperosmolality in body fluids by signalling the posterior pituitary gland to secrete ADH. This keeps serum sodium concentration - a proxy for solute concentration - at normal levels, prevents hypernatremia and turns off the osmoreceptors. Specifically, when the serum sodium rises above 142 mEq/L, ADH secretion is maximal (and thirst is stimulated as well); when it is below 135 mEq/L, there is no secretion. ADH activates V2 receptors on the basolateral membrane of principal cells in the renal collecting duct, initiating a cyclic AMP-dependent process that culminates in increased production of water channels (aquaporin 2), and their insertion into the cells' luminal membranes. Excessive ADH causes an inappropriate increase in the reabsorption in the kidneys of solute-free water ("free water"): excess water moves from the distal convoluted tubules (DCTs) and collecting tubules of the nephrons - via activation of aquaporins , the site of the ADH receptors - back into the circulation . This has two consequences. First, in the extracellular fluid (ECF) space, there is a dilution of blood solutes , causing hypo osmolality , including a low sodium concentration - hyponatremia . [There is no expansion of the ECF volume because as it attempts to expand, aldosterone is suppressed and atrial natriuretic peptide (ANP) is stimulated: both of these hormones cause isotonic ECF fluid to be excreted by the kidneys sufficient to keep ECF volume at a normal level.] Also, virtually simultaneously to these ECF events, the intracellular space (ICF) volume expands. This is because the osmolality of the ECF is (transiently) less than that of the ICF; and since water is readily permeable to cell membranes, solute-free water moves from the ECF to the ICF compartment by osmosis : all cells swell. Swelling of brain cells - cerebral edema - causes various neurological abnormalities which in acute and/or severe cases can result in convulsions , coma , and death . [ citation needed ] The normal function of ADH on the kidneys is to control the amount of water reabsorbed by kidney nephrons . ADH acts in the distal portion of the renal tubule ( Distal Convoluted Tubule ) as well as on the collecting duct and causes the retention of water, but not solute. Hence, ADH activity effectively dilutes the blood (decreasing the concentrations of solutes such as sodium ), causing hyponatremia ; this is compounded by the fact that the body responds to water retention by decreasing aldosterone , thus allowing even more sodium wasting. For this reason, a high urinary sodium excretion will be seen. The abnormalities underlying type D syndrome of inappropriate antidiuretic hormone hypersecretion concern individuals where vasopressin release and response are normal but where abnormal renal expression and translocation of aquaporin 2 , or both are found. It has been suggested that this is due to abnormalities in the secretion of secretin in the brain and that "Secretin as a neurosecretory hormone from the posterior pituitary, therefore, could be the long-sought vasopressin independent mechanism to solve the riddle that has puzzled clinicians and physiologists for decades." There are no abnormalities in total body sodium metabolism. Hyponatremia and inappropriately concentrated urine (U Osm >100 mOsm/L) are seen Diagnosis is based on clinical and laboratory findings of low serum osmolality and low serum sodium. Urinalysis reveals a highly concentrated urine with a high fractional excretion of sodium (high sodium urine content compared to the serum sodium). A suspected diagnosis is based on a serum sodium under 138. A confirmed diagnosis has seven elements: 1) a decreased effective serum osmolality - 1%; 7) a fractional urea excretion >55%; 8) an abnormal water load test; and 9) an elevated plasma AVP. Antidiuretic hormone (ADH) is released from the posterior pituitary for a number of physiologic reasons. The majority of people with hyponatremia, other than those with excessive water intake ( polydipsia ) or renal salt wasting, will have elevated ADH as the cause of their hyponatremia. However, not every person with hyponatremia and elevated ADH has SIADH. One approach to a diagnosis is to divide ADH release into appropriate (not SIADH) or inappropriate (SIADH). Appropriate ADH release can be a result of hypovolemia, a so-called non-osmotic trigger of ADH release. This may be true hypovolemia, as a result of dehydration with fluid losses replaced by free water. It can also be perceived hypovolemia, as in the conditions of congestive heart failure (CHF) and cirrhosis in which the kidneys perceive a lack of intravascular volume. The hyponatremia caused by appropriate ADH release (from the kidneys' perspective) in both CHF and cirrhosis have been shown to be an independent poor prognostic indicator of mortality. Appropriate ADH release can also be a result of non-osmotic triggers. Symptoms such as nausea/vomiting and pain are significant causes of ADH release. The combination of osmotic and non-osmotic triggers of ADH release can adequately explain the hyponatremia in the majority of people who are hospitalized with acute illness and are found to have mild to moderate hyponatremia. SIADH is less common than appropriate release of ADH. While it should be considered in a differential, other causes should be considered as well. Cerebral salt wasting syndrome (CSWS) also presents with hyponatremia , there are signs of dehydration for which reason the management is diametrically opposed to SIADH. Importantly CSWS can be associated with subarachnoid hemorrhage (SAH) which may require fluid supplementation rather than restriction to prevent brain damage. Most cases of hyponatremia in children are caused by appropriate secretion of antidiuretic hormone rather than SIADH or another cause. Antidiuretic hormone (ADH) is released from the posterior pituitary for a number of physiologic reasons. The majority of people with hyponatremia, other than those with excessive water intake ( polydipsia ) or renal salt wasting, will have elevated ADH as the cause of their hyponatremia. However, not every person with hyponatremia and elevated ADH has SIADH. One approach to a diagnosis is to divide ADH release into appropriate (not SIADH) or inappropriate (SIADH). Appropriate ADH release can be a result of hypovolemia, a so-called non-osmotic trigger of ADH release. This may be true hypovolemia, as a result of dehydration with fluid losses replaced by free water. It can also be perceived hypovolemia, as in the conditions of congestive heart failure (CHF) and cirrhosis in which the kidneys perceive a lack of intravascular volume. The hyponatremia caused by appropriate ADH release (from the kidneys' perspective) in both CHF and cirrhosis have been shown to be an independent poor prognostic indicator of mortality. Appropriate ADH release can also be a result of non-osmotic triggers. Symptoms such as nausea/vomiting and pain are significant causes of ADH release. The combination of osmotic and non-osmotic triggers of ADH release can adequately explain the hyponatremia in the majority of people who are hospitalized with acute illness and are found to have mild to moderate hyponatremia. SIADH is less common than appropriate release of ADH. While it should be considered in a differential, other causes should be considered as well. Cerebral salt wasting syndrome (CSWS) also presents with hyponatremia , there are signs of dehydration for which reason the management is diametrically opposed to SIADH. Importantly CSWS can be associated with subarachnoid hemorrhage (SAH) which may require fluid supplementation rather than restriction to prevent brain damage. Most cases of hyponatremia in children are caused by appropriate secretion of antidiuretic hormone rather than SIADH or another cause. Managing SIADH depends on whether symptoms are present, the severity of the hyponatremia, and the duration. Management of SIADH includes: 40% of all hospitalized adults aged 65 and older have hyponatremia, with an estimated 25-40% of those cases being due to inappropriate antidiuresis. The incidence of SIADH rises with increasing age with residents of nursing homes being at highest risk. The condition was first described at separate institutions by William Schwartz and Frederic Bartter in two people with lung cancer . Criteria were developed by Schwartz and Bartter in 1967 and have remained unchanged since then. The condition is occasionally referred to by the names of the authors of the first report: Schwartz-Bartter syndrome . Because not all people with this syndrome have elevated levels of vasopressin, the term "syndrome of inappropriate antidiuresis" (SIAD) has been proposed as a more accurate description of this condition.

