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Acute hemorrhagic fever syndrome

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Mosquito-borne disease

Mosquito-borne diseases or mosquito-borne illnesses are diseases caused by bacteria, viruses or parasites transmitted by mosquitoes . Nearly 700 million people get a mosquito-borne illness each year, resulting in over 725,000 deaths. Diseases transmitted by mosquitoes include malaria , dengue , West Nile virus , chikungunya , yellow fever , filariasis , tularemia , dirofilariasis , Japanese encephalitis , Saint Louis encephalitis , Western equine encephalitis , Eastern equine encephalitis , Venezuelan equine encephalitis , Ross River fever , Barmah Forest fever , La Crosse encephalitis , and Zika fever , as well as newly detected Keystone virus and Rift Valley fever . In January 2024, an Australian research group proved that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer is transmitted by mosquitos. This is the first described mosquito-borne transmission of a bacterial disease. There is no evidence as of April 2020 that COVID-19 can be transmitted by mosquitoes, and it is extremely unlikely this could occur. The female mosquito of the genus Anopheles may carry the malaria parasite . Four different species of protozoa cause malaria: Plasmodium falciparum , Plasmodium malariae , Plasmodium ovale and Plasmodium vivax (see Plasmodium ). Worldwide, malaria is a leading cause of premature mortality, particularly in children under the age of five, with an estimated 207 million cases and more than half a million deaths in 2012, according to the World Malaria Report 2013 published by the World Health Organization (WHO). The death toll increased to one million as of 2018 according to the American Mosquito Control Association. In January 2024, a publication by an Australian research group demonstrated significant genetic similarity between Mycobacterium ulcerans in humans and possums, compared to PCR screening of M. ulcerans from trapped Aedes notoscriptus mosquitoes, and concluded that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer , is transmitted by mosquitos. Botflies are known to parasitize humans or other mammalians, causing myiasis , and to use mosquitoes as intermediate vector agents to deposit eggs on a host. The human botfly Dermatobia hominis attaches its eggs to the underside of a mosquito, and when the mosquito takes a blood meal from a human or an animal, the body heat of the mammalian host induces hatching of the larvae. [ citation needed ] Some species of mosquito can carry the filariasis worm, a parasite that causes a disfiguring condition (often referred to as elephantiasis ) characterized by a great swelling of several parts of the body; worldwide, around 40 million people are living with a filariasis disability. [ citation needed ] The viral diseases yellow fever , dengue fever , Zika fever and chikungunya are transmitted mostly by Aedes aegypti mosquitoes. [ citation needed ] Other viral diseases like epidemic polyarthritis , Rift Valley fever , Ross River fever , St. Louis encephalitis , West Nile fever , Japanese encephalitis , La Crosse encephalitis and several other encephalitic diseases are carried by several different mosquitoes. Eastern equine encephalitis (EEE) and Western equine encephalitis (WEE) occur in the United States where they cause disease in humans, horses, and some bird species. Because of the high mortality rate, EEE and WEE are regarded as two of the most serious mosquito-borne diseases in the United States. Symptoms range from mild flu-like illness to encephalitis, coma, and death. Viruses carried by arthropods such as mosquitoes or ticks are known collectively as arboviruses . West Nile virus was accidentally introduced into the US in 1999 and by 2003 had spread to almost every state with over 3,000 cases in 2006. Other species of Aedes as well as Culex and Culiseta are also involved in the transmission of disease. [ citation needed ] Myxomatosis is spread by biting insects, including mosquitoes. The female mosquito of the genus Anopheles may carry the malaria parasite . Four different species of protozoa cause malaria: Plasmodium falciparum , Plasmodium malariae , Plasmodium ovale and Plasmodium vivax (see Plasmodium ). Worldwide, malaria is a leading cause of premature mortality, particularly in children under the age of five, with an estimated 207 million cases and more than half a million deaths in 2012, according to the World Malaria Report 2013 published by the World Health Organization (WHO). The death toll increased to one million as of 2018 according to the American Mosquito Control Association. In January 2024, a publication by an Australian research group demonstrated significant genetic similarity between Mycobacterium ulcerans in humans and possums, compared to PCR screening of M. ulcerans from trapped Aedes notoscriptus mosquitoes, and concluded that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer , is transmitted by mosquitos. Botflies are known to parasitize humans or other mammalians, causing myiasis , and to use mosquitoes as intermediate vector agents to deposit eggs on a host. The human botfly Dermatobia hominis attaches its eggs to the underside of a mosquito, and when the mosquito takes a blood meal from a human or an animal, the body heat of the mammalian host induces hatching of the larvae. [ citation needed ]Some species of mosquito can carry the filariasis worm, a parasite that causes a disfiguring condition (often referred to as elephantiasis ) characterized by a great swelling of several parts of the body; worldwide, around 40 million people are living with a filariasis disability. [ citation needed ]The viral diseases yellow fever , dengue fever , Zika fever and chikungunya are transmitted mostly by Aedes aegypti mosquitoes. [ citation needed ] Other viral diseases like epidemic polyarthritis , Rift Valley fever , Ross River fever , St. Louis encephalitis , West Nile fever , Japanese encephalitis , La Crosse encephalitis and several other encephalitic diseases are carried by several different mosquitoes. Eastern equine encephalitis (EEE) and Western equine encephalitis (WEE) occur in the United States where they cause disease in humans, horses, and some bird species. Because of the high mortality rate, EEE and WEE are regarded as two of the most serious mosquito-borne diseases in the United States. Symptoms range from mild flu-like illness to encephalitis, coma, and death. Viruses carried by arthropods such as mosquitoes or ticks are known collectively as arboviruses . West Nile virus was accidentally introduced into the US in 1999 and by 2003 had spread to almost every state with over 3,000 cases in 2006. Other species of Aedes as well as Culex and Culiseta are also involved in the transmission of disease. [ citation needed ] Myxomatosis is spread by biting insects, including mosquitoes. A mosquito's period of feeding is often undetected; the bite only becomes apparent because of the immune reaction it provokes. When a mosquito bites a human, it injects saliva and anti-coagulants . With the initial bite to an individual, there is no reaction, but with subsequent bites, the body's immune system develops antibodies . The bites become inflamed and itchy within 24 hours. This is the usual reaction in young children. With more bites, the sensitivity of the human immune system increases, and an itchy red hive appears in minutes where the immune response has broken capillary blood vessels and fluid has collected under the skin. This type of reaction is common in older children and adults. Some adults can become desensitized to mosquitoes and have little or no reaction to their bites, while others can become hyper-sensitive with bites causing blistering, bruising, and large inflammatory reactions, a response known as skeeter syndrome . One study found Dengue virus and Zika virus altered the skin bacteria of rats in a way that caused their body odor to be more attractive to mosquitoes. Symptoms of illness are specific to the type of viral infection and vary in severity, based on the individuals infected. Symptoms vary in severity, from mild unnoticeable symptoms to more common symptoms like fever, rash, headache, achy muscle and joints, and conjunctivitis. Symptoms can last several days to weeks, but death resulting from this infection is rare. Most people infected with the West Nile virus usually do not develop symptoms. However, some individuals can develop cases of severe fatigue, weakness, headaches, body aches, joint and muscle pain, vomiting, diarrhea, and rash, which can last for weeks or months. More serious symptoms have a greater risk of appearing in people over 60 years of age, or those with cancer, diabetes, hypertension, and kidney disease. Dengue fever is mostly characterized by high fever, headaches, joint pain, and rash. However, more severe instances can lead to hemorrhagic fever, internal bleeding, and breathing difficulty, which can be fatal. People infected with this virus can develop sudden onset fever along with debilitating joint and muscle pain, rash, headache, nausea, and fatigue. Symptoms can last a few days or be prolonged to weeks and months. Although patients can recover completely, there have been cases in which joint pain has persisted for several months and can extend beyond that for years. Other people can develop heart complications, eye problems, and even neurological complications. Symptoms vary in severity, from mild unnoticeable symptoms to more common symptoms like fever, rash, headache, achy muscle and joints, and conjunctivitis. Symptoms can last several days to weeks, but death resulting from this infection is rare. Most people infected with the West Nile virus usually do not develop symptoms. However, some individuals can develop cases of severe fatigue, weakness, headaches, body aches, joint and muscle pain, vomiting, diarrhea, and rash, which can last for weeks or months. More serious symptoms have a greater risk of appearing in people over 60 years of age, or those with cancer, diabetes, hypertension, and kidney disease. Dengue fever is mostly characterized by high fever, headaches, joint pain, and rash. However, more severe instances can lead to hemorrhagic fever, internal bleeding, and breathing difficulty, which can be fatal. People infected with this virus can develop sudden onset fever along with debilitating joint and muscle pain, rash, headache, nausea, and fatigue. Symptoms can last a few days or be prolonged to weeks and months. Although patients can recover completely, there have been cases in which joint pain has persisted for several months and can extend beyond that for years. Other people can develop heart complications, eye problems, and even neurological complications. Mosquitoes carrying such arboviruses stay healthy because their immune systems recognizes the virions as foreign particles and "chop off" the virus' genetic coding, rendering it inert. Human infection with a mosquito-borne virus occurs when a female mosquito bites someone while its immune system is still in the process of destroying the virus's harmful coding. [ clarification needed ] It is not completely known how mosquitoes handle eukaryotic parasites to carry them without being harmed. Data has shown that the malaria parasite Plasmodium falciparum alters the mosquito vector's feeding behavior by increasing frequency of biting in infected mosquitoes, thus increasing the chance of transmitting the parasite. The mechanism of transmission of this disease starts with the injection of the parasite into the victim's blood when malaria-infected female Anopheles mosquitoes bite into a human being. The parasite uses human liver cells as hosts for maturation where it will continue to replicate and grow, moving into other areas of the body via the bloodstream. The spread of this infection cycle then continues when other mosquitoes bite the same individual. The result will cause that mosquito to ingest the parasite and allow it to transmit the Malaria disease into another person through the same mode of bite injection. Flaviviridae viruses transmissible via vectors like mosquitoes include West Nile virus and yellow fever virus, which are single stranded, positive-sense RNA viruses enveloped in a protein coat. Once inside the host's body, the virus will attach itself to a cell's surface through receptor-mediated endocytosis. This essentially means that the proteins and DNA material of the virus are ingested into the host cell. The viral RNA material will undergo several changes and processes inside the host's cell so that it can release more viral RNA that can then be replicated and assembled to infect neighboring host cells. Mosquito-borne flaviviruses also encode viral antagonists to the innate immune system in order to cause persistent infection in mosquitoes and a broad spectrum of diseases in humans. The data on transmissibility via insect vectors of hepatitis C virus, also belonging to family Flaviviridae (as well as for hepatitis B virus, belonging to family Hepadnaviridae ) are inconclusive. WHO states that "There is no insect vector or animal reservoir for HCV", while there are experimental data supporting at least the presence of [PCR]-detectable hepatitis C viral RNA in Culex mosquitoes for up to 13 days. Currently, there are no specific vaccine therapies for West Nile virus approved for humans; however, vaccines are available and some show promise for animals, as a means to intervene with the mechanism of spreading such pathogens. Doctors can typically identify a mosquito bite by sight. A doctor will perform a physical examination and ask about medical history as well as any travel history. Be ready to give details on any international trips, including the dates you were traveling, the countries you visited and any contact you had with mosquitoes. Diagnosing dengue fever can be difficult, as its symptoms often overlap with many other diseases such as malaria and typhoid fever . Laboratory tests can detect evidence of the dengue viruses, however the results often come back too late to assist in directing treatment. Medical testing can confirm the presence of West Nile fever or a West Nile-related illness, such as meningitis or encephalitis. If infected, a blood test may show a rising level of antibodies to the West Nile virus. A lumbar puncture (spinal tap) is the most common way to diagnose meningitis, by analyzing the cerebrospinal fluid surrounding your brain and spinal cord. The fluid sample may show an elevated white cell count and antibodies to the West Nile virus if you were exposed. In some cases, an electroencephalography (EEG) or magnetic resonance imaging (MRI) scan can help detect brain inflammation. A Zika virus infection might be suspected if symptoms are present and an individual has traveled to an area with known Zika virus transmission. Zika virus can only be confirmed by a laboratory test of body fluids, such as urine or saliva, or by blood test. Laboratory blood tests can identify evidence of chikungunya or other similar viruses such as dengue and Zika. Blood test may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibodies are highest 3 to 5 weeks after the beginning of symptoms and will continue be present for about 2 months. Diagnosing dengue fever can be difficult, as its symptoms often overlap with many other diseases such as malaria and typhoid fever . Laboratory tests can detect evidence of the dengue viruses, however the results often come back too late to assist in directing treatment. Medical testing can confirm the presence of West Nile fever or a West Nile-related illness, such as meningitis or encephalitis. If infected, a blood test may show a rising level of antibodies to the West Nile virus. A lumbar puncture (spinal tap) is the most common way to diagnose meningitis, by analyzing the cerebrospinal fluid surrounding your brain and spinal cord. The fluid sample may show an elevated white cell count and antibodies to the West Nile virus if you were exposed. In some cases, an electroencephalography (EEG) or magnetic resonance imaging (MRI) scan can help detect brain inflammation. A Zika virus infection might be suspected if symptoms are present and an individual has traveled to an area with known Zika virus transmission. Zika virus can only be confirmed by a laboratory test of body fluids, such as urine or saliva, or by blood test. Laboratory blood tests can identify evidence of chikungunya or other similar viruses such as dengue and Zika. Blood test may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibodies are highest 3 to 5 weeks after the beginning of symptoms and will continue be present for about 2 months. There is a re-emergence of mosquito vectored viruses (arthropod-borne viruses) called arboviruses carried by the Aedes aegypti mosquito. Examples are the Zika virus, chikungunya virus, yellow fever and dengue fever. The re-emergence of the viruses has been at a faster rate, and over a wider geographic area, than in the past. The rapid re-emergence is due to expanding global transportation networks, the mosquito's increasing ability to adapt to urban settings, the disruption of traditional land use and the inability to control expanding mosquito populations. Like malaria, arboviruses do not have a vaccine. (The only exception is yellow fever.) Prevention is focused on reducing the adult mosquito populations, controlling mosquito larvae and protecting individuals from mosquito bites. Depending on the mosquito vector, and the affected community, a variety of prevention methods may be deployed at one time. The use of insecticide treated mosquito nets (ITNs) are at the forefront of preventing mosquito bites that cause malaria. The prevalence of ITNs in sub-Saharan Africa has grown from 3% of households to 50% of households from 2000 to 2010 with over 254 million insecticide treated nets distributed throughout sub-Saharan Africa for use against the mosquito vectors Anopheles gambiae and Anopheles funestus which carry malaria. Because the Anopheles gambiae feeds indoors (endophagic) and rests indoors after feeding (endophilic), insecticide treated nets (ITNs) interrupt the mosquito's feeding pattern. The ITNs continue to offer protection, even after there are holes in the nets, because of their excito-repellency properties which reduce the number of mosquitoes that enter the home. The World Health Organization (WHO) recommends treating ITNs with the pyrethroid class of insecticides. There is an emerging concern of mosquito resistance to insecticides used in ITNs. Twenty-seven (27) sub-Saharan African countries have reported Anopheles vector resistance to pyrethroid insecticides. Indoor spraying of insecticides is another prevention method widely used to control mosquito vectors. To help control the Aedes aegypti mosquito, homes are sprayed indoors with residual insecticide applications. Indoor residual spraying (IRS) reduces the female mosquito population and mitigates the risk of dengue virus transmission. Indoor residual spraying is completed usually once or twice a year. Mosquitoes rest on walls and ceilings after feeding and are killed by the insecticide. Indoor spraying can be combined with spraying the exterior of the building to help reduce the number of mosquito larvae and subsequently, the number of adult mosquitoes. There are other methods that an individual can use to protect themselves from mosquito bites. Limiting exposure to mosquitoes from dusk to dawn when the majority of mosquitoes are active and wearing long sleeves and long pants during the period mosquitoes are most active. Placing screens on windows and doors is a simple and effective means of reducing the number of mosquitoes indoors. Anticipating mosquito contact and using a topical mosquito repellant with icaridin or DEET is also recommended. Draining or covering water receptacles, both indoor and outdoors, is also a simple but effective prevention method. Removing debris and tires, cleaning drains, and cleaning gutters