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Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/Kyasanur_Forest_disease/html

Kyasanur Forest disease

Kyasanur forest disease ( KFD ) is a tick-borne viral haemorrhagic fever endemic to South-western part of India. The disease is caused by a virus belonging to the family Flaviviridae . KFDV is transmitted to humans through the bite of infected hard ticks ( Haemaphysalis spinigera ) which act as a reservoir of KFDV.The symptoms of the disease include a high fever with frontal headaches, chills, severe muscle pain, vomiting, and other gastrointestinal symptoms. Bleeding problems may occur 3–4 days after initial symptom onset. Patients may experience abnormally low blood pressure, and low platelet, red blood cell, and white blood cell count. After 1–2 weeks of symptoms, some patients recover without complication. However, the illness is biphasic for a subset of patients (10-20%) who experience a second wave of symptoms at the beginning of the third week. These symptoms include fever and signs of neurological manifestations, such as severe headache, mental disturbances, tremors, and vision deficits. The convalescent period is typically very long, lasting several months. Muscle aches and weakness also occur during this period, and the patient is unable to engage in physical activities.Kyasanur Forest virus The KFD virus is a typical flavivirus measuring about 40-60 nm in diameter. The genome of KFDV consists of 10,774 nucleotides of single-stranded, positive-sense RNA encoding a single polyprotein that is cleaved post-translationally into three structural (C, prM/M and E) and seven non-structural (NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5) proteins. The genome of KFDV is very similar (>92% homologous) to that of Alkhurma Hemorrhagic Fever Virus which is primarily found in Saudi Arabia . These two species both belong to the family Flaviviridae and diverged over 700 years ago and have thus remained geographically separated. A variety of animals are thought to be reservoir hosts for the disease, including porcupines, rats, squirrels, mice, and shrews. Monkeys are the main amplifying hosts for KFD virus and they are also affected by the virus. The surili Presbytis entellus and the bonnet macaque are very susceptible to the KFD virus. They develop tremendous viremia and infect the ticks. The vector for disease transmission is Haemaphysalis spinigera , a forest tick . Humans contract infection from the bite of nymphs of the tick. Man is a terminal host and there no human-to-human transmission because the human domestic environment does not sustain the ticks.Kyasanur Forest virus The KFD virus is a typical flavivirus measuring about 40-60 nm in diameter. The genome of KFDV consists of 10,774 nucleotides of single-stranded, positive-sense RNA encoding a single polyprotein that is cleaved post-translationally into three structural (C, prM/M and E) and seven non-structural (NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5) proteins. The genome of KFDV is very similar (>92% homologous) to that of Alkhurma Hemorrhagic Fever Virus which is primarily found in Saudi Arabia . These two species both belong to the family Flaviviridae and diverged over 700 years ago and have thus remained geographically separated. A variety of animals are thought to be reservoir hosts for the disease, including porcupines, rats, squirrels, mice, and shrews. Monkeys are the main amplifying hosts for KFD virus and they are also affected by the virus. The surili Presbytis entellus and the bonnet macaque are very susceptible to the KFD virus. They develop tremendous viremia and infect the ticks. The vector for disease transmission is Haemaphysalis spinigera , a forest tick . Humans contract infection from the bite of nymphs of the tick. Man is a terminal host and there no human-to-human transmission because the human domestic environment does not sustain the ticks.The pathogenesis of KFDV is not completely understood . Research using mice models found that KFDV primarily replicated in the brain. Other research has expanded on this by described neurological changes that occurred within infected organisms. This experiment was completed by using KFDV-infected mice and discovered that KFDV caused gliosis , inflammation, and cell death in the brain. They posited that KFDV could be primarily a neuropathic disease and other symptoms are due to this pathogenesis. In earlier days suspected case were confirmed in a laboratory by serum inoculation into suckling mice (Swiss Albino mice) and subsequent death of mice was leveled as KFD Positive case. Other methods of diagnosis included hemagglutination inhibition (HI), complement fixation , neutralization tests . However, new research has introduced more efficient molecular based methods to diagnose KFDV. These methods include: RT-PCR, nested RT-PCR , TaqMan-based real-time RT-PCR , Immunoglobin M antibodies and Immunoglobin G detection by ELISA . The two methods involving RT- PCR are able to function by attaching a primer to the NS-5 gene, which is highly conserved among the genus to which KFDV belongs. PCR positivity is limited to 8–10 days from the onset of symptoms. The ELISA based methods allows for the detections of anti-KFDV antibodies in patients typically from 5th day of onset of symptoms up to 3 months. Prevention is by vaccination, as well as preventive measures such as protective clothing and tick population control. The vaccine for KFDV consists of formalin -inactivated KFDV. The vaccine has a 62.4% effectiveness rate for individuals who receive two doses. For individuals who receive an additional dose, the effectiveness increases to 82.9%. Specific antiviral treatments are not available as of 2022. The spill-over of Kyasanur forest disease happens at the crossroads of the animal-human interaction, especially villages adjoining forest areas and inter-state borders. People who frequently visit the forest areas of the Western Ghats region such as forest guards and officials, range forest officer (RFO), forest watchers, shepherds, firewood collectors, dry leaf collectors, hunters, people who handle dead animal carcasses, travelers who camp in the forest areas, tribal communities living inside the forest areas (Jenu kurubas and Betta kurubas), cashew nut workers especially those who engage in cleaning the dry leaves before the harvest season (seen in Pali and Mauxi outbreaks, North Goa), and areca nut farm workers working in infected tick areas will have a high risk of acquiring KFD infection. People who live in the KFD endemic areas and refuse to take KFD vaccination are at risk in contracting the infection.The disease was first reported from Kattinakere village forest which is in the Kyasanur forest range of Karnataka in India in March 1957. When the officials visited the Kattinakere forest and discovered the diseases they noticed a sign board informing that this was the Kyasanur forest range. Hence the name. The disease first manifested as an epizootic outbreak among monkeys, killing several of them in the year 1957. Hence the disease is also locally known as "monkey disease" or "monkey fever". The similarity with Russian spring-summer encephalitis was noted by the British neurovirologist Hubert Webb and the possibility of migratory birds carrying the disease was raised. Studies began to look for the possible species that acted as reservoirs for the virus and the agents responsible for transmission. Subsequent studies failed to find any involvement of migratory birds, although the possibility of their role in initial establishment was not ruled out. The virus was found to be quite distinctive and not closely related to the Russian virus strains. Antigenic relatedness is, however, close to many other strains including the Omsk hemorrhagic fever (OHF) and birds from Siberia have been found to show an antigenic response to KFD virus. Sequence based studies note the distinctiveness of OHF. Early studies in India were conducted in collaboration with the US Army Medical Research Unit and this led to controversy and conspiracy theories. Subsequent studies based on sequencing found that the Alkhurma virus found in Saudi Arabia is closely related. In 1989 a patient in Nanjianin, China was found with fever symptoms and in 2009 its viral gene sequence was found to exactly match with that of the KFD reference virus of 1957. This has been questioned, though, since the Indian virus shows variations in sequence over time and the exact match with the virus sequence of 1957 and the Chinese virus of 1989 is not expected. This study also found using immune response tests that birds and humans in the region appeared to have been exposed to the virus. Another study has suggested that the virus is recent in origin dating the nearest common ancestor of it and related viruses to around 1942, based on the estimated rate of sequence substitutions. The study also raises the possibility of bird involvement in long-distance transfer. It appears that these viruses diverged 700 years ago. A recent outbreak in 2020, claimed two lives in Siddapura , Karnataka. The peak season for this disease in Malnad is from March till May but has been observed to peak earlier in the year as well. There were a total of 55 reported cases in Shivamogga district, Karntaka. The disease initially reported from Shimoga district of Karnataka which is a primitive sylvan territory in Western Ghats of India. The disease spread out to other districts of Karnataka involving districts of Chikkamagalore, Uttara Kannada, Dakshina Kannada, Udupi, Chamarajanagar (2012), Belagavi (2016). In 2013, KFDV was detected in monkey autopsies from Nilgiris district of Tamil Nadu state. Monkey deaths and human cases have now been reported from three neighbouring states bordering Karnataka, i.e., Wayanad (2013) and Malappuram districts of Kerala (2014), North Goa district of Goa state (2015), and Sindhudurg district of Maharashtra (2016). There are reported serological evidence for KFD detected in humans in other parts of India, namely Kutch and Saurashtra regions of Gujarat state, Kingaon and Parbatpur of West Bengal state. A seroprevalence study in Andaman and Nicobar islands in 2002 revealed a high prevalence of hemagglutination inhibition (HI) antibodies against KFDV. The disease has a fatality rate of 3-10%, and it affects 400-500 people annually. The disease was first noted at Kyasanur village near Sagar in Shivamogga district of Karnataka. The virus has been detected in monkeys in parts of Bandipur National Park (Chamarajnagar) and parts of the Nilgiris. Human infection occurred in Bandipur through handling of dead monkeys that were infected. A human carrier was also detected in Wayanad (Kerala). The disease has shown its presence in the adjacent states of Karnataka including Kerala, Maharashtra, Goa, Tamil Nadu and Gujarat.

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Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/Capillary_leak_syndrome/html

Capillary leak syndrome

Capillary leak syndrome , or vascular leak syndrome , is characterized by the escape of blood plasma through capillary walls , from the blood circulatory system to surrounding tissues, muscle compartments, organs or body cavities. It is a phenomenon most commonly witnessed in sepsis , and less frequently in autoimmune diseases , differentiation syndrome , engraftment syndrome , hemophagocytic lymphohistiocytosis , the ovarian hyperstimulation syndrome , viral hemorrhagic fevers , and snakebite and ricin poisoning. Pharmaceuticals, including the chemotherapy medications gemcitabine and denileukin diftitox , as well as certain interleukins and monoclonal antibodies , can also cause capillary leaks. These conditions and factors are sources of secondary capillary leak syndrome. Systemic capillary leak syndrome (SCLS), also called Clarkson's disease , or primary capillary leak syndrome, is a rare, grave and episodic medical condition observed largely in otherwise healthy individuals mostly in middle age. It is characterized by self-reversing episodes during which the endothelial cells which line the capillaries, usually of the extremities, separate for one to three days, causing a leakage of plasma mainly into the muscle compartments of the arms and legs. The abdomen, the central nervous system, and the organs (including the lungs) are typically spared, but the extravasation in the extremities is sufficiently massive to cause circulatory shock and compartment syndromes , with a dangerous hypotension (low blood pressure), hemoconcentration (thickening of the blood) and hypoalbuminemia (drop in albumin , a major protein) in the absence of other causes for such abnormalities. SCLS is thus a limb- and life-threatening illness, because each episode has the potential to cause damage to limb muscles and nerves, as well as to vital organs due to limited perfusion . It is often misdiagnosed as polycythemia , polycythemia vera , hyperviscosity syndrome , or sepsis . Most SCLS patients succumb to viral infections manifesting themselves by way of flu-like symptoms (like a runny nose), gastro-intestinal disorders (diarrhea or vomiting), or general weakness or pain in the limbs, but others get no particular or consistent warning signs ahead of their episodes. They subsequently develop thirst and lightheadedness and the following conditions measurable in a hospital emergency-room setting: Although the precise molecular cause of SCLS remains undetermined, scientific research in recent years, conducted mainly at a unit ( NIAID ) of the U.S. National Institutes of Health , has shed some light on its biological and chemical roots. The study of the peripheral microvasculature from patients' biopsy specimens has not evidenced gross anomalies, disrupted angiogenesis , or inflammatory cells or other factors suggestive of a disorder prone to damage the blood vessels by inflammation. The absence of structural abnormalities is thus consistent with the hypothesis of some kind of defective but curiously reversible cellular phenomenon in the capillaries. Studies suggest that the presence of various inflammatory factors during episodes of SCLS may explain the temporarily abnormal permeability of the endothelial cells lining the inner surface of the capillaries. These include transient spikes in monocyte - and macrophage -associated inflammatory mediators and temporary increases in the proteins vascular endothelial growth factors ( VEGF ) and angiopoietin-2 . The impairment of endothelial cells in laboratory conditions provoked by serum taken from patients who were having episodes of SCLS is also suggestive of biochemical factors at work. There is no evidence that SCLS is hereditary, and the role of specific gene defects in patients with SCLS, which might program their endothelial cells for an overreaction to external stimuli such as viral infections, has not been established. The significance, if any, of the paraprotein (MGUS) present in most patients with SCLS is unknown, other than it has been a precursor to multiple myeloma in a minority (7% in the largest reported cohort ) of SCLS patients. SCLS is often difficult to recognize and diagnose on initial presentation, and thus misdiagnoses are frequent. The characteristic triad of profound arterial hypotension, hemoconcentration (elevated hematocrit, leukocytosis , and thrombocytosis ), and hypoalbuminemia in the absence of secondary causes of shock and infection, requires diagnosis in a monitored hospital setting during or after an acute episode. The fact that the condition is exceedingly rare – an estimated one per million inhabitants – and that several other diseases exhibit features akin to SCLS, including secondary capillary-leak syndrome or hypoproteinemia, militate against early identification. Preserved consciousness, despite severe shock and hypotension, is an additional and most intriguing clinical manifestation often reported during episodes at hospital admission. The natural history of SCLS episodes indicates they usually resolve spontaneously within 2-to-4 days, and that they consist of two distinct phases: The initial stage is the capillary leak phase, lasting from 1 to 3 days, during which up to 70% of total plasma volume invades body cavities, especially in the extremities. The most common clinical features are flu-like symptoms such as fatigue; runny nose; lightheadedness up to and including syncope (fainting); limb, abdominal or generalized pain; facial or other edema ; dyspnea ; and hypotension that results in circulatory shock and potentially in cardiopulmonary collapse and other organ distress or damage. Acute kidney injury or failure is a common risk due to acute tubular necrosis consequent to hypovolemia and rhabdomyolysis . The escape of fluid out of the capillaries has similar effects on the circulation as dehydration , slowing both the flow of oxygen delivered to tissues and organs as well as the output of urine , causing oliguria . Urgent medical attention in this phase often features fluid resuscitation efforts, mainly the intravenous administration of saline solution plus hetastarch or albumin and colloids (to increase the remaining blood flow to vital organs like the kidneys), as well as glucocorticoids (steroids like methylprednisolone , to reduce or stop the capillary leak). However, the impact of such fluid therapy is always transient and leads to increased extravascular fluid accumulation, engendering multiple complications especially compartment syndrome and thus limb-destructive rhabdomyolysis. Consequently, fluid resuscitation should be minimized as much as possible in patients experiencing episodes of SCLS, and they should be closely monitored in a hospital intensive-care setting including for orthopedic complications requiring surgical decompression. Recent clinical experience suggests that administration of immunoglobulins (IVIG) with minimal additional intravenous fluids, close to the start of an episode of SCLS, is a safe way to support patients during their leak phase and is associated with rapid clinical improvement. The second stage features the reabsorption of the initially extravasated fluid and albumin from the tissues, and it usually lasts 1 to 2 days. Intravascular fluid overload leads to polyuria and can cause flash pulmonary edema and cardiac arrest , with possibly fatal consequences. Death from SCLS typically occurs during this recruitment phase because of pulmonary edema arising from excessive intravenous fluid administration during the earlier leak phase. The severity of the problem depends on to the quantity of fluid supplied in the initial phase, the damage that may have been sustained by the kidneys, and the promptness with which diuretics are administered to help the patient discharge the accumulated fluids quickly. A recent study of 59 acute episodes occurring in 37 hospitalized SCLS patients concluded that high-volume fluid therapy was independently associated with poorer clinical outcomes, and that the main complications of SCLS episodes were recovery-phase pulmonary edema (24%), cardiac arrhythmia (24%), compartment syndrome (20%), and acquired infections (19%). The prevention of episodes of SCLS has involved two approaches. The earliest was advocated by the Mayo Clinic, and it recommended treatment with high doses of