help larval control and reduce the number of adult mosquitoes. There is a vaccine for yellow fever which was developed in the 1930s, the yellow 17D vaccine , and it is still in use today. The initial yellow fever vaccination provides lifelong protection for most people and provides immunity within 30 days of the vaccine. Reactions to the yellow fever vaccine have included mild headache and fever, and muscle aches. There are rare cases of individuals presenting with symptoms that mirror the disease itself. The risk of complications from the vaccine are greater for individuals over 60 years of age. In addition, the vaccine is not usually administered to babies under nine months of age, pregnant women, people with allergies to egg protein, and individuals living with AIDS/HIV . The World Health Organization (WHO) reports that 105 million people have been vaccinated for yellow fever in West Africa from 2000 to 2015. To date, there are relatively few vaccines against mosquito-borne diseases, this is due to the fact that most viruses and bacteria caused by mosquitos are highly mutatable. The National Institute of Allergy and Infectious Disease (NIAID) began Phase 1 clinical trials of a new vaccine that would be nearly universal in protecting against the majority of mosquito-borne diseases. The arboviruses have expanded their geographic range and infected populations that had no recent community knowledge of the diseases carried by the Aedes aegypti mosquito. Education and community awareness campaigns are necessary for prevention to be effective. Communities are educated on how the disease is spread, how they can protect themselves from infection and the symptoms of infection. Community health education programs can identify and address the social/economic and cultural issues that can hinder preventative measures. Community outreach and education programs can identify which preventative measures a community is most likely to employ. Leading to a targeted prevention method that has a higher chance of success in that particular community. Community outreach and education includes engaging community health workers and local healthcare providers, local schools and community organizations to educate the public on mosquito vector control and disease prevention. The use of insecticide treated mosquito nets (ITNs) are at the forefront of preventing mosquito bites that cause malaria. The prevalence of ITNs in sub-Saharan Africa has grown from 3% of households to 50% of households from 2000 to 2010 with over 254 million insecticide treated nets distributed throughout sub-Saharan Africa for use against the mosquito vectors Anopheles gambiae and Anopheles funestus which carry malaria. Because the Anopheles gambiae feeds indoors (endophagic) and rests indoors after feeding (endophilic), insecticide treated nets (ITNs) interrupt the mosquito's feeding pattern. The ITNs continue to offer protection, even after there are holes in the nets, because of their excito-repellency properties which reduce the number of mosquitoes that enter the home. The World Health Organization (WHO) recommends treating ITNs with the pyrethroid class of insecticides. There is an emerging concern of mosquito resistance to insecticides used in ITNs. Twenty-seven (27) sub-Saharan African countries have reported Anopheles vector resistance to pyrethroid insecticides. Indoor spraying of insecticides is another prevention method widely used to control mosquito vectors. To help control the Aedes aegypti mosquito, homes are sprayed indoors with residual insecticide applications. Indoor residual spraying (IRS) reduces the female mosquito population and mitigates the risk of dengue virus transmission. Indoor residual spraying is completed usually once or twice a year. Mosquitoes rest on walls and ceilings after feeding and are killed by the insecticide. Indoor spraying can be combined with spraying the exterior of the building to help reduce the number of mosquito larvae and subsequently, the number of adult mosquitoes. There are other methods that an individual can use to protect themselves from mosquito bites. Limiting exposure to mosquitoes from dusk to dawn when the majority of mosquitoes are active and wearing long sleeves and long pants during the period mosquitoes are most active. Placing screens on windows and doors is a simple and effective means of reducing the number of mosquitoes indoors. Anticipating mosquito contact and using a topical mosquito repellant with icaridin or DEET is also recommended. Draining or covering water receptacles, both indoor and outdoors, is also a simple but effective prevention method. Removing debris and tires, cleaning drains, and cleaning gutters help larval control and reduce the number of adult mosquitoes. There is a vaccine for yellow fever which was developed in the 1930s, the yellow 17D vaccine , and it is still in use today. The initial yellow fever vaccination provides lifelong protection for most people and provides immunity within 30 days of the vaccine. Reactions to the yellow fever vaccine have included mild headache and fever, and muscle aches. There are rare cases of individuals presenting with symptoms that mirror the disease itself. The risk of complications from the vaccine are greater for individuals over 60 years of age. In addition, the vaccine is not usually administered to babies under nine months of age, pregnant women, people with allergies to egg protein, and individuals living with AIDS/HIV . The World Health Organization (WHO) reports that 105 million people have been vaccinated for yellow fever in West Africa from 2000 to 2015. To date, there are relatively few vaccines against mosquito-borne diseases, this is due to the fact that most viruses and bacteria caused by mosquitos are highly mutatable. The National Institute of Allergy and Infectious Disease (NIAID) began Phase 1 clinical trials of a new vaccine that would be nearly universal in protecting against the majority of mosquito-borne diseases. The arboviruses have expanded their geographic range and infected populations that had no recent community knowledge of the diseases carried by the Aedes aegypti mosquito. Education and community awareness campaigns are necessary for prevention to be effective. Communities are educated on how the disease is spread, how they can protect themselves from infection and the symptoms of infection. Community health education programs can identify and address the social/economic and cultural issues that can hinder preventative measures. Community outreach and education programs can identify which preventative measures a community is most likely to employ. Leading to a targeted prevention method that has a higher chance of success in that particular community. Community outreach and education includes engaging community health workers and local healthcare providers, local schools and community organizations to educate the public on mosquito vector control and disease prevention. Numerous drugs have been used to treat yellow fever disease with minimal satisfaction to date. Patients with multisystem organ involvement will require critical care support such as possible hemodialysis or mechanical ventilation . Rest, fluids, and acetaminophen are also known to relieve milder symptoms of fever and muscle pain. Due to hemorrhagic complications, aspirin should be avoided. Infected individuals should avoid mosquito exposure by staying indoors or using a mosquito net . Dengue infection's therapeutic management is simple, cost effective and successful in saving lives by adequately performing timely institutionalized interventions. Treatment options are restricted, while no effective antiviral drugs for this infection have been accessible to date. Patients in the early phase of the dengue virus may recover without hospitalization. However, ongoing clinical research is in the works to find specific anti-dengue drugs. Dengue fever occurs via Aedes aegypti mosquito (it acts as a vector). Zika virus vaccine clinical trials are to be conducted and established. There are efforts being put toward advancing antiviral therapeutics against zika virus for swift control. Present day Zika virus treatment is symptomatic through antipyretics and analgesics . Currently there are no publications regarding viral drug screening. Nevertheless, therapeutics for this infection have been used. There are no treatment modalities for acute and chronic chikungunya that currently exist. Most treatment plans use supportive and symptomatic care like analgesics for pain and anti-inflammatories for inflammation caused by arthritis . In acute stages of this virus, rest, antipyretics and analgesics are used to subside symptoms. Most use non-steroidal anti-inflammatory drugs (NSAIDs). In some cases, joint pain may resolve from treatment but stiffness remains. The sterile insect technique (SIT) uses irradiation to sterilize insect pests before releasing them in large numbers to mate with wild females. Since they do not produce any offspring, the population, and consequently the disease incidence, is reduced over time. Used successfully for decades to combat fruit flies and livestock pests such as screwworm and tsetse flies , the technique can be adapted also for some disease-transmitting mosquito species. Pilot projects are being initiated or are under way in different parts of the world. Numerous drugs have been used to treat yellow fever disease with minimal satisfaction to date. Patients with multisystem organ involvement will require critical care support such as possible hemodialysis or mechanical ventilation . Rest, fluids, and acetaminophen are also known to relieve milder symptoms of fever and muscle pain. Due to hemorrhagic complications, aspirin should be avoided. Infected individuals should avoid mosquito exposure by staying indoors or using a mosquito net . Dengue infection's therapeutic management is simple, cost effective and successful in saving lives by adequately performing timely institutionalized interventions. Treatment options are restricted, while no effective antiviral drugs for this infection have been accessible to date. Patients in the early phase of the dengue virus may recover without hospitalization. However, ongoing clinical research is in the works to find specific anti-dengue drugs. Dengue fever occurs via Aedes aegypti mosquito (it acts as a vector).Zika virus vaccine clinical trials are to be conducted and established. There are efforts being put toward advancing antiviral therapeutics against zika virus for swift control. Present day Zika virus treatment is symptomatic through antipyretics and analgesics . Currently there are no publications regarding viral drug screening. Nevertheless, therapeutics for this infection have been used. There are no treatment modalities for acute and chronic chikungunya that currently exist. Most treatment plans use supportive and symptomatic care like analgesics for pain and anti-inflammatories for inflammation caused by arthritis . In acute stages of this virus, rest, antipyretics and analgesics are used to subside symptoms. Most use non-steroidal anti-inflammatory drugs (NSAIDs). In some cases, joint pain may resolve from treatment but stiffness remains. The sterile insect technique (SIT) uses irradiation to sterilize insect pests before releasing them in large numbers to mate with wild females. Since they do not produce any offspring, the population, and consequently the disease incidence, is reduced over time. Used successfully for decades to combat fruit flies and livestock pests such as screwworm and tsetse flies , the technique can be adapted also for some disease-transmitting mosquito species. Pilot projects are being initiated or are under way in different parts of the world. Mosquito-borne diseases, such as dengue fever and malaria , typically affect developing countries and areas with tropical climates. Mosquito vectors are sensitive to climate changes and tend to follow seasonal patterns. Between years there are often dramatic shifts in incidence rates. The occurrence of this phenomenon in endemic areas makes mosquito-borne viruses difficult to treat. Dengue fever is caused by infection through viruses of the family Flaviviridae. The illness is most commonly transmitted by Aedes aegypti mosquitoes in tropical and subtropical regions. Dengue virus has four different serotypes, each of which are antigenically related but have limited cross-immunity to reinfection. Although dengue fever has a global incidence of 50–100 million cases, only several hundreds of thousands of these cases are life-threatening. The geographic prevalence of the disease can be examined by the spread of Aedes aegypti . Over the last twenty years, there has been a geographic spread of the disease. Dengue incidence rates have risen sharply within urban areas which have recently become endemic hot spots for the disease. The recent spread of Dengue can also be attributed to rapid population growth, increased coagulation in urban areas, and global travel. Without sufficient vector control, the dengue virus has evolved rapidly over time, posing challenges to both government and public health officials. [ citation needed ] Malaria is caused by a protozoan called Plasmodium falciparum . P. falciparum parasites are transmitted mainly by the Anopheles gambiae complex in rural Africa. In just this area, P. falciparum infections comprise an estimated 200 million clinical cases and 1 million annual deaths. 75% of individuals affected in this region are children. As with dengue, changing environmental conditions have led to novel disease characteristics. Due to increased illness severity, treatment complications, and mortality rates, many public health officials concede that malaria patterns are rapidly transforming in Africa. Scarcity of health services, rising instances of drug resistance, and changing vector migration patterns are factors that public health officials believe contribute to malaria's dissemination. Climate heavily affects mosquito vectors of malaria and dengue. Climate patterns influence the lifespan of mosquitos as well as the rate and frequency of reproduction. Climate change impacts have been of great interest to those studying these diseases and their vectors. Additionally, climate impacts mosquito blood feeding patterns as well as extrinsic incubation periods. Climate consistency gives researchers an ability to accurately predict annual cycling of the disease but recent climate unpredictability has eroded researchers' ability to track the disease with such precision.In many insect species, such as Drosophila melanogaster , researchers found that a natural infection with the bacteria strain Wolbachia pipientis increases the fitness of the host by increasing resistance to RNA viral infections. Robert L. Glaser and Mark A. Meola investigated Wolbachia -induced resistance to West Nile virus (WNV) in Drosophila melanogaster (fruit flies). Two groups of fruit flies were naturally infected with Wolbachia . Glaser and Meola then cured one group of fruit flies of Wolbachia using tetracycline. Both the infected group and the cured groups were then infected with WNV. Flies infected with Wolbachia were found to have a changed phenotype that caused resistance to WNV. The phenotype was found to be caused by a "dominant, maternally transmitted, cytoplasmic factor". The WNV-resistance phenotype was then reversed by curing the fruit flies of Wolbachia . Since Wolbachia is also maternally transmitted, it was found that the WNV-resistant phenotype is directly related to the Wolbachia infection. West Nile virus is transmitted to humans and animals through the Southern house mosquito, Culex quinquefasciatus . Glaser and Meola knew vector compatibility could be reduced through Wolbachia infection due to studies done with other species of mosquitoes, mainly, Aedes aegypti . Their goal was to transfer WNV resistance to Cx. quinquefasciatus by inoculating the embryos of the mosquito with the same strain of Wolbachia that naturally occurred in the fruit flies. Upon infection, Cx. quinquefasciatus showed an increased resistance to WNV that was transferable to offspring. The ability to genetically modify mosquitoes in the lab and then have the infected mosquitoes transmit it to their offspring showed that it was possible to transmit the bacteria to wild populations to decrease human infections. [ citation needed ] In 2011, Ary Hoffmann and associates produced the first case of Wolbachia -induced arbovirus resistance in wild populations of Aedes aegypti through a small project called Eliminate Dengue: Our Challenge. This was made possible by an engineered strain of Wolbachia termed w Mel that came from D. melanogaster . The transfer of w Mel from D. melanogaster into field-caged populations of the mosquito Aedes aegypti induced resistance to dengue, yellow fever, and chikungunya viruses. Although other strains of Wolbachia also reduced susceptibility to dengue infection, they also put a greater demand on the fitness of Ae. aegypti . w Mel was different in that it was thought to only cost the organism a small portion of its fitness. w Mel-infected Ae. aegypti were released into two residential areas in the city of Cairns, Australia over a 14-week period. Hoffmann and associates, released a total of 141,600 infected adult mosquitoes in Yorkeys Knob suburb and 157,300 in Gordonvale suburb. After release, the populations were monitored for three years to record the spread of w Mel. Population monitoring was gauged by measuring larvae laid in traps. At the beginning of the monitoring period but still within the release period, it was found that w Mel-infected Ae. aegypti had doubled in Yorkeys Knob and increased 1.5-fold in Gordonvale. Uninfected Ae. aegypti populations were in decline. By the end of the three years, w Mel-infected Ae. aegypti had stable populations of about 90%. However, these populations were isolated to the Yorkeys Knob and Gordonvale suburbs due to unsuitable habitat surrounding the neighborhoods. Although populations flourished in these areas with nearly 100% transmission, no signs of spread were noted, proving disappointing for some. Following this experiment, Tom L. Schmidt and his colleagues conducted an experiment releasing Wolbachia -infected Aedes aegypti using different site selection methods occurred in different areas of Cairns during 2013. The release sites were monitored over two years. This time the release was done in urban areas that were adjacent to adequate habitat to encourage mosquito dispersal. Over the two years, the population doubled, and spatial spread was also increased, unlike the first release, giving ample satisfactory results. By increasing the spread of the Wolbachia -infected mosquitoes, the researchers were able to establish that population of a large city was possible if the mosquitoes were given adequate habitat to spread into upon release in different local locations throughout the city. In both of these studies, no adverse effects on public health or the natural ecosystem occurred. This made it an extremely attractive alternative to traditional insecticide methods given the increased pesticide resistance occurring from heavy use. From the success seen in Australia, the researchers were able to begin operating in more threatened portions of the world. The Eliminate Dengue program spread to 10 countries throughout Asia, Latin America, and the Western Pacific blooming into the non-profit organization, World Mosquito Program, as of September 2017. They still use the same technique of infecting wild populations of Ae. aegypti as they did in Australia, but their target diseases now include Zika, chikungunya and yellow fever as well as dengue. Although not alone in their efforts to use Wolbachia- infected mosquitoes to reduce mosquito-borne disease, the World Mosquito Program method is praised for being self-sustaining in that it causes permanent phenotype change rather than reducing mosquito populations through cytoplasmic incompatibility through male-only dispersal.

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Acute hemorrhagic fever syndrome

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Aspirin

2-acetoxybenzoic acid o -acetylsalicylic acid acetylsalicylic acid acetyl salicylate O=C(C)Oc1ccccc1C(=O)O InChI=1S/C9H8O4/c1-6(10)13-8-5-3-2-4-7(8)9(11)12/h2-5H,1H3,(H,11,12) Y Key:BSYNRYMUTXBXSQ-UHFFFAOYSA-N Y Aspirin , also known as acetylsalicylic acid ( ASA ), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain , fever , and/or inflammation , and as an antithrombotic . Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease , pericarditis , and rheumatic fever . Aspirin is also used long-term to help prevent further heart attacks , ischaemic strokes , and blood clots in people at high risk. For pain or fever, effects typically begin within 30 minutes. Aspirin works similarly to other NSAIDs but also suppresses the normal functioning of platelets . One common adverse effect is an upset stomach . More significant side effects include stomach ulcers , stomach bleeding , and worsening asthma . Bleeding risk is greater among those who are older, drink alcohol , take other NSAIDs, or are on other blood thinners . Aspirin is not recommended in the last part of pregnancy . It is not generally recommended in children with infections because of the risk of Reye syndrome . High doses may result in ringing in the ears . A precursor to aspirin found in the bark of the willow tree (genus Salix ) has been used for its health effects for at least 2,400 years. In 1853, chemist Charles Frédéric Gerhardt treated the medicine sodium salicylate with acetyl chloride to produce acetylsalicylic acid for the first time. Over the next 50 years, other chemists, mostly of the German company Bayer , established the chemical structure and devised more efficient production methods. : 69–75 Aspirin is available without medical prescription as a proprietary or generic medication in most jurisdictions. It is one of the most widely used medications globally, with an estimated 40,000 tonnes (44,000 tons) (50 to 120 billion pills ) [ clarification needed ] consumed each year, and is on the World Health Organization's List of Essential Medicines . In 2021, it was the 34th most commonly prescribed medication in the United States, with more than 17 million prescriptions. In 1897, scientists at the Bayer company began studying acetylsalicylic acid as a less-irritating replacement medication for common salicylate medicines. : 69–75 By 1899, Bayer had named it "Aspirin" and was selling it around the world. Aspirin's popularity grew over the first half of the 20th century, leading to competition between many brands and formulations. The word Aspirin was Bayer's brand name; however, their rights to the trademark were lost or sold in many countries . The name is ultimately a blend of the prefix a (cetyl) + spir Spiraea , the meadowsweet plant genus from which the acetylsalicylic acid was originally derived at Bayer + -in , the common chemical suffix. [ citation needed ]Aspirin decomposes rapidly in solutions of ammonium acetate or the acetates , carbonates , citrates , or hydroxides of the alkali metals . It is stable in dry air, but gradually hydrolyses in contact with moisture to acetic and salicylic acids . In solution with alkalis, the hydrolysis proceeds rapidly and the clear solutions formed may consist entirely of acetate and salicylate. Like flour mills , factories producing aspirin tablets must control the amount of the powder that becomes airborne inside the building, because the powder-air mixture can be explosive . The National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit in the United States of 5 mg/m 3 (time-weighted average). In 1989, the Occupational Safety and Health Administration (OSHA) set a legal permissible exposure limit for aspirin of 5 mg/m 3 , but this was vacated by the AFL-CIO v. OSHA decision in 1993. The synthesis of aspirin is classified as an esterification reaction. Salicylic acid is treated with acetic anhydride , an acid derivative, causing a chemical reaction that turns salicylic acid's hydroxyl group into an ester group (R-OH → R-OCOCH 3 ). This process yields aspirin and acetic acid , which is considered a byproduct of this reaction. Small amounts of sulfuric acid (and occasionally phosphoric acid ) are almost always used as a catalyst . This method is commonly demonstrated in undergraduate teaching labs. Reaction between acetic acid and salicylic acid can also form aspirin but this esterification reaction is reversible and the presence of water can lead to hydrolysis of the aspirin. So, an anhydrous reagent is preferred. Formulations containing high concentrations of aspirin often smell like vinegar because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic and acetic acids. The synthesis of aspirin is classified as an esterification reaction. Salicylic acid is treated with acetic anhydride , an acid derivative, causing a chemical reaction that turns salicylic acid's hydroxyl group into an ester group (R-OH → R-OCOCH 3 ). This process yields aspirin and acetic acid , which is considered a byproduct of this reaction. Small amounts of sulfuric acid (and occasionally phosphoric acid ) are almost always used as a catalyst . This method is commonly demonstrated in undergraduate teaching labs. Reaction between acetic acid and salicylic acid can also form aspirin but this esterification reaction is reversible and the presence of water can lead to hydrolysis of the aspirin. So, an anhydrous reagent is preferred. Formulations containing high concentrations of aspirin often smell like vinegar because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic and acetic acids. Aspirin, an acetyl derivative of salicylic acid, is a white, crystalline, weakly acidic substance, which melts at 136 °C (277 °F) , and decomposes around 140 °C (284 °F) . Its acid dissociation constant (p K a ) is 3.5 at 25 °C (77 °F) . Polymorphism , or the ability of a substance to form more than one crystal structure , is important in the development of pharmaceutical ingredients. Many drugs receive regulatory approval for only a single crystal form or polymorph. There was only one proven polymorph Form I of aspirin, though the existence of another polymorph was debated since the 1960s, and one report from 1981 reported that when crystallized in the presence of aspirin anhydride , the diffractogram of aspirin has weak additional peaks. Though at the time it was dismissed as mere impurity, it was, in retrospect, Form II aspirin. Form II was reported in 2005, found after attempted co-crystallization of aspirin and levetiracetam from hot acetonitrile . In form I, pairs of aspirin molecules form centrosymmetric dimers through the acetyl groups with the (acidic) methyl proton to carbonyl hydrogen bonds . In form II, each aspirin molecule forms the same hydrogen bonds, but with two neighbouring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups, both polymorphs form identical dimer structures. The aspirin polymorphs contain identical 2-dimensional sections and are therefore more precisely described as polytypes. Pure Form II aspirin could be prepared by seeding the batch with aspirin anhydrate in 15% weight. Polymorphism , or the ability of a substance to form more than one crystal structure , is important in the development of pharmaceutical ingredients. Many drugs receive regulatory approval for only a single crystal form or polymorph. There was only one proven polymorph Form I of aspirin, though the existence of another polymorph was debated since the 1960s, and one report from 1981 reported that when crystallized in the presence of aspirin anhydride , the diffractogram of aspirin has weak additional peaks. Though at the time it was dismissed as mere impurity, it was, in retrospect, Form II aspirin. Form II was reported in 2005, found after attempted co-crystallization of aspirin and levetiracetam from hot acetonitrile . In form I, pairs of aspirin molecules form centrosymmetric dimers through the acetyl groups with the (acidic) methyl proton to carbonyl hydrogen bonds . In form II, each aspirin molecule forms the same hydrogen bonds, but with two neighbouring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups, both polymorphs form identical dimer structures. The aspirin polymorphs contain identical 2-dimensional sections and are therefore more precisely described as polytypes. Pure Form II aspirin could be prepared by seeding the batch with aspirin anhydrate in 15% weight. In 1971, British pharmacologist John Robert Vane , then employed by the Royal College of Surgeons in London, showed aspirin suppressed the production of prostaglandins and thromboxanes . For this discovery he was awarded the 1982 Nobel Prize in Physiology or Medicine , jointly with Sune Bergström and Bengt Ingemar Samuelsson . Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX; officially known as prostaglandin-endoperoxide synthase, PTGS) enzyme required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme ( Suicide inhibition ). This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen ), which are reversible inhibitors. Low-dose aspirin use irreversibly blocks the formation of thromboxane A 2 in platelets, producing an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (8–9 days). This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks in people who have had a heart attack, unstable angina, ischemic stroke or transient ischemic attack. 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A 2 release provoked acutely, with the prostaglandin I 2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition. Prostaglandins, local hormones produced in the body, have diverse effects, including the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots . Heart attacks are caused primarily by blood clots, and low doses of aspirin are seen as an effective medical intervention to prevent a second acute myocardial infarction. At least two different types of cyclooxygenases , COX-1 and COX-2 , are acted on by aspirin. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally produces prostanoids , most of which are proinflammatory. Aspirin-modified COX-2 (aka prostaglandin-endoperoxide synthase 2 or PTGS2) produces lipoxins, most of which are anti-inflammatory. [ verification needed ] Newer NSAID drugs, COX-2 inhibitors (coxibs), have been developed to inhibit only COX-2, with the intent to reduce the incidence of gastrointestinal side effects. Several COX-2 inhibitors, such as rofecoxib (Vioxx), have been withdrawn from the market, after evidence emerged that COX-2 inhibitors increase the risk of heart attack and stroke. Endothelial cells lining the microvasculature in the body are proposed to express COX-2, and, by selectively inhibiting COX-2, prostaglandin production (specifically, PGI 2 ; prostacyclin) is downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anticoagulative effect of PGI 2 is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference as compared with reversible inhibitors. Furthermore, aspirin, while inhibiting the ability of COX-2 to form pro-inflammatory products such as the prostaglandins , converts this enzyme's activity from a prostaglandin-forming cyclooxygenase to a lipoxygenase -like enzyme: aspirin-treated COX-2 metabolizes a variety of polyunsaturated fatty acids to hydroperoxy products which are then further metabolized to specialized proresolving mediators such as the aspirin-triggered lipoxins , aspirin-triggered resolvins , and aspirin-triggered maresins . These mediators possess potent anti-inflammatory activity. It is proposed that this aspirin-triggered transition of COX-2 from cyclooxygenase to lipoxygenase activity and the consequential formation of specialized proresolving mediators contributes to the anti-inflammatory effects of aspirin. Aspirin has been shown to have at least three additional modes of action. It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons. Aspirin buffers and transports the protons. When high doses are given, it may actually cause fever, owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. In addition, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion is an important step in the immune response to infection; however, evidence is insufficient to show aspirin helps to fight infection. More recent data also suggest salicylic acid and its derivatives modulate signalling through NF-κB . NF-κB, a transcription factor complex, plays a central role in many biological processes, including inflammation. Aspirin is readily broken down in the body to salicylic acid, which itself has anti-inflammatory, antipyretic, and analgesic effects. In 2012, salicylic acid was found to activate AMP-activated protein kinase , which has been suggested as a possible explanation for some of the effects of both salicylic acid and aspirin. The acetyl portion of the aspirin molecule has its own targets. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the post-translational level. Aspirin is able to acetylate several other targets in addition to COX isoenzymes. These acetylation reactions may explain many hitherto unexplained effects of aspirin. In 1971, British pharmacologist John Robert Vane , then employed by the Royal College of Surgeons in London, showed aspirin suppressed the production of prostaglandins and thromboxanes . For this discovery he was awarded the 1982 Nobel Prize in Physiology or Medicine , jointly with Sune Bergström and Bengt Ingemar Samuelsson . Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX; officially known as prostaglandin-endoperoxide synthase, PTGS) enzyme required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme ( Suicide inhibition ). This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen ), which are reversible inhibitors. Low-dose aspirin use irreversibly blocks the formation of thromboxane A 2 in platelets, producing an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (8–9 days). This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks in people who have had a heart attack, unstable angina, ischemic stroke or transient ischemic attack. 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A 2 release provoked acutely, with the prostaglandin I 2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition. Prostaglandins, local hormones produced in the body, have diverse effects, including the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots . Heart attacks are caused primarily by blood clots, and low doses of aspirin are seen as an effective medical intervention to prevent a second acute myocardial infarction. At least two different types of cyclooxygenases , COX-1 and COX-2 , are acted on by aspirin. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally produces prostanoids , most of which are proinflammatory. Aspirin-modified COX-2 (aka prostaglandin-endoperoxide synthase 2 or PTGS2) produces lipoxins, most of which are anti-inflammatory. [ verification needed ] Newer NSAID drugs, COX-2 inhibitors (coxibs), have been developed to inhibit only COX-2, with the intent to reduce the incidence of gastrointestinal side effects. Several COX-2 inhibitors, such as rofecoxib (Vioxx), have been withdrawn from the market, after evidence emerged that COX-2 inhibitors increase the risk of heart attack and stroke. Endothelial cells lining the microvasculature in the body are proposed to express COX-2, and, by selectively inhibiting COX-2, prostaglandin production (specifically, PGI 2 ; prostacyclin) is downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anticoagulative effect of PGI 2 is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference as compared with reversible inhibitors. Furthermore, aspirin, while inhibiting the ability of COX-2 to form pro-inflammatory products such as the prostaglandins , converts this enzyme's activity from a prostaglandin-forming cyclooxygenase to a lipoxygenase -like enzyme: aspirin-treated COX-2 metabolizes a variety of polyunsaturated fatty acids to hydroperoxy products which are then further metabolized to specialized proresolving mediators such as the aspirin-triggered lipoxins , aspirin-triggered resolvins , and aspirin-triggered maresins . These mediators possess potent anti-inflammatory activity. It is proposed that this aspirin-triggered transition of COX-2 from cyclooxygenase to lipoxygenase activity and the consequential formation of specialized proresolving mediators contributes to the anti-inflammatory effects of aspirin. Aspirin has been shown to have at least three additional modes of action. It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons. Aspirin buffers and transports the protons. When high doses are given, it may actually cause fever, owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. In addition, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion is an important step in the immune response to infection; however, evidence is insufficient to show aspirin helps to fight infection. More recent data also suggest salicylic acid and its derivatives modulate signalling through NF-κB . NF-κB, a transcription factor complex, plays a central role in many biological processes, including inflammation. Aspirin is readily broken down in the body to salicylic acid, which itself has anti-inflammatory, antipyretic, and analgesic effects. In 2012, salicylic acid was found to activate AMP-activated protein kinase , which has been suggested as a possible explanation for some of the effects of both salicylic acid and aspirin. The acetyl portion of the aspirin molecule has its own targets. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the post-translational level. Aspirin is able to acetylate several other targets in addition to COX isoenzymes. These acetylation reactions may explain many hitherto unexplained effects of aspirin. Aspirin is produced in many formulations, with some differences in effect. In particular, aspirin can cause gastrointestinal bleeding , and formulations are sought which deliver the benefits of aspirin while mitigating harmful bleeding. Formulations may be combined (e.g., buffered + vitamin C). Tablets, typically of about 75–100 mg and 300–320 mg of immediate-release aspirin (IR-ASA). Dispersible tablets. Enteric-coated tablets. Buffered formulations containing aspirin with one of many buffering agents. Formulations of aspirin with vitamin C (ASA-VitC) A phospholipid-aspirin complex liquid formulation, PL-ASA. As of 2023 [ update ] the phospholipid coating was being trialled to determine if it caused less gastrointestinal damage. Acetylsalicylic acid is a weak acid , and very little of it is ionized in the stomach after oral administration. Acetylsalicylic acid is quickly absorbed through the cell membrane in the acidic conditions of the stomach. The increased pH and larger surface area of the small intestine causes aspirin to be absorbed more slowly there, as more of it is ionized. Owing to the formation of concretions, aspirin is absorbed much more slowly during overdose, and plasma concentrations can continue to rise for up to 24 hours after ingestion. About 50–80% of salicylate in the blood is bound to human serum albumin , while the rest remains in the active, ionized state; protein binding is concentration-dependent. Saturation of binding sites leads to more free salicylate and increased toxicity. The volume of distribution is 0.1–0.2 L/kg. Acidosis increases the volume of distribution because of enhancement of tissue penetration of salicylates. As much as 80% of therapeutic doses of salicylic acid is metabolized in the liver . Conjugation with glycine forms salicyluric acid , and with glucuronic acid to form two different glucuronide esters. The conjugate with the acetyl group intact is referred to as the acyl glucuronide ; the deacetylated conjugate is the phenolic glucuronide . These metabolic pathways have only a limited capacity. Small amounts of salicylic acid are also hydroxylated to gentisic acid . With large salicylate doses, the kinetics switch from first-order to zero-order, as metabolic pathways become saturated and renal excretion becomes increasingly important. Salicylates are excreted mainly by the kidneys as salicyluric acid (75%), free salicylic acid (10%), salicylic phenol (10%), and acyl glucuronides (5%), gentisic acid ( 12 months) DAPT in high risk patients. In conclusion, the optimal duration of DAPT after PCIs should be personalized after outweighing each patient's risks of ischemic events and risks of bleeding events with consideration of multiple patient-related and procedure-related factors. Moreover, aspirin should be continued indefinitely after DAPT is complete. The status of the use of aspirin for the primary prevention in cardiovascular disease is conflicting and inconsistent, with recent changes from previously recommending it widely decades ago, and that some referenced newer trials in clinical guidelines show less of benefit of adding aspirin alongside other anti-hypertensive and cholesterol lowering therapies. The ASCEND study demonstrated that in high-bleeding risk diabetics with no prior cardiovascular disease, there is no overall clinical benefit (12% decrease in risk of ischaemic events v/s 29% increase in GI bleeding) of low dose aspirin in preventing the serious vascular events over a period of 7.4 years. Similarly, the results of the ARRIVE study also showed no benefit of same dose of aspirin in reducing the time to first cardiovascular outcome in patients with moderate risk of cardiovascular disease over a period of five years. Aspirin has also been suggested as a component of a polypill for prevention of cardiovascular disease. Complicating the use of aspirin for prevention is the phenomenon of aspirin resistance. For people who are resistant, aspirin's efficacy is reduced. Some authors have suggested testing regimens to identify people who are resistant to aspirin. As of April 2022 [ update ] , the United States Preventive Services Task Force (USPSTF) determined that there was a "small net benefit" for patients aged 40–59 with a 10% or greater 10-year cardiovascular disease (CVD) risk, and "no net benefit" for patients aged over 60. Determining the net benefit was based on balancing the risk reduction of taking aspirin for heart attacks and ischaemic strokes, with the increased risk of gastrointestinal bleeding , intracranial bleeding , and hemorrhagic strokes . Their recommendations state that age changes the risk of the medicine, with the magnitude of the benefit of aspirin coming from starting at a younger age, while the risk of bleeding, while small, increases with age, particular for adults over 60, and can be compounded by other risk factors such as diabetes and a history of gastrointestinal bleeding. As a result, the USPSTF suggests that "people ages 40 to 59 who are at higher risk for CVD should decide with their clinician whether to start taking aspirin; people 60 or older should not start taking aspirin to prevent a first heart attack or stroke." Primary prevention guidelines from September 2019 [ update ] made by the American College of Cardiology and the American Heart Association state they might consider aspirin for patients aged 40–69 with a higher risk of atherosclerotic CVD, without an increased bleeding risk, while stating they would not recommend aspirin for patients aged over 70 or adults of any age with an increased