beta agonists such as terbutaline , phosphodiesterase - inhibitor theophylline , and leukotriene - receptor antagonists montelukast sodium . The rationale for use of these drugs was their ability to increase intracellular cyclic AMP (adenosine monophosphate) levels, which might counteract inflammatory signaling pathways that induce endothelial permeability. It was the standard of care until the early 2000s, but was sidelined afterwards because patients frequently experienced renewed episodes of SCLS, and because these drugs were poorly tolerated due to their unpleasant side effects. The second, more recent approach pioneered in France during the early 2000s involves monthly intravenous infusions of immunoglobulins (IVIG), with an initial dose of 1-2 gr/kg/month of body weight, which has proven very successful as per abundant case-report evidence from around the world. IVIG has long been used for the treatment of autoimmune and MGUS-associated syndromes, because of its potential immunomodulatory and anticytokine properties. The precise mechanism of action of IVIG in patients with SCLS is unknown, but it is likely that it neutralizes their proinflammatory cytokines that provoke endothelial dysfunction. A review of clinical experience with 69 mostly European SCLS patients found that preventive treatment with IVIG was the strongest factor associated with their survival, such that an IVIG therapy should be the first-line preventive agent for SCLS patients. According to an NIH survey of patient experience, IVIG prophylaxis is associated with a dramatic reduction in the occurrence of SCLS episodes in most patients, with minimal side effects, so it may be considered as frontline therapy for those with a clear-cut diagnosis of SCLS and a history of recurrent episodes. A recent study involving 59 patients to evaluate the safety of IVIG tapering and withdrawal in French and Italian patients with SCLS concluded that the incidence of severe flares was not statistically different across the different dosages of IVIG, but that withdrawal was associated with increased mortality and higher rates of recurrence, such that lifelong treatment with IVIG is recommended for patients with SCLS. The initial stage is the capillary leak phase, lasting from 1 to 3 days, during which up to 70% of total plasma volume invades body cavities, especially in the extremities. The most common clinical features are flu-like symptoms such as fatigue; runny nose; lightheadedness up to and including syncope (fainting); limb, abdominal or generalized pain; facial or other edema ; dyspnea ; and hypotension that results in circulatory shock and potentially in cardiopulmonary collapse and other organ distress or damage. Acute kidney injury or failure is a common risk due to acute tubular necrosis consequent to hypovolemia and rhabdomyolysis . The escape of fluid out of the capillaries has similar effects on the circulation as dehydration , slowing both the flow of oxygen delivered to tissues and organs as well as the output of urine , causing oliguria . Urgent medical attention in this phase often features fluid resuscitation efforts, mainly the intravenous administration of saline solution plus hetastarch or albumin and colloids (to increase the remaining blood flow to vital organs like the kidneys), as well as glucocorticoids (steroids like methylprednisolone , to reduce or stop the capillary leak). However, the impact of such fluid therapy is always transient and leads to increased extravascular fluid accumulation, engendering multiple complications especially compartment syndrome and thus limb-destructive rhabdomyolysis. Consequently, fluid resuscitation should be minimized as much as possible in patients experiencing episodes of SCLS, and they should be closely monitored in a hospital intensive-care setting including for orthopedic complications requiring surgical decompression. Recent clinical experience suggests that administration of immunoglobulins (IVIG) with minimal additional intravenous fluids, close to the start of an episode of SCLS, is a safe way to support patients during their leak phase and is associated with rapid clinical improvement. The second stage features the reabsorption of the initially extravasated fluid and albumin from the tissues, and it usually lasts 1 to 2 days. Intravascular fluid overload leads to polyuria and can cause flash pulmonary edema and cardiac arrest , with possibly fatal consequences. Death from SCLS typically occurs during this recruitment phase because of pulmonary edema arising from excessive intravenous fluid administration during the earlier leak phase. The severity of the problem depends on to the quantity of fluid supplied in the initial phase, the damage that may have been sustained by the kidneys, and the promptness with which diuretics are administered to help the patient discharge the accumulated fluids quickly. A recent study of 59 acute episodes occurring in 37 hospitalized SCLS patients concluded that high-volume fluid therapy was independently associated with poorer clinical outcomes, and that the main complications of SCLS episodes were recovery-phase pulmonary edema (24%), cardiac arrhythmia (24%), compartment syndrome (20%), and acquired infections (19%). The prevention of episodes of SCLS has involved two approaches. The earliest was advocated by the Mayo Clinic, and it recommended treatment with high doses of beta agonists such as terbutaline , phosphodiesterase - inhibitor theophylline , and leukotriene - receptor antagonists montelukast sodium . The rationale for use of these drugs was their ability to increase intracellular cyclic AMP (adenosine monophosphate) levels, which might counteract inflammatory signaling pathways that induce endothelial permeability. It was the standard of care until the early 2000s, but was sidelined afterwards because patients frequently experienced renewed episodes of SCLS, and because these drugs were poorly tolerated due to their unpleasant side effects. The second, more recent approach pioneered in France during the early 2000s involves monthly intravenous infusions of immunoglobulins (IVIG), with an initial dose of 1-2 gr/kg/month of body weight, which has proven very successful as per abundant case-report evidence from around the world. IVIG has long been used for the treatment of autoimmune and MGUS-associated syndromes, because of its potential immunomodulatory and anticytokine properties. The precise mechanism of action of IVIG in patients with SCLS is unknown, but it is likely that it neutralizes their proinflammatory cytokines that provoke endothelial dysfunction. A review of clinical experience with 69 mostly European SCLS patients found that preventive treatment with IVIG was the strongest factor associated with their survival, such that an IVIG therapy should be the first-line preventive agent for SCLS patients. According to an NIH survey of patient experience, IVIG prophylaxis is associated with a dramatic reduction in the occurrence of SCLS episodes in most patients, with minimal side effects, so it may be considered as frontline therapy for those with a clear-cut diagnosis of SCLS and a history of recurrent episodes. A recent study involving 59 patients to evaluate the safety of IVIG tapering and withdrawal in French and Italian patients with SCLS concluded that the incidence of severe flares was not statistically different across the different dosages of IVIG, but that withdrawal was associated with increased mortality and higher rates of recurrence, such that lifelong treatment with IVIG is recommended for patients with SCLS. In mostly European experience with 69 patients during 1996–2016, the 5- and 10-year survival rates for SCLS patients were 78% and 69%, respectively, but the survivors received significantly more frequent preventive treatment with IVIG than did non-survivors. Five- and 10-year survival rates in patients treated with IVIG were 91% and 77%, respectively, compared to 47% and 37% in patients not treated with IVIG. Moreover, better identification and management of this condition appears to be resulting in lower mortality and improving survival and quality-of-life results as of late. The syndrome was first described by a team of New York City physicians led by Dr. Bayard D. Clarkson in 1960, after whom it was later informally named. Beyond numerous case reports published since then, three comprehensive reviews of clinical and research experience were published in 2017.