bleeding risk. They state a CVD risk estimation and a risk discussion should be done before starting on aspirin, while stating aspirin should be used "infrequently in the routine primary prevention of (atherosclerotic CVD) because of lack of net benefit". As of August 2021 [ update ] , the European Society of Cardiology made similar recommendations; considering aspirin specifically to patients aged less than 70 at high or very high CVD risk, without any clear contraindications, on a case-by-case basis considering both ischemic risk and bleeding risk. Aspirin may reduce the overall risk of both getting cancer and dying from cancer. There is substantial evidence for lowering the risk of colorectal cancer (CRC), but aspirin must be taken for at least 10–20 years to see this benefit. It may also slightly reduce the risk of endometrial cancer and prostate cancer . Some conclude the benefits are greater than the risks due to bleeding in those at average risk. Others are unclear if the benefits are greater than the risk. Given this uncertainty, the 2007 United States Preventive Services Task Force (USPSTF) guidelines on this topic recommended against the use of aspirin for prevention of CRC in people with average risk. Nine years later however, the USPSTF issued a grade B recommendation for the use of low-dose aspirin (75 to 100 mg/day) "for the primary prevention of CVD [cardiovascular disease] and CRC in adults 50 to 59 years of age who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years". A meta-analysis through 2019 said that there was an association between taking aspirin and lower risk of cancer of the colorectum, esophagus, and stomach. In 2021, the U.S. Preventive services Task Force raised questions about the use of aspirin in cancer prevention. It notes the results of the 2018 ASPREE (Aspirin in Reducing Events in the Elderly) Trial, in which the risk of cancer-related death was higher in the aspirin-treated group than in the placebo group. Aspirin, along with several other agents with anti-inflammatory properties, has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar disorder in light of the possible role of inflammation in the pathogenesis of severe mental disorders. A 2022 systematic review concluded that aspirin exposure reduced the risk of depression in a pooled cohort of three studies (HR 0.624, 95% CI: 0.0503, 1.198, P=0.033). However, further high-quality, longer-duration, double-blind randomized controlled trials (RCTs) are needed to determine whether aspirin is an effective add-on treatment for bipolar depression. Thus, notwithstanding the biological rationale, the clinical perspectives of aspirin and anti-inflammatory agents in the treatment of bipolar depression remain uncertain. Although cohort and longitudinal studies have shown low-dose aspirin has a greater likelihood of reducing the incidence of dementia, numerous randomized controlled trials have not validated this. Some researchers have speculated the anti-inflammatory effects of aspirin may be beneficial for schizophrenia. Small trials have been conducted but evidence remains lacking. Aspirin is a first-line treatment for the fever and joint-pain symptoms of acute rheumatic fever . The therapy often lasts for one to two weeks, and is rarely indicated for longer periods. After fever and pain have subsided, the aspirin is no longer necessary, since it does not decrease the incidence of heart complications and residual rheumatic heart disease. Naproxen has been shown to be as effective as aspirin and less toxic, but due to the limited clinical experience, naproxen is recommended only as a second-line treatment. Along with rheumatic fever, Kawasaki disease remains one of the few indications for aspirin use in children in spite of a lack of high quality evidence for its effectiveness. Low-dose aspirin supplementation has moderate benefits when used for prevention of pre-eclampsia . This benefit is greater when started in early pregnancy. Aspirin has also demonstrated anti-tumoral effects, via inhibition of the PTTG1 gene, which is often overexpressed in tumors. For some people, aspirin does not have as strong an effect on platelets as for others, an effect known as aspirin-resistance or insensitivity. One study has suggested women are more likely to be resistant than men, and a different, aggregate study of 2,930 people found 28% were resistant. A study in 100 Italian people found, of the apparent 31% aspirin-resistant subjects, only 5% were truly resistant, and the others were noncompliant . Another study of 400 healthy volunteers found no subjects who were truly resistant, but some had "pseudoresistance, reflecting delayed and reduced drug absorption". Meta-analysis and systematic reviews have concluded that laboratory confirmed aspirin resistance confers increased rates of poorer outcomes in cardiovascular and neurovascular diseases. Although the majority of research conducted has surrounded cardiovascular and neurovascular, there is emerging research into the risk of aspirin resistance after orthopaedic surgery where aspirin is used for venous thromboembolism prophylaxis. Aspirin resistance in orthopaedic surgery, specifically after total hip and knee arthroplasties, is of interest as risk factors for aspirin resistance are also risk factors for venous thromboembolisms and osteoarthritis; the sequelae of requiring a total hip or knee arthroplasty. Some of these risk factors include obesity, advancing age, diabetes mellitus, dyslipidemia and inflammatory diseases. Aspirin is an effective analgesic for acute pain, although it is generally considered inferior to ibuprofen because aspirin is more likely to cause gastrointestinal bleeding . Aspirin is generally ineffective for those pains caused by muscle cramps , bloating , gastric distension , or acute skin irritation. As with other NSAIDs, combinations of aspirin and caffeine provide slightly greater pain relief than aspirin alone. Effervescent formulations of aspirin relieve pain faster than aspirin in tablets, which makes them useful for the treatment of migraines . Topical aspirin may be effective for treating some types of neuropathic pain . Aspirin, either by itself or in a combined formulation, effectively treats certain types of a headache , but its efficacy may be questionable for others. Secondary headaches, meaning those caused by another disorder or trauma, should be promptly treated by a medical provider. Among primary headaches, the International Classification of Headache Disorders distinguishes between tension headache (the most common), migraine, and cluster headache . Aspirin or other over-the-counter analgesics are widely recognized as effective for the treatment of tension headaches. Aspirin, especially as a component of an aspirin/paracetamol/caffeine combination , is considered a first-line therapy in the treatment of migraine, and comparable to lower doses of sumatriptan . It is most effective at stopping migraines when they are first beginning. Like its ability to control pain, aspirin's ability to control fever is due to its action on the prostaglandin system through its irreversible inhibition of COX . Although aspirin's use as an antipyretic in adults is well established, many medical societies and regulatory agencies, including the American Academy of Family Physicians , the American Academy of Pediatrics , and the Food and Drug Administration , strongly advise against using aspirin for the treatment of fever in children because of the risk of Reye's syndrome , a rare but often fatal illness associated with the use of aspirin or other salicylates in children during episodes of viral or bacterial infection. Because of the risk of Reye's syndrome in children, in 1986, the US Food and Drug Administration (FDA) required labeling on all aspirin-containing medications advising against its use in children and teenagers. Aspirin is used as an anti-inflammatory agent for both acute and long-term inflammation , as well as for the treatment of inflammatory diseases, such as rheumatoid arthritis . Aspirin is an important part of the treatment of those who have had a heart attack . It is generally not recommended for routine use by people with no other health problems, including those over the age of 70. The 2009 Antithrombotic Trialists' Collaboration published in Lancet evaluated the efficacy and safety of low dose aspirin in secondary prevention. In those with prior ischaemic stroke or acute myocardial infarction, daily low dose aspirin was associated with a 19% relative risk reduction of serious cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death). This did come at the expense of a 0.19% absolute risk increase in gastrointestinal bleeding; however, the benefits outweigh the hazard risk in this case. [ citation needed ] Data from previous trials have suggested that weight-based dosing of aspirin has greater benefits in primary prevention of cardiovascular outcomes. However, more recent trials were not able to replicate similar outcomes using low dose aspirin in low body weight ( 12 months) DAPT in high risk patients. In conclusion, the optimal duration of DAPT after PCIs should be personalized after outweighing each patient's risks of ischemic events and risks of bleeding events with consideration of multiple patient-related and procedure-related factors. Moreover, aspirin should be continued indefinitely after DAPT is complete. The status of the use of aspirin for the primary prevention in cardiovascular disease is conflicting and inconsistent, with recent changes from previously recommending it widely decades ago, and that some referenced newer trials in clinical guidelines show less of benefit of adding aspirin alongside other anti-hypertensive and cholesterol lowering therapies. The ASCEND study demonstrated that in high-bleeding risk diabetics with no prior cardiovascular disease, there is no overall clinical benefit (12% decrease in risk of ischaemic events v/s 29% increase in GI bleeding) of low dose aspirin in preventing the serious vascular events over a period of 7.4 years. Similarly, the results of the ARRIVE study also showed no benefit of same dose of aspirin in reducing the time to first cardiovascular outcome in patients with moderate risk of cardiovascular disease over a period of five years. Aspirin has also been suggested as a component of a polypill for prevention of cardiovascular disease. Complicating the use of aspirin for prevention is the phenomenon of aspirin resistance. For people who are resistant, aspirin's efficacy is reduced. Some authors have suggested testing regimens to identify people who are resistant to aspirin. As of April 2022 [ update ] , the United States Preventive Services Task Force (USPSTF) determined that there was a "small net benefit" for patients aged 40–59 with a 10% or greater 10-year cardiovascular disease (CVD) risk, and "no net benefit" for patients aged over 60. Determining the net benefit was based on balancing the risk reduction of taking aspirin for heart attacks and ischaemic strokes, with the increased risk of gastrointestinal bleeding , intracranial bleeding , and hemorrhagic strokes . Their recommendations state that age changes the risk of the medicine, with the magnitude of the benefit of aspirin coming from starting at a younger age, while the risk of bleeding, while small, increases with age, particular for adults over 60, and can be compounded by other risk factors such as diabetes and a history of gastrointestinal bleeding. As a result, the USPSTF suggests that "people ages 40 to 59 who are at higher risk for CVD should decide with their clinician whether to start taking aspirin; people 60 or older should not start taking aspirin to prevent a first heart attack or stroke." Primary prevention guidelines from September 2019 [ update ] made by the American College of Cardiology and the American Heart Association state they might consider aspirin for patients aged 40–69 with a higher risk of atherosclerotic CVD, without an increased bleeding risk, while stating they would not recommend aspirin for patients aged over 70 or adults of any age with an increased bleeding risk. They state a CVD risk estimation and a risk discussion should be done before starting on aspirin, while stating aspirin should be used "infrequently in the routine primary prevention of (atherosclerotic CVD) because of lack of net benefit". As of August 2021 [ update ] , the European Society of Cardiology made similar recommendations; considering aspirin specifically to patients aged less than 70 at high or very high CVD risk, without any clear contraindications, on a case-by-case basis considering both ischemic risk and bleeding risk. Aspirin may reduce the overall risk of both getting cancer and dying from cancer. There is substantial evidence for lowering the risk of colorectal cancer (CRC), but aspirin must be taken for at least 10–20 years to see this benefit. It may also slightly reduce the risk of endometrial cancer and prostate cancer . Some conclude the benefits are greater than the risks due to bleeding in those at average risk. Others are unclear if the benefits are greater than the risk. Given this uncertainty, the 2007 United States Preventive Services Task Force (USPSTF) guidelines on this topic recommended against the use of aspirin for prevention of CRC in people with average risk. Nine years later however, the USPSTF issued a grade B recommendation for the use of low-dose aspirin (75 to 100 mg/day) "for the primary prevention of CVD [cardiovascular disease] and CRC in adults 50 to 59 years of age who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years". A meta-analysis through 2019 said that there was an association between taking aspirin and lower risk of cancer of the colorectum, esophagus, and stomach. In 2021, the U.S. Preventive services Task Force raised questions about the use of aspirin in cancer prevention. It notes the results of the 2018 ASPREE (Aspirin in Reducing Events in the Elderly) Trial, in which the risk of cancer-related death was higher in the aspirin-treated group than in the placebo group. Aspirin, along with several other agents with anti-inflammatory properties, has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar disorder in light of the possible role of inflammation in the pathogenesis of severe mental disorders. A 2022 systematic review concluded that aspirin exposure reduced the risk of depression in a pooled cohort of three studies (HR 0.624, 95% CI: 0.0503, 1.198, P=0.033). However, further high-quality, longer-duration, double-blind randomized controlled trials (RCTs) are needed to determine whether aspirin is an effective add-on treatment for bipolar depression. Thus, notwithstanding the biological rationale, the clinical perspectives of aspirin and anti-inflammatory agents in the treatment of bipolar depression remain uncertain. Although cohort and longitudinal studies have shown low-dose aspirin has a greater likelihood of reducing the incidence of dementia, numerous randomized controlled trials have not validated this. Some researchers have speculated the anti-inflammatory effects of aspirin may be beneficial for schizophrenia. Small trials have been conducted but evidence remains lacking. Aspirin, along with several other agents with anti-inflammatory properties, has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar disorder in light of the possible role of inflammation in the pathogenesis of severe mental disorders. A 2022 systematic review concluded that aspirin exposure reduced the risk of depression in a pooled cohort of three studies (HR 0.624, 95% CI: 0.0503, 1.198, P=0.033). However, further high-quality, longer-duration, double-blind randomized controlled trials (RCTs) are needed to determine whether aspirin is an effective add-on treatment for bipolar depression. Thus, notwithstanding the biological rationale, the clinical perspectives of aspirin and anti-inflammatory agents in the treatment of bipolar depression remain uncertain. Although cohort and longitudinal studies have shown low-dose aspirin has a greater likelihood of reducing the incidence of dementia, numerous randomized controlled trials have not validated this. Some researchers have speculated the anti-inflammatory effects of aspirin may be beneficial for schizophrenia. Small trials have been conducted but evidence remains lacking. Aspirin is a first-line treatment for the fever and joint-pain symptoms of acute rheumatic fever . The therapy often lasts for one to two weeks, and is rarely indicated for longer periods. After fever and pain have subsided, the aspirin is no longer necessary, since it does not decrease the incidence of heart complications and residual rheumatic heart disease. Naproxen has been shown to be as effective as aspirin and less toxic, but due to the limited clinical experience, naproxen is recommended only as a second-line treatment. Along with rheumatic fever, Kawasaki disease remains one of the few indications for aspirin use in children in spite of a lack of high quality evidence for its effectiveness. Low-dose aspirin supplementation has moderate benefits when used for prevention of pre-eclampsia . This benefit is greater when started in early pregnancy. Aspirin has also demonstrated anti-tumoral effects, via inhibition of the PTTG1 gene, which is often overexpressed in tumors. For some people, aspirin does not have as strong an effect on platelets as for others, an effect known as aspirin-resistance or insensitivity. One study has suggested women are more likely to be resistant than men, and a different, aggregate study of 2,930 people found 28% were resistant. A study in 100 Italian people found, of the apparent 31% aspirin-resistant subjects, only 5% were truly resistant, and the others were noncompliant . Another study of 400 healthy volunteers found no subjects who were truly resistant, but some had "pseudoresistance, reflecting delayed and reduced drug absorption". Meta-analysis and systematic reviews have concluded that laboratory confirmed aspirin resistance confers increased rates of poorer outcomes in cardiovascular and neurovascular diseases. Although the majority of research conducted has surrounded cardiovascular and neurovascular, there is emerging research into the risk of aspirin resistance after orthopaedic surgery where aspirin is used for venous thromboembolism prophylaxis. Aspirin resistance in orthopaedic surgery, specifically after total hip and knee arthroplasties, is of interest as risk factors for aspirin resistance are also risk factors for venous thromboembolisms and osteoarthritis; the sequelae of requiring a total hip or knee arthroplasty. Some of these risk factors include obesity, advancing age, diabetes mellitus, dyslipidemia and inflammatory diseases. Adult aspirin tablets are produced in standardised sizes, which vary slightly from country to country, for example 300 mg in Britain and 325 mg in the United States. Smaller doses are based on these standards, e.g. , 75 mg and 81 mg tablets. The 81 mg tablets are commonly called "baby aspirin" or "baby-strength", because they were originally – but no longer – intended to be administered to infants and children. No medical significance occurs due to the slight difference in dosage between the 75 mg and the 81 mg tablets. The dose required for benefit appears to depend on a person's weight. For those weighing less than 70 kilograms (154 lb) , low dose is effective for preventing cardiovascular disease; for patients above this weight, higher doses are required. In general, for adults, doses are taken four times a day for fever or arthritis, with doses near the maximal daily dose used historically for the treatment of rheumatic fever . For the prevention of myocardial infarction (MI) in someone with documented or suspected coronary artery disease , much lower doses are taken once daily. March 2009 recommendations from the USPSTF on the use of aspirin for the primary prevention of coronary heart disease encourage men aged 45–79 and women aged 55–79 to use aspirin when the potential benefit of a reduction in MI for men or stroke for women outweighs the potential harm of an increase in gastrointestinal hemorrhage . [ needs update ] The WHI study of postmenopausal women found that aspirin resulted in a 25% lower risk of death from cardiovascular disease and a 14% lower risk of death from any cause, though there was no significant difference between 81 mg and 325 mg aspirin doses. The 2021 ADAPTABLE study also showed no significant difference in cardiovascular events or major bleeding between 81 mg and 325 mg doses of aspirin in patients (both men and women) with established cardiovascular disease. Low-dose aspirin use was also associated with a trend toward lower risk of cardiovascular events, and lower aspirin doses (75 or 81 mg/day) may optimize efficacy and safety for people requiring aspirin for long-term prevention. In children with Kawasaki disease, aspirin is taken at dosages based on body weight, initially four times a day for up to two weeks and then at a lower dose once daily for a further six to eight weeks. In October 2020, the US Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. One exception to the recommendation is the use of low-dose 81 mg aspirin at any point in pregnancy under the direction of a health care professional. Aspirin should not be taken by people who are allergic to ibuprofen or naproxen , or who have salicylate intolerance or a more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID-precipitated bronchospasm . Owing to its effect on the stomach lining, manufacturers recommend people with peptic ulcers , mild diabetes, or gastritis seek medical advice before using aspirin. Even if none of these conditions is present, the risk of stomach bleeding is still increased when aspirin is taken with alcohol or warfarin . People with hemophilia or other bleeding tendencies should not take aspirin or other salicylates. Aspirin is known to cause hemolytic anemia in people who have the genetic disease glucose-6-phosphate dehydrogenase deficiency , particularly in large doses and depending on the severity of the disease. Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. Aspirin taken at doses of ≤325 mg and ≤100 mg per day for ≥2 days can increase the odds of suffering a gout attack by 81% and 91% respectively. This effect may potentially be worsened by high purine diets, diuretics, and kidney disease, but is eliminated by the urate lowering drug allopurinol. Daily low dose aspirin does not appear to worsen kidney function. Aspirin may reduce cardiovascular risk in those without established cardiovascular disease in people with moderate CKD, without significantly increasing the risk of bleeding. Aspirin should not be given to children or adolescents under the age of 16 to control cold or influenza symptoms, as this has been linked with Reye's syndrome . Aspirin increases the risk of upper gastrointestinal bleeding . Enteric coating on aspirin may be used in manufacturing to prevent release of aspirin into the stomach to reduce gastric harm, but enteric coating does not reduce gastrointestinal bleeding risk. Enteric-coated aspirin may not be as effective at reducing blood clot risk. Combining aspirin with other NSAIDs has been shown to further increase the risk of gastrointestinal bleeding. Using aspirin in combination with clopidogrel or warfarin also increases the risk of upper gastrointestinal bleeding. Blockade of COX-1 by aspirin apparently results in the upregulation of COX-2 as part of a gastric defense. There is no clear evidence that simultaneous use of a COX-2 inhibitor with aspirin may increase the risk of gastrointestinal injury. " Buffering " is an additional method used with the intent to mitigate gastrointestinal bleeding, such as by preventing aspirin from concentrating in the walls of the stomach, although the benefits of buffered aspirin are disputed. Almost any buffering agent used in antacids can be used; Bufferin, for example, uses magnesium oxide . Other preparations use calcium carbonate . Gas-forming agents in effervescent tablet and powder formulations can also double as a buffering agent, one example being sodium bicarbonate , used in Alka-Seltzer . Taking vitamin C with aspirin has been investigated as a method of protecting the stomach lining. In trials vitamin C-releasing aspirin (ASA-VitC) or a buffered aspirin formulation containing vitamin C was found to cause less stomach damage than aspirin alone. It is a widespread habit among eye specialists (ophthalmologists) to prescribe aspirin as an add-on medication for patients with retinal vein occlusion (RVO), such as central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). The reason of this widespread use is the evidence of its proven effectiveness in major systemic venous thrombotic disorders, and it has been assumed that may be similarly beneficial in various types of retinal vein occlusion. However, a large-scale investigation based on data of nearly 700 patients showed "that aspirin or other antiplatelet aggregating agents or anticoagulants adversely influence the visual outcome in patients with CRVO and hemi-CRVO, without any evidence of protective or beneficial effect". Several expert groups, including the Royal College of Ophthalmologists , recommended against the use of antithrombotic drugs (incl. aspirin) for patients with RVO. Large doses of salicylate , a metabolite of aspirin, cause temporary tinnitus (ringing in the ears) based on experiments in rats, via the action on arachidonic acid and NMDA receptors cascade. Reye's syndrome, a rare but severe illness characterized by acute encephalopathy and fatty liver , can occur when children or adolescents are given aspirin for a fever or other illness or infection. From 1981 to 1997, 1207 cases of Reye's syndrome in people younger than 18 were reported to the US Centers for Disease Control and Prevention (CDC). Of these, 93% reported being ill in the three weeks preceding the onset of Reye's syndrome, most commonly with a respiratory infection , chickenpox , or diarrhea . Salicylates were detectable in 81.9% of children for whom test results were reported. After the association between Reye's syndrome and aspirin was reported, and safety measures to prevent it (including a Surgeon General 's warning, and changes to the labeling of aspirin-containing drugs) were implemented, aspirin taken by children declined considerably in the United States, as did the number of reported cases of Reye's syndrome; a similar decline was found in the United Kingdom after warnings against pediatric aspirin use were issued. The US Food and Drug Administration recommends aspirin (or aspirin-containing products) should not be given to anyone under the age of 12 who has a fever, and the UK National Health Service recommends children who are under 16 years of age should not take aspirin, unless it is on the advice of a doctor. For a small number of people, taking aspirin can result in symptoms including hives , swelling, and headache. Aspirin can exacerbate symptoms among those with chronic hives, or create acute symptoms of hives. These responses can be due to allergic reactions to aspirin, or more often due to its effect of inhibiting the COX-1 enzyme. Skin reactions may also tie to systemic contraindications, seen with NSAID-precipitated bronchospasm , or those with atopy . Aspirin and other NSAIDs, such as ibuprofen, may delay the healing of skin wounds. Earlier findings from two small, low-quality trials suggested a benefit with aspirin (alongside compression therapy) on venous leg ulcer healing time and leg ulcer size, however larger, more recent studies of higher quality have been unable to corroborate these outcomes. As such, further research is required to clarify the role of aspirin in this context. Aspirin can induce swelling of skin tissues in some people. In one study, angioedema appeared one to six hours after ingesting aspirin in some of the people. However, when the aspirin was taken alone, it did not cause angioedema in these people; the aspirin had been taken in combination with another NSAID-induced drug when angioedema appeared. Aspirin causes an increased risk of cerebral microbleeds having the appearance on MRI scans of 5 to 10 mm or smaller, hypointense (dark holes) patches. A study of a group with a mean dosage of aspirin of 270 mg per day estimated an average absolute risk increase in intracerebral hemorrhage (ICH) of 12 events per 10,000 persons. In comparison, the estimated absolute risk reduction in myocardial infarction was 137 events per 10,000 persons, and a reduction of 39 events per 10,000 persons in ischemic stroke. In cases where ICH already has occurred, aspirin use results in higher mortality, with a dose of about 250 mg per day resulting in a relative risk of death within three months after the ICH around 2.5 (95% confidence interval 1.3 to 4.6). Aspirin and other NSAIDs can cause abnormally high blood levels of potassium by inducing a hyporeninemic hypoaldosteronism state via inhibition of prostaglandin synthesis; however, these agents do not typically cause hyperkalemia by themselves in the setting of normal renal function and euvolemic state. Use of low-dose aspirin before a surgical procedure has been associated with an increased risk of bleeding events in some patients, however, ceasing aspirin prior to surgery has also been associated with an increase in major adverse cardiac events. An analysis of multiple studies found a three-fold increase in adverse events such as myocardial infarction in patients who ceased aspirin prior to surgery. The analysis found that the risk is dependent on the type of surgery being performed and the patient indication for aspirin use. On 9 July 2015, the US Food and Drug Administration (FDA) toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAID). Aspirin is an NSAID but is not affected by the new warnings. Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, higher than normal doses are taken over a period of time. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal, with a mortality rate of 25%; chronic overdose may be especially severe in children. Toxicity is managed with a number of potential treatments, including activated charcoal , intravenous dextrose and normal saline, sodium bicarbonate , and dialysis . The diagnosis of poisoning usually involves measurement of plasma salicylate, the active metabolite of aspirin, by automated spectrophotometric methods. Plasma salicylate levels in general range from 30 to 100 mg/L after usual therapeutic doses, 50–300 mg/L in people taking high doses and 700–1400 mg/L following acute overdose. Salicylate is also produced as a result of exposure to bismuth subsalicylate , methyl salicylate , and sodium salicylate . Aspirin is known to interact with other drugs. For example, acetazolamide and ammonium chloride are known to enhance the intoxicating effect of salicylates, and alcohol also increases the gastrointestinal bleeding associated with these types of drugs. Aspirin is known to displace a number of drugs from protein-binding sites in the blood, including the antidiabetic drugs tolbutamide and chlorpropamide , warfarin , methotrexate , phenytoin , probenecid , valproic acid (as well as interfering with beta oxidation , an important part of valproate metabolism), and other NSAIDs. Corticosteroids may also reduce the concentration of aspirin. Other NSAIDs, such as ibuprofen and naproxen, may reduce the antiplatelet effect of aspirin. Although limited evidence suggests this may not result in a reduced cardioprotective effect of aspirin. Analgesic doses of aspirin decrease sodium loss induced by spironolactone in the urine, however this does not reduce the antihypertensive effects of spironolactone. Furthermore, antiplatelet doses of aspirin are deemed too small to produce an interaction with spironolactone. Aspirin is known to compete with penicillin G for renal tubular secretion. Aspirin may also inhibit the absorption of vitamin C. [ unreliable medical source? ] Aspirin should not be taken by people who are allergic to ibuprofen or naproxen , or who have salicylate intolerance or a more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID-precipitated bronchospasm . Owing to its effect on the stomach lining, manufacturers recommend people with peptic ulcers , mild diabetes, or gastritis seek medical advice before using aspirin. Even if none of these conditions is present, the risk of stomach bleeding is still increased when aspirin is taken with alcohol or warfarin . People with hemophilia or other bleeding tendencies should not take aspirin or other salicylates. Aspirin is known to cause hemolytic anemia in people who have the genetic disease glucose-6-phosphate dehydrogenase deficiency , particularly in large doses and depending on the severity of the disease. Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. Aspirin taken at doses of ≤325 mg and ≤100 mg per day for ≥2 days can increase the odds of suffering a gout attack by 81% and 91% respectively. This effect may potentially be worsened by high purine diets, diuretics, and kidney disease, but is eliminated by the urate lowering drug allopurinol. Daily low dose aspirin does not appear to worsen kidney function. Aspirin may reduce cardiovascular risk in those without established cardiovascular disease in people with moderate CKD, without significantly increasing the risk of bleeding. Aspirin should not be given to children or adolescents under the age of 16 to control cold or influenza symptoms, as this has been linked with Reye's syndrome . Aspirin increases the risk of upper gastrointestinal bleeding . Enteric coating on aspirin may be used in manufacturing to prevent release of aspirin into the stomach to reduce gastric harm, but enteric coating does not reduce gastrointestinal bleeding risk. Enteric-coated aspirin may not be as effective at reducing blood clot risk. Combining aspirin with other NSAIDs has been shown to further increase the risk of gastrointestinal bleeding. Using aspirin in combination with clopidogrel or warfarin also increases the risk of upper gastrointestinal bleeding. Blockade of COX-1 by aspirin apparently results in the upregulation of COX-2 as part of a gastric defense. There is no clear evidence that simultaneous use of a COX-2 inhibitor with aspirin may increase the risk of gastrointestinal injury. " Buffering " is an additional method used with the intent to mitigate gastrointestinal bleeding, such as by preventing aspirin from concentrating in the walls of the stomach, although the benefits of buffered aspirin are disputed. Almost any buffering agent used in antacids can be used; Bufferin, for example, uses magnesium oxide . Other preparations use calcium carbonate . Gas-forming agents in effervescent tablet and powder formulations can also double as a buffering agent, one example being sodium bicarbonate , used in Alka-Seltzer . Taking vitamin C with aspirin has been investigated as a method of protecting the stomach lining. In trials vitamin C-releasing aspirin (ASA-VitC) or a buffered aspirin formulation containing vitamin C was found to cause less stomach damage than aspirin alone. It is a widespread habit among eye specialists (ophthalmologists) to prescribe aspirin as an add-on medication for patients with retinal vein occlusion (RVO), such as central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). The reason of this widespread use is the evidence of its proven effectiveness in major systemic venous thrombotic disorders, and it has been assumed that may be similarly beneficial in various types of retinal vein occlusion. However, a large-scale investigation based on data of nearly 700 patients showed "that aspirin or other antiplatelet aggregating agents or anticoagulants adversely influence the visual outcome in patients with CRVO and hemi-CRVO, without any evidence of protective or beneficial effect". Several expert groups, including the Royal College of Ophthalmologists , recommended against the use of antithrombotic drugs (incl. aspirin) for patients with RVO. Large doses of salicylate , a metabolite of aspirin, cause temporary tinnitus (ringing in the ears) based on experiments in rats, via the action on arachidonic acid and NMDA receptors cascade. Reye's syndrome, a rare but severe illness characterized by acute encephalopathy and fatty liver , can occur when children or adolescents are given aspirin for a fever or other illness or infection. From 1981 to 1997, 1207 cases of Reye's syndrome in people younger than 18 were reported to the US Centers for Disease Control and Prevention (CDC). Of these, 93% reported being ill in the three weeks preceding the onset of Reye's syndrome, most commonly with a respiratory infection , chickenpox , or diarrhea . Salicylates were detectable in 81.9% of children for whom test results were reported. After the association between Reye's syndrome and aspirin was reported, and safety measures to prevent it (including a Surgeon General 's warning, and changes to the labeling of aspirin-containing drugs) were implemented, aspirin taken by children declined considerably in the United States, as did the number of reported cases of Reye's syndrome; a similar decline was found in the United Kingdom after warnings against pediatric aspirin use were issued. The US Food and Drug Administration recommends aspirin (or aspirin-containing products) should not be given to anyone under the age of 12 who has a fever, and the UK National Health Service recommends children who are under 16 years of age should not take aspirin, unless it is on the advice of a doctor. For a small number of people, taking aspirin can result in symptoms including hives , swelling, and headache. Aspirin can exacerbate symptoms among those with chronic hives, or create acute symptoms of hives. These responses can be due to allergic reactions to aspirin, or more often due to its effect of inhibiting the COX-1 enzyme. Skin reactions may also tie to systemic contraindications, seen with NSAID-precipitated bronchospasm , or those with atopy . Aspirin and other NSAIDs, such as ibuprofen, may delay the healing of skin wounds. Earlier findings from two small, low-quality trials suggested a benefit with aspirin (alongside compression therapy) on venous leg ulcer healing time and leg ulcer size, however larger, more recent studies of higher quality have been unable to corroborate these outcomes. As such, further research is required to clarify the role of aspirin in this context.Aspirin can induce swelling of skin tissues in some people. In one study, angioedema appeared one to six hours after ingesting aspirin in some of the people. However, when the aspirin was taken alone, it did not cause angioedema in these people; the aspirin had been taken in combination with another NSAID-induced drug when angioedema appeared. Aspirin causes an increased risk of cerebral microbleeds having the appearance on MRI scans of 5 to 10 mm or smaller, hypointense (dark holes) patches. A study of a group with a mean dosage of aspirin of 270 mg per day estimated an average absolute risk increase in intracerebral hemorrhage (ICH) of 12 events per 10,000 persons. In comparison, the estimated absolute risk reduction in myocardial infarction was 137 events per 10,000 persons, and a reduction of 39 events per 10,000 persons in ischemic stroke. In cases where ICH already has occurred, aspirin use results in higher mortality, with a dose of about 250 mg per day resulting in a relative risk of death within three months after the ICH around 2.5 (95% confidence interval 1.3 to 4.6). Aspirin and other NSAIDs can cause abnormally high blood levels of potassium by inducing a hyporeninemic hypoaldosteronism state via inhibition of prostaglandin synthesis; however, these agents do not typically cause hyperkalemia by themselves in the setting of normal renal function and euvolemic state. Use of low-dose aspirin before a surgical procedure has been associated with an increased risk of bleeding events in some patients, however, ceasing aspirin prior to surgery has also been associated with an increase in major adverse cardiac events. An analysis of multiple studies found a three-fold increase in adverse events such as myocardial infarction in patients who ceased aspirin prior to surgery. The analysis found that the risk is dependent on the type of surgery being performed and the patient indication for aspirin use. On 9 July 2015, the US Food and Drug Administration (FDA) toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAID). Aspirin is an NSAID but is not affected by the new warnings. Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, higher than normal doses are taken over a period of time. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal, with a mortality rate of 25%; chronic overdose may be especially severe in children. Toxicity is managed with a number of potential treatments, including activated charcoal , intravenous dextrose and normal saline, sodium bicarbonate , and dialysis . The diagnosis of poisoning usually involves measurement of plasma salicylate, the active metabolite of aspirin, by automated spectrophotometric methods. Plasma salicylate levels in general range from 30 to 100 mg/L after usual therapeutic doses, 50–300 mg/L in people taking high doses and 700–1400 mg/L following acute overdose. Salicylate is also produced as a result of exposure to bismuth subsalicylate , methyl salicylate , and sodium salicylate . Aspirin is known to interact with other drugs. For example, acetazolamide and ammonium chloride are known to enhance the intoxicating effect of salicylates, and alcohol also increases the gastrointestinal bleeding associated with these types of drugs. Aspirin is known to displace a number of drugs from protein-binding sites in the blood, including the antidiabetic drugs tolbutamide and chlorpropamide , warfarin , methotrexate , phenytoin , probenecid , valproic acid (as well as interfering with beta oxidation , an important part of valproate metabolism), and other NSAIDs. Corticosteroids may also reduce the concentration of aspirin. Other NSAIDs, such as ibuprofen and naproxen, may reduce the antiplatelet effect of aspirin. Although limited evidence suggests this may not result in a reduced cardioprotective effect of aspirin. Analgesic doses of aspirin decrease sodium loss induced by spironolactone in the urine, however this does not reduce the antihypertensive effects of spironolactone. Furthermore, antiplatelet doses of aspirin are deemed too small to produce an interaction with spironolactone. Aspirin is known to compete with penicillin G for renal tubular secretion. Aspirin may also inhibit the absorption of vitamin C. [ unreliable medical source? ] The ISIS-2 trial demonstrated that aspirin at doses of 160 mg daily for one month, decreased the mortality by 21% of participants with a suspected myocardial infarction in the first five weeks. A single daily dose of 324 mg of aspirin for 12 weeks has a highly protective effect against acute myocardial infarction and death in men with unstable angina. Aspirin has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar disorder . However, meta-analytic evidence is based on very few studies and does not suggest any efficacy of aspirin in the treatment of bipolar depression. Thus, notwithstanding the biological rationale, the clinical perspectives of aspirin and anti-inflammatory agents in the treatment of bipolar depression remain uncertain. Several studies investigated the anti-infective properties of aspirin for bacterial, viral and parasitic infections. Aspirin was demonstrated to limit platelet activation induced by Staphylococcus aureus and Enterococcus faecalis and to reduce streptococcal adhesion to heart valves. In patients with tuberculous meningitis, the addition of aspirin reduced the risk of new cerebral infarction [RR = 0.52 (0.29-0.92)]. A role of aspirin on bacterial and fungal biofilm is also being supported by growing evidence. Evidence from observational studies were conflicting on the effect of aspirin in breast cancer prevention, a randomized controlled trial showed that aspirin had no significant effect in reducing breast cancer thus further studies are needed to clarify aspirin effect in cancer prevention. There are many anecdotal reportings that aspirin can improve plant's growth and resistance though most research involved salicylic acid instead of aspirin. Aspirin has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar disorder . However, meta-analytic evidence is based on very few studies and does not suggest any efficacy of aspirin in the treatment of bipolar depression. Thus, notwithstanding the biological rationale, the clinical perspectives of aspirin and anti-inflammatory agents in the treatment of bipolar depression remain uncertain. Several studies investigated the anti-infective properties of aspirin for bacterial, viral and parasitic infections. Aspirin was demonstrated to limit platelet activation induced by Staphylococcus aureus and Enterococcus faecalis and to reduce streptococcal adhesion to heart valves. In patients with tuberculous meningitis, the addition of aspirin reduced the risk of new cerebral infarction [RR = 0.52 (0.29-0.92)]. A role of aspirin on bacterial and fungal biofilm is also being supported by growing evidence. Evidence from observational studies were conflicting on the effect of aspirin in breast cancer prevention, a randomized controlled trial showed that aspirin had no significant effect in reducing breast cancer thus further studies are needed to clarify aspirin effect in cancer prevention.There are many anecdotal reportings that aspirin can improve plant's growth and resistance though most research involved salicylic acid instead of aspirin. Aspirin is sometimes used in veterinary medicine as an anticoagulant or to relieve pain associated with musculoskeletal inflammation or osteoarthritis . Aspirin should only be given to animals under the direct supervision of a veterinarian , as adverse effects—including gastrointestinal issues—are common. An aspirin overdose in any species may result in salicylate poisoning , characterized by hemorrhaging, seizures, coma, and even death. Dogs are better able to tolerate aspirin than cats are. Cats metabolize aspirin slowly because they lack the glucuronide conjugates that aid in the excretion of aspirin, making it potentially toxic if dosing is not spaced out properly. No clinical signs of toxicosis occurred when cats were given 25 mg/kg of aspirin every 48 hours for 4 weeks, but the recommended dose for relief of pain and fever and for treating blood clotting diseases in cats is 10 mg/kg every 48 hours to allow for metabolization.

Wiki

Acute hemorrhagic fever syndrome

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

Fulminant

Fulminant ( / ˈ f ʊ l m ɪ n ən t / ) is a medical descriptor for any event or process that occurs suddenly and escalates quickly, and is intense and severe to the point of lethality, i.e., it has an explosive character. The word comes from Latin fulmināre , to strike with lightning . There are several diseases described by this adjective: Beyond these particular uses, the term is used more generally as a descriptor for sudden-onset medical conditions that are immediately threatening to life or limb. Some viral hemorrhagic fevers , such as Ebola , Lassa fever , and Lábrea fever , may kill in as little as two to five days. Diseases that cause rapidly developing lung edema , such as some kinds of pneumonia , may kill in a few hours. It was said of the " black death " (pneumonic bubonic plague ) that some of its victims would die in a matter of hours after the initial symptoms appeared. Other pathologic conditions that may be fulminating in character are acute respiratory distress syndrome , asthma , acute anaphylaxis , septic shock , and disseminated intravascular coagulation . The term is generally not used to refer to immediate death by trauma, such as gunshot wound, but can refer to trauma-induced secondary conditions, such as commotio cordis , a sudden cardiac arrest caused by a blunt, non-penetrating trauma to the precordium , which causes ventricular fibrillation of the heart. Cardiac arrest and stroke in certain parts of the brain , such as in the brainstem (which controls cardiovascular and respiratory system functions), and massive hemorrhage of the great arteries (such as in perforation of the walls by trauma or by sudden opening of an aneurysm of the aorta ) may be very quick, causing "fulminant death". Sudden infant death syndrome (SIDS) is still a mysterious cause of respiratory arrest in infants. Certain infections of the brain, such as rabies , meningococcal meningitis , or primary amebic meningoencephalitis can kill within hours to days after symptoms appear. Some toxins , such as cyanide , may also provoke fulminant death. Abrupt hyperkalemia provoked by intravenous injection of potassium chloride leads to fulminant death by cardiac arrest.