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Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/Acute_promyelocytic_leukemia/html

Acute promyelocytic leukemia

Acute promyelocytic leukemia ( APML , APL ) is a subtype of acute myeloid leukemia (AML), a cancer of the white blood cells . In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes . The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha ( RARA ) gene and is distinguished from other forms of AML by its responsiveness to all- trans retinoic acid (ATRA; also known as tretinoin) therapy. Acute promyelocytic leukemia was first characterized in 1957 by French and Norwegian physicians as a hyperacute fatal illness, with a median survival time of less than a week. Today, prognoses have drastically improved; 10-year survival rates are estimated to be approximately 80-90% according to one study. The symptoms tend to be similar to AML in general with the following being possible symptoms: Easy bleeding from low platelets may include:Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the retinoic acid receptor alpha ( RARA ) gene on chromosome 17 . In 95% of cases of APL, the RARA gene on chromosome 17 is involved in a reciprocal translocation with the promyelocytic leukemia gene ( PML ) on chromosome 15 , a translocation denoted as t(15;17)(q22;q21). The RAR receptor is dependent on retinoic acid for regulation of transcription. Eight other rare gene rearrangements have been described in APL fusing RARA to promyelocytic leukemia zinc finger ( PLZF ), nucleophosmin , nuclear matrix associated, signal transducer and activator of transcription 5b ( STAT5B ), protein kinase A regulatory subunit 1α ( PRKAR1A ), factor interacting with PAPOLA and CPSF1 ( FIP1L1 ), BCL-6 corepressor or oligonucleotide / oligosaccharide -binding fold containing 2A ( NABP1 ) genes. Some of these rearrangements are ATRA-sensitive or have unknown sensitivity to ATRA because they are so rare; STAT5B/RARA and PLZF/RARA are known to be resistant to ATRA. The fusion of PML and RARA results in expression of a hybrid protein with altered functions. This fusion protein binds with enhanced affinity to sites on the cell's DNA, blocking transcription and differentiation of granulocytes. It does so by enhancing interaction of nuclear co-repressor (NCOR) molecule and histone deacetylase (HDAC). Although the chromosomal translocation involving RARA is believed to be the initiating event, additional mutations are required for the development of leukemia . RARA/PLZF gene fusion produces a subtype of APL that is unresponsive to tretinoin therapy and less responsive to standard anthracycline chemotherapy hence leading to poorer long-term outcomes in this subset of patients. Acute promyelocytic leukemia can be distinguished from other types of AML based on microscopic examination of the blood film or a bone marrow aspirate or biopsy as well as finding the characteristic rearrangement. The presence of promyelocytes containing multiple Auer rods (termed faggot cells ) on the peripheral blood smear is highly suggestive of acute promyelocytic leukemia. Definitive diagnosis requires testing for the PML/RARA fusion gene. This may be done by polymerase chain reaction (PCR), fluorescence in situ hybridization , or conventional cytogenetics of peripheral blood or bone marrow. This mutation involves a translocation of the long arms of chromosomes 15 and 17. On rare occasions, a cryptic translocation may occur which cannot be detected by cytogenetic testing ; on these occasions PCR testing is essential to confirm the diagnosis. APL is unique among leukemias due to its sensitivity to all- trans retinoic acid (ATRA; tretinoin), the acid form of vitamin A . Treatment with ATRA dissociates the NCOR-HDAC complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant action. Unlike other chemotherapies, ATRA does not directly kill the malignant cells . ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA alone is capable of inducing remission but it is short-lived in the absence of concurrent "traditional" chemotherapy. As of 2013 the standard of treatment for concurrent chemotherapy has become arsenic trioxide , which combined with ATRA is referred to ATRA-ATO; before 2013 the standard of treatment was anthracycline (e.g. daunorubicin , doxorubicin , idarubicin or mitoxantrone )-based chemotherapy. Both chemotherapies result in a clinical remission in approximately 90% of patients with arsenic trioxide having a more favorable side effect profile. ATRA therapy is associated with the unique side effect of differentiation syndrome . This is associated with the development of dyspnea , fever, weight gain, peripheral edema and is treated with dexamethasone . The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes. The monoclonal antibody , gemtuzumab ozogamicin , has been used successfully as a treatment for APL, although it has been withdrawn from the US market due to concerns regarding potential toxicity of the drug and it is not currently marketed in Australia, Canada or the UK. Given in conjunction with ATRA, it produces a response in around 84% of patients with APL, which is comparable to the rate seen in patients treated with ATRA and anthracycline-based therapy. It produces less cardiotoxicity than anthracycline-based treatments and hence may be preferable in these patients. After stable remission was induced, the standard of care previously was to undergo 2 years of maintenance chemotherapy with methotrexate , mercaptopurine and ATRA. A significant portion of patients relapsed without consolidation therapy . In the 2000 European APL study, the 2-year relapse rate for those that did not receive consolidation chemotherapy (ATRA not included) therapy was 27% compared to 11% in those that did receive consolidation therapy (p<0.01). Likewise in the 2000 US APL study, the survival rates in those receiving ATRA maintenance was 61% compared to just 36% without ATRA maintenance. However, recent research on consolidation therapy following ATRA-ATO, which became the standard treatment in 2013, has found that maintenance therapy in low-risk patients following this therapy may be unnecessary, although this is controversial. Arsenic trioxide (As 2 O 3 ) is currently being evaluated for treatment of relapsed/refractory disease. Remission with arsenic trioxide has been reported. Studies have shown arsenic reorganizes nuclear bodies and degrades the mutant PML-RAR fusion protein. Arsenic also increases caspase activity which then induces apoptosis . It does reduce the relapse rate for high risk patients. In Japan a synthetic retinoid, tamibarotene , is licensed for use as a treatment for ATRA-resistant APL. Some evidence supports the potential therapeutic utility of histone deacetylase inhibitors such as valproic acid or vorinostat in treating APL. According to one study, a cinnamon extract has effect on the apoptotic process in acute myeloid leukemia HL-60 cells. APL is unique among leukemias due to its sensitivity to all- trans retinoic acid (ATRA; tretinoin), the acid form of vitamin A . Treatment with ATRA dissociates the NCOR-HDAC complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant action. Unlike other chemotherapies, ATRA does not directly kill the malignant cells . ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA alone is capable of inducing remission but it is short-lived in the absence of concurrent "traditional" chemotherapy. As of 2013 the standard of treatment for concurrent chemotherapy has become arsenic trioxide , which combined with ATRA is referred to ATRA-ATO; before 2013 the standard of treatment was anthracycline (e.g. daunorubicin , doxorubicin , idarubicin or mitoxantrone )-based chemotherapy. Both chemotherapies result in a clinical remission in approximately 90% of patients with arsenic trioxide having a more favorable side effect profile. ATRA therapy is associated with the unique side effect of differentiation syndrome . This is associated with the development of dyspnea , fever, weight gain, peripheral edema and is treated with dexamethasone . The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes. The monoclonal antibody , gemtuzumab ozogamicin , has been used successfully as a treatment for APL, although it has been withdrawn from the US market due to concerns regarding potential toxicity of the drug and it is not currently marketed in Australia, Canada or the UK. Given in conjunction with ATRA, it produces a response in around 84% of patients with APL, which is comparable to the rate seen in patients treated with ATRA and anthracycline-based therapy. It produces less cardiotoxicity than anthracycline-based treatments and hence may be preferable in these patients. After stable remission was induced, the standard of care previously was to undergo 2 years of maintenance chemotherapy with methotrexate , mercaptopurine and ATRA. A significant portion of patients relapsed without consolidation therapy . In the 2000 European APL study, the 2-year relapse rate for those that did not receive consolidation chemotherapy (ATRA not included) therapy was 27% compared to 11% in those that did receive consolidation therapy (p<0.01). Likewise in the 2000 US APL study, the survival rates in those receiving ATRA maintenance was 61% compared to just 36% without ATRA maintenance. However, recent research on consolidation therapy following ATRA-ATO, which became the standard treatment in 2013, has found that maintenance therapy in low-risk patients following this therapy may be unnecessary, although this is controversial. Arsenic trioxide (As 2 O 3 ) is currently being evaluated for treatment of relapsed/refractory disease. Remission with arsenic trioxide has been reported. Studies have shown arsenic reorganizes nuclear bodies and degrades the mutant PML-RAR fusion protein. Arsenic also increases caspase activity which then induces apoptosis . It does reduce the relapse rate for high risk patients. In Japan a synthetic retinoid, tamibarotene , is licensed for use as a treatment for ATRA-resistant APL. Some evidence supports the potential therapeutic utility of histone deacetylase inhibitors such as valproic acid or vorinostat in treating APL. According to one study, a cinnamon extract has effect on the apoptotic process in acute myeloid leukemia HL-60 cells. Prognosis is generally good relative to other leukemias. Because of the acuteness of onset compared to other leukemias, early death is comparatively more common. If untreated, it has median survival of less than a month. It has been transformed from a highly fatal disease to a highly curable one. The cause of early death is most commonly severe bleeding, often intracranial hemorrhage . Early death from hemorrhage occurs in 5–10% of patients in countries with adequate access to healthcare and 20–30% of patients in less developed countries. Risk factors for early death due to hemorrhage include delayed diagnosis, late treatment initiation, and high white blood cell count on admission. Despite advances in treatment, early death rates have remained relatively constant, as described by several groups including Scott McClellan, Bruno Medeiros, and Ash Alizadeh at Stanford University . Relapse rates are extremely low. Most deaths following remission are from other causes, such as second malignancies, which in one study occurred in 8% of patients. In this study, second malignancies accounted for 41% of deaths, and heart disease, 29%. Survival rates were 88% at 6.3 years and 82% at 7.9 years. In another study, 10-year survival rate was estimated to be approximately 77%. Acute promyelocytic leukemia represents 10–12% of AML cases. The median age is approximately 30–40 years, which is considerably younger than the other subtypes of AML (70 years), however in elderly population APL has peculiar characteristics. Incidence is higher among individuals of Latin American or South European origin. It can also occur as a secondary malignancy in those that receive treatment with topoisomerase II inhibitors (such as the anthracyclines and etoposide ) due to the carcinogenic effects of these agents, with patients with breast cancer representing the majority of such patients. Around 40% of patients with APL also have a chromosomal abnormality such as trisomy 8 or isochromosome 17 which do not appear to impact on long-term outcomes.

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Acute hemorrhagic fever syndrome

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Uveitis

Uveitis ( / ˌ juː v i . aɪ t ɪ s / ) is inflammation of the uvea , the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea . The uvea consists of the middle layer of pigmented vascular structures of the eye and includes the iris , ciliary body , and choroid . Uveitis is described anatomically, by the part of the eye affected, as anterior, intermediate or posterior, or panuveitic if all parts are involved. Anterior uveitis ( iridocyclitis ) is the most common, with the incidence of uveitis overall affecting approximately 1:4500, most commonly those between the ages of 20-60. Symptoms include eye pain, eye redness, floaters and blurred vision, and ophthalmic examination may show dilated ciliary blood vessels and the presence of cells in the anterior chamber . Uveitis may arise spontaneously, have a genetic component, or be associated with an autoimmune disease or infection . While the eye is a relatively protected environment, its immune mechanisms may be overcome resulting in inflammation and tissue destruction associated with T-cell activation. Uveitis is an ophthalmic emergency that requires urgent control of the inflammation to prevent vision loss. Treatment typically involves the use of topical eye drop steroids , intravitreal injection, newer biologics , and treating any underlying disease. While initial treatment is usually successful, complications include other ocular disorders, such as uveitic glaucoma , retinal detachment , optic nerve damage, cataracts , and in some cases, a permanent loss of vision . In the United States uveitis accounts for about 10%-20% of cases of blindness.Uveitis is classified anatomically into anterior, intermediate, posterior, and panuveitis forms—based on the part of the eye primarily affected. Before the twentieth century, uveitis was typically referred to in English as "ophthalmia." Uveitis is usually an isolated illness, but can be associated with many other medical conditions. In anterior uveitis, no associated condition or syndrome is found in approximately one-half of cases. However, anterior uveitis is often one of the syndromes associated with HLA-B27 . Presence of this type of HLA allele has a relative risk of evolving this disease by approximately 15%. The most common form of uveitis is acute anterior uveitis (AAU). It is most commonly associated with HLA-B27, which has important features: HLA-B27 AAU can be associated with ocular inflammation alone or in association with systemic disease. HLA-B27 AAU has characteristic clinical features including male preponderance, unilateral alternating acute onset, a non-granulomatous appearance, and frequent recurrences, whereas HLA-B27 negative AAU has an equivalent male to female onset, bilateral chronic course, and more frequent granulomatous appearance. Rheumatoid arthritis is not uncommon in Asian countries as a significant association of uveitis. Systemic disorders that can be associated with uveitis include: Uveitis may be an immune response to fight an infection caused by an organism in the eye. They are less common than non-infectious causes and require antimicrobial/ viral/ parasitic treatment in addition to inflammatory control. Infectious causes in order of global burden include: Occasionally, uveitis is not associated with a systemic condition: the inflammation is confined to the eye and has unknown cause. In some of these cases, the presentation in the eye is characteristic of a described syndrome, which are called white dot syndromes , and include the following diagnoses: Masquerade syndromes are those conditions that include the presence of intraocular cells but are not due to immune-mediated uveitis entities. These may be divided into neoplastic and non-neoplastic conditions. Non-neoplastic: Neoplastic:Systemic disorders that can be associated with uveitis include: Uveitis may be an immune response to fight an infection caused by an organism in the eye. They are less common than non-infectious causes and require antimicrobial/ viral/ parasitic treatment in addition to inflammatory control. Infectious causes in order of global burden include:Occasionally, uveitis is not associated with a systemic condition: the inflammation is confined to the eye and has unknown cause. In some of these cases, the presentation in the eye is characteristic of a described syndrome, which are called white dot syndromes , and include the following diagnoses:Masquerade syndromes are those conditions that include the presence of intraocular cells but are not due to immune-mediated uveitis entities. These may be divided into neoplastic and non-neoplastic conditions. Non-neoplastic: Neoplastic:The disease course, anatomy, and laterality can vary widely and are important to consider in diagnosis and treatment. Cases may be acute (sudden onset with < 3 month duration) and monophonic, acute and recurrent, or chronic. The signs and symptoms of uveitis may include the following: Most common: Floaters , which are dark spots that float in the visual field Blurred vision Intermediate uveitis usually affects one eye. Less common is the presence of pain and photophobia. Inflammation in the back of the eye is commonly characterized by: Floaters Blurred visionMost common: Floaters , which are dark spots that float in the visual field Blurred vision Intermediate uveitis usually affects one eye. Less common is the presence of pain and photophobia. Inflammation in the back of the eye is commonly characterized by: Floaters Blurred visionOnset of uveitis can broadly be described as a failure of the ocular immune system and the disease results from inflammation and tissue destruction. Uveitis is driven by the Th17 T cell sub-population that bear T-cell receptors specific for proteins found in the eye. These are often not deleted centrally whether due to ocular antigen not being presented in the thymus (therefore not negatively selected) or a state of anergy is induced to prevent self targeting. Autoreactive T cells must normally be held in check by the suppressive environment produced by microglia and dendritic cells in the eye. These cells produce large amounts of TGF beta and other suppressive cytokines , including IL-10 , to prevent damage to the eye by reducing inflammation and causing T cells to differentiate to inducible T reg cells. Innate immune stimulation by bacteria and cellular stress is normally suppressed by myeloid suppression while inducible Treg cells prevent activation and clonal expansion of the autoreactive Th1 and Th17 cells that possess potential to cause damage to the eye. Whether through infection or other causes, this balance can be upset and autoreactive T cells allowed to proliferate and migrate to the eye. Upon entry to the eye, these cells may be returned to an inducible Treg state by the presence of IL-10 and TGF-beta from microglia. Failure of this mechanism leads to neutrophil and other leukocyte recruitment from the peripheral blood through IL-17 secretion. Tissue destruction is mediated by non-specific macrophage activation and the resulting cytokine cascades. Serum TNF-α is significantly elevated in cases while IL-6 and IL-8 are present in significantly higher quantities in the aqueous humour in patients with both quiescent and active uveitis. These are inflammatory markers that non-specifically activate local macrophages causing tissue damage. The cause of non-infectious uveitis is unknown but there are some strong genetic factors that predispose disease onset including HLA-B27 and the PTPN22 genotype. Recent evidence has pointed to reactivation of herpes simplex , varicella zoster and other viruses as important causes of developing what was previously described as idiopathic anterior uveitis. Bacterial infection is another significant contributing factor in developing uveitis. Onset of uveitis can broadly be described as a failure of the ocular immune system and the disease results from inflammation and tissue destruction. Uveitis is driven by the Th17 T cell sub-population that bear T-cell receptors specific for proteins found in the eye. These are often not deleted centrally whether due to ocular antigen not being presented in the thymus (therefore not negatively selected) or a state of anergy is induced to prevent self targeting. Autoreactive T cells must normally be held in check by the suppressive environment produced by microglia and dendritic cells in the eye. These cells produce large amounts of TGF beta and other suppressive cytokines , including IL-10 , to prevent damage to the eye by reducing inflammation and causing T cells to differentiate to inducible T reg cells. Innate immune stimulation by bacteria and cellular stress is normally suppressed by myeloid suppression while inducible Treg cells prevent activation and clonal expansion of the autoreactive Th1 and Th17 cells that possess potential to cause damage to the eye. Whether through infection or other causes, this balance can be upset and autoreactive T cells allowed to proliferate and migrate to the eye. Upon entry to the eye, these cells may be returned to an inducible Treg state by the presence of IL-10 and TGF-beta from microglia. Failure of this mechanism leads to neutrophil and other leukocyte recruitment from the peripheral blood through IL-17 secretion. Tissue destruction is mediated by non-specific macrophage activation and the resulting cytokine cascades. Serum TNF-α is significantly elevated in cases while IL-6 and IL-8 are present in significantly higher quantities in the aqueous humour in patients with both quiescent and active uveitis. These are inflammatory markers that non-specifically activate local macrophages causing tissue damage.The cause of non-infectious uveitis is unknown but there are some strong genetic factors that predispose disease onset including HLA-B27 and the PTPN22 genotype. Recent evidence has pointed to reactivation of herpes simplex , varicella zoster and other viruses as important causes of developing what was previously described as idiopathic anterior uveitis. Bacterial infection is another significant contributing factor in developing uveitis. Uveitis is assessed as part of a dilated eye exam . Diagnosis includes dilated fundus examination to rule out posterior uveitis, which presents with white spots across the retina along with retinitis and vasculitis . Laboratory testing is usually used to diagnose specific underlying diseases, including rheumatologic tests (e.g. antinuclear antibody, rheumatoid factor) and serology for infectious diseases (Syphilis, Toxoplasmosis, Tuberculosis). Major histocompatibility antigen testing may be performed to investigate genetic susceptibility to uveitis. The most common antigens include HLA-B27, HLA-A29 (in birdshot chorioretinopathy) and HLA-B51 (in Behçet disease). [ citation needed ] Radiology X-ray may be used to show coexisting arthritis and chest X-ray may be helpful in sarcoidosis.Uveitis is typically treated with glucocorticoid steroids , either as topical eye drops (prednisolone acetate) or as oral therapy. Prior to the administration of corticosteroids, corneal ulcers must be ruled out. This is typically done using a fluorescence dye test. In addition to corticosteroids, topical cycloplegics , such as atropine or homatropine , may be used. Successful treatment of active uveitis increases T-regulatory cells in the eye, which likely contributes to disease regression. In severe cases an injection of posterior subtenon triamcinolone acetate may also be given to reduce the swelling of the eye. Intravitrial injection of steroid has proven to be a newer useful way to control inflammation for longer without the need for daily eyedrops. Dexamethasone and fluocinolone acetonide are two more commonly used options for noninfectious uveitis. Non-biologic, steroid sparing therapies for noninfectious uveitis in adults are now more available. These include the disease-modifying antirheumatic drugs (DMARDs) methotrexate, mycophenolate, cyclosporine, azathioprine, and tacrolimus. In comparing various studies, methotrexate is more efficacious than mycophenolate in inflammatory control for most forms of panuveitis. Methotrexate also had little to no differences in safety outcomes compared to mycophenolate. Antimetabolite medications, such as methotrexate are often used for recalcitrant or more aggressive cases of uveitis. Experimental treatments with Infliximab or other anti-TNF infusions may prove helpful. The anti-diabetic drug metformin is reported to inhibit the process that causes the inflammation in uveitis. In the case of herpetic uveitis, anti-viral medications, such as valaciclovir or aciclovir , may be administered to treat the causative viral infection. Uveitis affects approximately 1 in 4500 people and is most common between the ages 20 to 60 with men and women affected equally. In western countries, anterior uveitis accounts for between 50% and 90% of uveitis cases. In Asian countries the proportion is between 28% and 50%. Uveitis is estimated to be responsible for approximately 10%-20% of the blindness in the United States. For non-infectious uveitis, women are more likely (57%) to be affected than men, possibly due to their higher prevalence of related autoimmune diseases . Vitamin D deficiency and smoking are risk factors for non-infectious uveitis. The prognosis is generally good for those who receive prompt diagnosis and treatment, but serious complication including cataracts , uveitic glaucoma , band keratopathy , macular edema and permanent vision loss may result if left untreated. The type of uveitis, as well as its severity, duration, and responsiveness to treatment or any associated illnesses, all factor into the outlook.

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Acute hemorrhagic fever syndrome

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Systemic inflammatory response syndrome

In immunology , systemic inflammatory response syndrome ( SIRS ) is an inflammatory state affecting the whole body. It is the body's response to an infectious or noninfectious insult . Although the definition of SIRS refers to it as an "inflammatory" response, it actually has pro- and anti-inflammatory components.SIRS is frequently complicated by failure of one or more organs or organ systems . The complications of SIRS includeSIRS is frequently complicated by failure of one or more organs or organ systems . The complications of SIRS includeThe causes of SIRS are broadly classified as infectious or noninfectious. Causes of SIRS include: [ citation needed ] Other causes include: SIRS is a serious condition related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of cytokine storm , in which there is abnormal regulation of various cytokines . SIRS is also closely related to sepsis , in which patients satisfy criteria for SIRS and have a suspected or proven infection. Many experts consider the current criteria for a SIRS diagnosis to be overly sensitive, as nearly all (>90%) of patients admitted to the ICU meet the SIRS criteria. Manifestations of SIRS include, but are not limited to: When two or more of these criteria are met with or without evidence of infection, patients may be diagnosed with "SIRS". Patients with SIRS and acute organ dysfunction may be termed "severe SIRS". Note: Fever and an increased white blood cell count are features of the acute-phase reaction , while an increased heart rate is often the initial sign of hemodynamic compromise. An increased rate of breathing may be related to the increased metabolic stress due to infection and inflammation, but may also be an ominous sign of inadequate perfusion resulting in the onset of anaerobic cellular metabolism. [ citation needed ] The International Pediatric Sepsis Consensus has proposed some changes to adapt these criteria to the pediatric population. In children, the SIRS criteria are modified in the following fashion: Temperature or white blood cell count must be abnormal to qualify as SIRS in pediatric patients. Manifestations of SIRS include, but are not limited to: When two or more of these criteria are met with or without evidence of infection, patients may be diagnosed with "SIRS". Patients with SIRS and acute organ dysfunction may be termed "severe SIRS". Note: Fever and an increased white blood cell count are features of the acute-phase reaction , while an increased heart rate is often the initial sign of hemodynamic compromise. An increased rate of breathing may be related to the increased metabolic stress due to infection and inflammation, but may also be an ominous sign of inadequate perfusion resulting in the onset of anaerobic cellular metabolism. [ citation needed ]The International Pediatric Sepsis Consensus has proposed some changes to adapt these criteria to the pediatric population. In children, the SIRS criteria are modified in the following fashion: Temperature or white blood cell count must be abnormal to qualify as SIRS in pediatric patients. Generally, the treatment for SIRS is directed towards the underlying problem or inciting cause (i.e. adequate fluid replacement for hypovolemia, IVF/ NPO for pancreatitis, epinephrine/steroids/ diphenhydramine for anaphylaxis). Selenium , glutamine , and eicosapentaenoic acid have shown effectiveness in improving symptoms in clinical trials. Other antioxidants such as vitamin E may be helpful as well. Septic treatment protocol and diagnostic tools have been created due to the potentially severe outcome septic shock. For example, the SIRS criteria were created as mentioned above to be extremely sensitive in suggesting which patients may have sepsis. However, these rules lack specificity, i.e. not a true diagnosis of the condition, but rather a suggestion to take necessary precautions. The SIRS criteria are guidelines set in place to ensure septic patients receive care as early as possible. In cases caused by an implanted mesh, removal (explantation) of the polypropylene surgical mesh implant may be indicated. The concept of SIRS was first conceived of and presented by William R. Nelson, of the Department of Surgery of the University of Toronto . SIRS was more broadly adopted in 1991 at the American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference with the goal of aiding in the early detection of sepsis . Criteria for SIRS were established in 1992 as part of the American College of Chest Physicians / Society of Critical Care Medicine Consensus Conference. The conference concluded that the manifestations of SIRS include, but are not limited to the first four described above under adult SIRS criteria. [ citation needed ] In septic patients, these clinical signs can also be seen in other proinflammatory conditions, such as trauma, burns, pancreatitis, etc. A follow-up conference, therefore, decided to define the patients with a documented or highly suspicious infection that results in a systemic inflammatory response as having sepsis. Note that SIRS criteria are non-specific, and must be interpreted carefully within the clinical context. These criteria exist primarily for the purpose of more objectively classifying critically ill patients so that future clinical studies may be more rigorous and more easily reproducible. [ citation needed ]

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