Wiki

Acute hemorrhagic fever syndrome

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

Cerebral edema

Cerebral edema is excess accumulation of fluid ( edema ) in the intracellular or extracellular spaces of the brain . This typically causes impaired nerve function, increased pressure within the skull , and can eventually lead to direct compression of brain tissue and blood vessels . Symptoms vary based on the location and extent of edema and generally include headaches , nausea, vomiting, seizures, drowsiness, visual disturbances, dizziness, and in severe cases, death. Cerebral edema is commonly seen in a variety of brain injuries including ischemic stroke , subarachnoid hemorrhage , traumatic brain injury, subdural , epidural , or intracerebral hematoma , hydrocephalus , brain cancer , brain infections, low blood sodium levels , high altitude , and acute liver failure . Diagnosis is based on symptoms and physical examination findings and confirmed by serial neuroimaging ( computed tomography scans and magnetic resonance imaging ). The treatment of cerebral edema depends on the cause and includes monitoring of the person's airway and intracranial pressure , proper positioning, controlled hyperventilation, medications, fluid management, steroids. Extensive cerebral edema can also be treated surgically with a decompressive craniectomy . Cerebral edema is a major cause of brain damage and contributes significantly to the mortality of ischemic strokes and traumatic brain injuries . As cerebral edema is present with many common cerebral pathologies, the epidemiology of the disease is not easily defined. The incidence of this disorder should be considered in terms of its potential causes and is present in most cases of traumatic brain injury, central nervous system tumors , brain ischemia , and intracerebral hemorrhage . For example, malignant brain edema was present in roughly 31% of people with ischemic strokes within 30 days after onset. The extent and severity of the symptoms of cerebral edema depend on the exact etiology but are generally related to an acute increase of the pressure within the skull . As the skull is a fixed and inelastic space, the accumulation of cerebral edema can displace and compress vital brain tissue, cerebral spinal fluid , and blood vessels, according to the Monro–Kellie doctrine . Increased intracranial pressure (ICP) is a life-threatening surgical emergency marked by symptoms of headache, nausea, vomiting, decreased consciousness. Symptoms are frequently accompanied by visual disturbances such as gaze paresis , reduced vision, and dizziness. Increased pressures within the skull can cause a compensatory elevation of blood pressure to maintain cerebral blood flow , which, when associated with irregular breathing and a decreased heart rate , is called the Cushing reflex . The Cushing reflex often indicates compression of the brain on brain tissue and blood vessels, leading to decreased blood flow to the brain and eventually death. Cerebral edema is frequently encountered in acute brain injuries from a variety of origins, including but not limited to: Cerebral edema is present with many common cerebral pathologies and risk factors for development of cerebral edema will depend on the cause. The following were reliable predictors for development of early cerebral edema in ischemic strokes. Younger age Higher severity of symptoms on the National Institutes of Health Stroke Scale Signs of current ischemia on clinical exam Decreased level of consciousness Hyper dense artery sign and larger affected area on CT imaging Higher blood glucoseCerebral edema is present with many common cerebral pathologies and risk factors for development of cerebral edema will depend on the cause. The following were reliable predictors for development of early cerebral edema in ischemic strokes. Younger age Higher severity of symptoms on the National Institutes of Health Stroke Scale Signs of current ischemia on clinical exam Decreased level of consciousness Hyper dense artery sign and larger affected area on CT imaging Higher blood glucoseCerebral edema has been traditional classified into two major sub-types: cytotoxic and vasogenic cerebral edema. This simple classification helps guide medical decision making and treatment of patients affected with cerebral edema. There are, however, several more differentiated types including but not limited to interstitial, osmotic, hydrostatic, and high altitude associated edema. Within one affected person, many individual sub-types can be present simultaneously. The following individual sub-types have been identified: In general, cytotoxic edema is linked to cell death in the brain through excessive cellular swelling. During cerebral ischemia for example, the blood–brain barrier remains intact but decreased blood flow and glucose supply leads to a disruption in cellular metabolism and creation of energy sources, such as adenosine triphosphate (ATP). Exhaustion of energy sources impairs functioning of the sodium and potassium pump in the cell membrane, leading to cellular retention of sodium ions . Accumulation of sodium in the cell causes a rapid uptake of water through osmosis , with subsequent swelling of the cells. The ultimate consequence of cytotoxic edema is the oncotic death of neurons. The swelling of the individual cells of the brain is the main distinguishing characteristic of cytotoxic edema, as opposed to vasogenic edema, wherein the influx of fluid is typically seen in the interstitial space rather than within the cells themselves. Researchers have proposed that "cellular edema" may be more preferable to the term "cytotoxic edema" given the distinct swelling and lack of consistent "toxic" substance involved. There are several clinical conditions in which cytotoxic edema is present: Extracellular brain edema, or vasogenic edema, is caused by an increase in the permeability of the blood–brain barrier . The blood–brain barrier consists of astrocytes and pericytes joined with adhesion proteins producing tight junctions . Return of blood flow to these cells after an ischemic stroke can cause excitotoxicity and oxidative stress leading to dysfunction of the endothelial cells and disruption of the blood-brain barrier. The breakdown of the tight endothelial junctions that make up the blood–brain barrier causes extravasation of fluid, ions, and plasma proteins, such as albumin , into the brain parenchyma . Accumulation of extracellular fluid increases brain volume and then intracranial pressure causing the symptoms of cerebral edema. There are several clinical conditions in which vasogenic edema is present: In ionic edema, the solute concentration ( osmolality ) of the brain exceeds that of the plasma and the abnormal pressure gradient leads to accumulation of water intake into the brain parenchyma through the process of osmosis . The blood-brain barrier is intact and maintains the osmotic gradient. The solute concentration of the blood plasma can be diluted by several mechanisms: Ionic brain edema can also occur around the sites of brain hemorrhages, infarcts, or contusions due to a local plasma osmolality pressure gradient when compared to the high osmolality in the affected tissue. Interstitial edema can be best characterized by in noncomunnicating hydrocephalus where there is an obstruction to the outflow of cerebrospinal fluid within the ventricular system . The obstruction creates a rise in the intraventricular pressure and causes CSF to flow through the wall of the ventricles into the extracellular fluid within brain. The fluid has roughly the same composition of CSF. Other causes of interstitial edema include but are not limited to communicating hydrocephalus, and normal pressure hydrocephalus . Hydrostatic extracellular brain edema is typically caused by severe arterial hypertension. A difference in the hydrostatic pressure within the arterial system relative to the endothelial cells allows ultrafiltration of water, ions, and low molecular weight substances (such as glucose, small amino acids) into the brain parenchyma . The blood-brain barrier is intact usually and the extent of the edema depends on the arterial pressure. The regulatory processes of the brain circulation can function up to systolic arterial pressures of 150 mm Hg and will have impaired function at higher blood pressures. Cytotoxic, osmotic, and vasogenic edema exist on a continuum. The mechanism of the cause of cerebral edema can often overlap between these types. In most instances, cytotoxic and vasogenic edema occur together. When the two edema types evolve simultaneously, the damage of one type reaches a limit and will bring about the other type of injury. For example, when cytotoxic edema occurs in the endothelial cells of the blood–brain barrier , oncotic cell death contributes to loss of integrity of the blood–brain barrier and promotes the progression to vasogenic edema. When brain edema types are combined, there is typically a primary form and the edema type and context of the cause must be determined in order to start appropriate medical or surgical therapy. The use of specific MRI techniques has allowed for some differentiation between the mechanisms. If not properly acclimatized to high altitude, a person may be negatively affected by the lower oxygen concentration available. These hypoxia-related illnesses include acute mountain sickness (AMS) , high-altitude pulmonary edema , and high-altitude cerebral edema (HACE). High-altitude cerebral edema is a severe and sometimes fatal form of altitude sickness that results from capillary fluid leakage due to the effects of hypoxia on the mitochondria -rich endothelial cells of the blood–brain barrier . The edema can be characterized by vasogenic cerebral edema with symptoms of impaired consciousness and truncal ataxia . Altitude-related illnesses can be prevented most effectively with slow ascent to high altitudes, an average ascent of 300 to 500 meters per day is recommended. Pharmacological prophylaxis with acetazolamide or corticosteroids can be used in non pre-acclimatized individuals. If symptoms of high-altitude cerebral edema do not resolve or worsen, immediate descent is necessary, and symptoms can be improved with administration of dexamethasone. Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in neuroimaging of Alzheimer's disease patients given targeted amyloid-modifying therapies. Human monoclonal antibodies such as aducanumab , solanezumab , and bapineuzumab have been associated with these neuroimaging changes and additionally, cerebral edema. These therapies are associated with dysfunction of the tight endothelial junctions of the blood-brain barrier, leading to vasogenic edema as described above. In addition to edema, these therapies are associated with microhemorrhages in the brain known as ARIA-H. Familiarity with ARIA can aid radiologists and clinicians in determining optimal management for those affected. Posterior reversible encephalopathy syndrome (PRES) is a rare clinical disease characterized by cerebral edema. The exact pathophysiology , or cause, of the syndrome is still debated but is hypothesized to be related to the disruption of the blood-brain barrier. The syndrome features acute neurological symptoms and reversible subcortical vasogenic edema predominantly involving the parieto-occipital areas on MR imaging . PRES in general has a benign course, but PRES-related intracranial hemorrhage has been associated with a poor prognosis. Deep brain stimulation (DBS) is effective treatment for several neurological and psychiatric disorders, most notably Parkinson's disease . DBS is not without risks and although rare, idiopathic delayed-onset edema (IDE) surrounding the DBS leads have been reported. Symptoms can be mild and nonspecific, including reduction of the stimulation effect, and can be confused for other causes of edema. Thus, imaging is recommended to rule out other causes. The condition is generally self-limiting and the exact mechanism of the cause is unexplained. Early identification can help persons affected avoid unnecessary surgical procedures or antibiotic treatments. Decompressive craniectomy is frequently performed in cases of resistant intracranial hypertension secondary to several neurological conditions and is commonly followed by cranioplasty . Complications, such as infection and hematomas after cranioplasty occur in roughly about a third of cases. Massive brain swelling after cranioplasty (MSBC) is a rare and potentially fatal complication of an uneventful cranioplasty that has recently been elucidated. Preoperative sinking skin flap (SSF) and intracranial hypotension were factors associated with the development of MSBC after cranioplasty. Data suggests that pathologic changes are triggered immediately following the procedure, especially an acute increase in intracranial pressure. With the rise of sophisticated treatment modalities such as gamma knife , Cyberknife , and intensity-modulated radiotherapy , a large number of individuals with brain tumors are treated with radiosurgery and radiotherapy. Radiation-induced brain edema (RIBE) is a potentially life-threatening complication of brain tissue radiation and is characterized radiation necrosis, endothelial cell dysfunction, increased capillary permeability, and breakdown of the blood–brain barrier . Symptoms include headache, seizure, psychomotor slowing, irritability, and focal neurological deficits. Options for management of RIBE are limited and include corticosteroids , antiplatelet drugs , anticoagulants , hyperbaric oxygen therapy , multivitamins, and bevacizumab . This kind of cerebral edema is a significant cause of morbidity and mortality in patients with brain tumors and characterized by a disruption of the blood brain barrier and vasogenic edema. The exact mechanism is unclear but hypothesized that cancerous glial cells ( glioma ) of the brain can increase secretion of vascular endothelial growth factor (VEGF), which weakens the tight junctions of the blood–brain barrier . Historically, corticosteroids such as dexamethasone were used to reduce brain tumor-associated vascular permeability through poorly understood mechanisms and was associated with systemic side effects. Agents that target the VEGF signaling pathways, such as cediranib , have been promising in prolonging survival in rat models but associated with local and systemic side effects as well. In general, cytotoxic edema is linked to cell death in the brain through excessive cellular swelling. During cerebral ischemia for example, the blood–brain barrier remains intact but decreased blood flow and glucose supply leads to a disruption in cellular metabolism and creation of energy sources, such as adenosine triphosphate (ATP). Exhaustion of energy sources impairs functioning of the sodium and potassium pump in the cell membrane, leading to cellular retention of sodium ions . Accumulation of sodium in the cell causes a rapid uptake of water through osmosis , with subsequent swelling of the cells. The ultimate consequence of cytotoxic edema is the oncotic death of neurons. The swelling of the individual cells of the brain is the main distinguishing characteristic of cytotoxic edema, as opposed to vasogenic edema, wherein the influx of fluid is typically seen in the interstitial space rather than within the cells themselves. Researchers have proposed that "cellular edema" may be more preferable to the term "cytotoxic edema" given the distinct swelling and lack of consistent "toxic" substance involved. There are several clinical conditions in which cytotoxic edema is present:Extracellular brain edema, or vasogenic edema, is caused by an increase in the permeability of the blood–brain barrier . The blood–brain barrier consists of astrocytes and pericytes joined with adhesion proteins producing tight junctions . Return of blood flow to these cells after an ischemic stroke can cause excitotoxicity and oxidative stress leading to dysfunction of the endothelial cells and disruption of the blood-brain barrier. The breakdown of the tight endothelial junctions that make up the blood–brain barrier causes extravasation of fluid, ions, and plasma proteins, such as albumin , into the brain parenchyma . Accumulation of extracellular fluid increases brain volume and then intracranial pressure causing the symptoms of cerebral edema. There are several clinical conditions in which vasogenic edema is present:In ionic edema, the solute concentration ( osmolality ) of the brain exceeds that of the plasma and the abnormal pressure gradient leads to accumulation of water intake into the brain parenchyma through the process of osmosis . The blood-brain barrier is intact and maintains the osmotic gradient. The solute concentration of the blood plasma can be diluted by several mechanisms: Ionic brain edema can also occur around the sites of brain hemorrhages, infarcts, or contusions due to a local plasma osmolality pressure gradient when compared to the high osmolality in the affected tissue. Interstitial edema can be best characterized by in noncomunnicating hydrocephalus where there is an obstruction to the outflow of cerebrospinal fluid within the ventricular system . The obstruction creates a rise in the intraventricular pressure and causes CSF to flow through the wall of the ventricles into the extracellular fluid within brain. The fluid has roughly the same composition of CSF. Other causes of interstitial edema include but are not limited to communicating hydrocephalus, and normal pressure hydrocephalus . Hydrostatic extracellular brain edema is typically caused by severe arterial hypertension. A difference in the hydrostatic pressure within the arterial system relative to the endothelial cells allows ultrafiltration of water, ions, and low molecular weight substances (such as glucose, small amino acids) into the brain parenchyma . The blood-brain barrier is intact usually and the extent of the edema depends on the arterial pressure. The regulatory processes of the brain circulation can function up to systolic arterial pressures of 150 mm Hg and will have impaired function at higher blood pressures. Cytotoxic, osmotic, and vasogenic edema exist on a continuum. The mechanism of the cause of cerebral edema can often overlap between these types. In most instances, cytotoxic and vasogenic edema occur together. When the two edema types evolve simultaneously, the damage of one type reaches a limit and will bring about the other type of injury. For example, when cytotoxic edema occurs in the endothelial cells of the blood–brain barrier , oncotic cell death contributes to loss of integrity of the blood–brain barrier and promotes the progression to vasogenic edema. When brain edema types are combined, there is typically a primary form and the edema type and context of the cause must be determined in order to start appropriate medical or surgical therapy. The use of specific MRI techniques has allowed for some differentiation between the mechanisms. If not properly acclimatized to high altitude, a person may be negatively affected by the lower oxygen concentration available. These hypoxia-related illnesses include acute mountain sickness (AMS) , high-altitude pulmonary edema , and high-altitude cerebral edema (HACE). High-altitude cerebral edema is a severe and sometimes fatal form of altitude sickness that results from capillary fluid leakage due to the effects of hypoxia on the mitochondria -rich endothelial cells of the blood–brain barrier . The edema can be characterized by vasogenic cerebral edema with symptoms of impaired consciousness and truncal ataxia . Altitude-related illnesses can be prevented most effectively with slow ascent to high altitudes, an average ascent of 300 to 500 meters per day is recommended. Pharmacological prophylaxis with acetazolamide or corticosteroids can be used in non pre-acclimatized individuals. If symptoms of high-altitude cerebral edema do not resolve or worsen, immediate descent is necessary, and symptoms can be improved with administration of dexamethasone. Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in neuroimaging of Alzheimer's disease patients given targeted amyloid-modifying therapies. Human monoclonal antibodies such as aducanumab , solanezumab , and bapineuzumab have been associated with these neuroimaging changes and additionally, cerebral edema. These therapies are associated with dysfunction of the tight endothelial junctions of the blood-brain barrier, leading to vasogenic edema as described above. In addition to edema, these therapies are associated with microhemorrhages in the brain known as ARIA-H. Familiarity with ARIA can aid radiologists and clinicians in determining optimal management for those affected. Posterior reversible encephalopathy syndrome (PRES) is a rare clinical disease characterized by cerebral edema. The exact pathophysiology , or cause, of the syndrome is still debated but is hypothesized to be related to the disruption of the blood-brain barrier. The syndrome features acute neurological symptoms and reversible subcortical vasogenic edema predominantly involving the parieto-occipital areas on MR imaging . PRES in general has a benign course, but PRES-related intracranial hemorrhage has been associated with a poor prognosis. Deep brain stimulation (DBS) is effective treatment for several neurological and psychiatric disorders, most notably Parkinson's disease . DBS is not without risks and although rare, idiopathic delayed-onset edema (IDE) surrounding the DBS leads have been reported. Symptoms can be mild and nonspecific, including reduction of the stimulation effect, and can be confused for other causes of edema. Thus, imaging is recommended to rule out other causes. The condition is generally self-limiting and the exact mechanism of the cause is unexplained. Early identification can help persons affected avoid unnecessary surgical procedures or antibiotic treatments. Decompressive craniectomy is frequently performed in cases of resistant intracranial hypertension secondary to several neurological conditions and is commonly followed by cranioplasty . Complications, such as infection and hematomas after cranioplasty occur in roughly about a third of cases. Massive brain swelling after cranioplasty (MSBC) is a rare and potentially fatal complication of an uneventful cranioplasty that has recently been elucidated. Preoperative sinking skin flap (SSF) and intracranial hypotension were factors associated with the development of MSBC after cranioplasty. Data suggests that pathologic changes are triggered immediately following the procedure, especially an acute increase in intracranial pressure. With the rise of sophisticated treatment modalities such as gamma knife , Cyberknife , and intensity-modulated radiotherapy , a large number of individuals with brain tumors are treated with radiosurgery and radiotherapy. Radiation-induced brain edema (RIBE) is a potentially life-threatening complication of brain tissue radiation and is characterized radiation necrosis, endothelial cell dysfunction, increased capillary permeability, and breakdown of the blood–brain barrier . Symptoms include headache, seizure, psychomotor slowing, irritability, and focal neurological deficits. Options for management of RIBE are limited and include corticosteroids , antiplatelet drugs , anticoagulants , hyperbaric oxygen therapy , multivitamins, and bevacizumab . This kind of cerebral edema is a significant cause of morbidity and mortality in patients with brain tumors and characterized by a disruption of the blood brain barrier and vasogenic edema. The exact mechanism is unclear but hypothesized that cancerous glial cells ( glioma ) of the brain can increase secretion of vascular endothelial growth factor (VEGF), which weakens the tight junctions of the blood–brain barrier . Historically, corticosteroids such as dexamethasone were used to reduce brain tumor-associated vascular permeability through poorly understood mechanisms and was associated with systemic side effects. Agents that target the VEGF signaling pathways, such as cediranib , have been promising in prolonging survival in rat models but associated with local and systemic side effects as well. If not properly acclimatized to high altitude, a person may be negatively affected by the lower oxygen concentration available. These hypoxia-related illnesses include acute mountain sickness (AMS) , high-altitude pulmonary edema , and high-altitude cerebral edema (HACE). High-altitude cerebral edema is a severe and sometimes fatal form of altitude sickness that results from capillary fluid leakage due to the effects of hypoxia on the mitochondria -rich endothelial cells of the blood–brain barrier . The edema can be characterized by vasogenic cerebral edema with symptoms of impaired consciousness and truncal ataxia . Altitude-related illnesses can be prevented most effectively with slow ascent to high altitudes, an average ascent of 300 to 500 meters per day is recommended. Pharmacological prophylaxis with acetazolamide or corticosteroids can be used in non pre-acclimatized individuals. If symptoms of high-altitude cerebral edema do not resolve or worsen, immediate descent is necessary, and symptoms can be improved with administration of dexamethasone. Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in neuroimaging of Alzheimer's disease patients given targeted amyloid-modifying therapies. Human monoclonal antibodies such as aducanumab , solanezumab , and bapineuzumab have been associated with these neuroimaging changes and additionally, cerebral edema. These therapies are associated with dysfunction of the tight endothelial junctions of the blood-brain barrier, leading to vasogenic edema as described above. In addition to edema, these therapies are associated with microhemorrhages in the brain known as ARIA-H. Familiarity with ARIA can aid radiologists and clinicians in determining optimal management for those affected. Posterior reversible encephalopathy syndrome (PRES) is a rare clinical disease characterized by cerebral edema. The exact pathophysiology , or cause, of the syndrome is still debated but is hypothesized to be related to the disruption of the blood-brain barrier. The syndrome features acute neurological symptoms and reversible subcortical vasogenic edema predominantly involving the parieto-occipital areas on MR imaging . PRES in general has a benign course, but PRES-related intracranial hemorrhage has been associated with a poor prognosis. Deep brain stimulation (DBS) is effective treatment for several neurological and psychiatric disorders, most notably Parkinson's disease . DBS is not without risks and although rare, idiopathic delayed-onset edema (IDE) surrounding the DBS leads have been reported. Symptoms can be mild and nonspecific, including reduction of the stimulation effect, and can be confused for other causes of edema. Thus, imaging is recommended to rule out other causes. The condition is generally self-limiting and the exact mechanism of the cause is unexplained. Early identification can help persons affected avoid unnecessary surgical procedures or antibiotic treatments. Decompressive craniectomy is frequently performed in cases of resistant intracranial hypertension secondary to several neurological conditions and is commonly followed by cranioplasty . Complications, such as infection and hematomas after cranioplasty occur in roughly about a third of cases. Massive brain swelling after cranioplasty (MSBC) is a rare and potentially fatal complication of an uneventful cranioplasty that has recently been elucidated. Preoperative sinking skin flap (SSF) and intracranial hypotension were factors associated with the development of MSBC after cranioplasty. Data suggests that pathologic changes are triggered immediately following the procedure, especially an acute increase in intracranial pressure. With the rise of sophisticated treatment modalities such as gamma knife , Cyberknife , and intensity-modulated radiotherapy , a large number of individuals with brain tumors are treated with radiosurgery and radiotherapy. Radiation-induced brain edema (RIBE) is a potentially life-threatening complication of brain tissue radiation and is characterized radiation necrosis, endothelial cell dysfunction, increased capillary permeability, and breakdown of the blood–brain barrier . Symptoms include headache, seizure, psychomotor slowing, irritability, and focal neurological deficits. Options for management of RIBE are limited and include corticosteroids , antiplatelet drugs , anticoagulants , hyperbaric oxygen therapy , multivitamins, and bevacizumab . This kind of cerebral edema is a significant cause of morbidity and mortality in patients with brain tumors and characterized by a disruption of the blood brain barrier and vasogenic edema. The exact mechanism is unclear but hypothesized that cancerous glial cells ( glioma ) of the brain can increase secretion of vascular endothelial growth factor (VEGF), which weakens the tight junctions of the blood–brain barrier . Historically, corticosteroids such as dexamethasone were used to reduce brain tumor-associated vascular permeability through poorly understood mechanisms and was associated with systemic side effects. Agents that target the VEGF signaling pathways, such as cediranib , have been promising in prolonging survival in rat models but associated with local and systemic side effects as well. Cerebral edema is commonly present in a variety of neurological injuries. Thus, determining a definitive contribution of cerebral edema to the neurological status of an affected person can be challenging. Close bedside monitoring of a person's level of consciousness and awareness of any new or worsening focal neurological deficits is imperative but demanding, frequently requiring admission into the intensive care unit (ICU). Cerebral edema with sustained increased intracranial hypertension and brain herniation can signify impending catastrophic neurological events which require immediate recognition and treatment to prevent injury and even death. Therefore, diagnosis of cerebral edema earlier with rapid intervention can improve clinical outcomes and can mortality , or risk of death. Diagnosis of cerebral edema relies on the following: Serial neuroimaging ( CT scans and magnetic resonance imaging ) can be useful in diagnosing or excluding intracranial hemorrhage , large masses, acute hydrocephalus , or brain herniation as well as providing information on the type of edema present and the extent of affected area. CT scan is the imaging modality of choice as it is widely available, quick, and with minimal risks. However, CT scan can be limited in determining the exact cause of cerebral edema in which cases, CT angiography (CTA), MRI, or digital subtraction angiography (DSA) may be necessary. MRI is particularly useful as it can differentiate between cytotoxic and vasogenic edema, guiding future treatment decisions. Intracranial pressure (ICP) and its management is a fundamental concept in traumatic brain injury (TBI). The Brain Trauma Foundation guidelines recommend ICP monitoring in individuals with TBI that have decreased Glasgow Coma Scale (GCS) scores, abnormal CT scans, or additional risk factors such as older age and elevated blood pressure. However, no such guidelines exist for ICP monitoring in other brain injuries such as ischemic stroke , intracerebral hemorrhage , cerebral neoplasm . Clinical researches have recommended ICP and cerebral perfusion pressure (CPP) monitoring in any persons with cerebral injury who are at risk of elevated intracranial pressure based on clinical and neuroimaging features. Early monitoring can be used to guide medical and surgical decision making and to detect potentially life-threatening brain herniation. There was however, conflicting evidence on the threshold values of ICP that indicated the need for intervention. Researches also recommend that medical decisions should be tailored to the specific diagnosis (e.g. subarachnoid hemorrhage , TBI, encephalitis ) and that ICP elevation should be used in conjunction with clinical and neuroimaging and not as an isolated prognostic marker. Serial neuroimaging ( CT scans and magnetic resonance imaging ) can be useful in diagnosing or excluding intracranial hemorrhage , large masses, acute hydrocephalus , or brain herniation as well as providing information on the type of edema present and the extent of affected area. CT scan is the imaging modality of choice as it is widely available, quick, and with minimal risks. However, CT scan can be limited in determining the exact cause of cerebral edema in which cases, CT angiography (CTA), MRI, or digital subtraction angiography (DSA) may be necessary. MRI is particularly useful as it can differentiate between cytotoxic and vasogenic edema, guiding future treatment decisions. Intracranial pressure (ICP) and its management is a fundamental concept in traumatic brain injury (TBI). The Brain Trauma Foundation guidelines recommend ICP monitoring in individuals with TBI that have decreased Glasgow Coma Scale (GCS) scores, abnormal CT scans, or additional risk factors such as older age and elevated blood pressure. However, no such guidelines exist for ICP monitoring in other brain injuries such as ischemic stroke , intracerebral hemorrhage , cerebral neoplasm . Clinical researches have recommended ICP and cerebral perfusion pressure (CPP) monitoring in any persons with cerebral injury who are at risk of elevated intracranial pressure based on clinical and neuroimaging features. Early monitoring can be used to guide medical and surgical decision making and to detect potentially life-threatening brain herniation. There was however, conflicting evidence on the threshold values of ICP that indicated the need for intervention. Researches also recommend that medical decisions should be tailored to the specific diagnosis (e.g. subarachnoid hemorrhage , TBI, encephalitis ) and that ICP elevation should be used in conjunction with clinical and neuroimaging and not as an isolated prognostic marker. The primary goal in cerebral edema is to optimize and regulate cerebral perfusion , oxygenation, and venous drainage, decrease cerebral metabolic demands, and to stabilize the osmolality pressure gradient between the brain and the surrounding vasculature. As cerebral edema is linked to increased intracranial pressure (ICP), many of the therapies will focus on ICP. Finding the optimal head position in persons with cerebral edema is necessary to avoid compression of the jugular vein and obstruction of venous outflow from the skull, and for decreasing cerebrospinal fluid hydrostatic pressure . The current recommendation is to elevate the head of the bed to 30 degrees to optimize cerebral perfusion pressure and control the increase in intracranial pressure. It is also worth noting that measures should be taken to reduce restrictive neck dressings or garments as these may lead to compression of the internal jugular veins and reduce venous outflow. Decreased oxygen concentration in the blood, hypoxia , and increase in the carbon dioxide concentration in the blood, hypercapnia , are potent vasodilators in the cerebral vasculature, and should be avoided in those with cerebral edema. It is recommended that persons with decreased levels of consciousness be intubated for airway protection and maintenance of oxygen and carbon dioxide levels. However, the laryngeal instrumentation involved in the intubation process is associated with an acute, brief rise in intracranial pressure. Pretreatment with a sedative agent and neuromuscular blocking agent to induce unconsciousness and motor paralysis has been recommended as part of standard Rapid Sequence Intubation (RSI). Intravenous lidocaine prior to RSI has been suggested to reduce the rise in ICP but there is no supporting data at this time. Additionally, ventilation with use of positive pressure ( PEEP ) can improve oxygenation with the negative effect of decreasing cerebral venous drainage and increasing intracranial pressure (ICP), and thus, must be used with caution. Maintenance of cerebral perfusion pressure using appropriate fluid management is essential in patients with brain injury. Dehydration , or intravascular volume loss, and the use of hypotonic fluids, such as D5W or half normal saline , should be avoided. Blood serum ion concentration, or osmolality , should be maintained in the normo to hyperosmolar range. Judicial use of hypertonic saline can be used to increase serum osmolality and decrease cerebral edema, as discussed below. Blood pressure should be sufficient so as to sustain cerebral perfusion pressures greater than 60 mm Hg for optimal blood blow to the brain. Vasopressors may be used to achieve adequate blood pressures with minimal risk of increasing intracranial pressures. However, sharp rises in blood pressure should be avoided. Maximum blood pressures tolerated are variable and controversial depending on the clinical situation. Seizures , including subclinical seizure activity, can complicate clinical courses and increase progression of brain herniation in persons with cerebral edema and increased intracranial pressure. Anticonvulsants can be used to treat seizures caused by acute brain injuries from a variety of origins. However, there are no clear guidelines on the use of anticonvulsants for prophylactic use. Their use may be warranted on depending on the clinical scenario and studies have shown that anticonvulsants such as phenytoin can be given prophylactically without a significant increase in drug-related side effects. Fever has been demonstrated to increase metabolism and oxygen demand in the brain. The increased metabolic demand results in an increase in cerebral blood flow and can increase the intracranial pressure within the skull. Therefore, maintaining a stable body temperature within the normal range is strongly recommended. This can be achieved through the use of antipyretics such as acetaminophen ( paracetamol ) and cooling the body, as described below. Elevated blood glucose levels, known as hyperglycemia , can exacerbate brain injury and cerebral edema and has been associated with worse clinical outcomes in persons affected by traumatic brain injuries , subarachnoid hemorrhages , and ischemic strokes . Pain and agitation can worsen cerebral edema, acutely increase intracranial pressure (ICP), and should be controlled. Careful use of pain medication such as morphine or fentanyl can be used for analgesia . For those persons with decreased levels of consciousness, sedation is necessary for endotracheal intubation and maintenance of a secure airway. Sedative medication used in the intubation process, specifically propofol , have been shown to control ICP, decrease cerebral metabolic demand, and have antiseizure properties. Due to a short half-life , propofol , is a quick-acting medication whose administration and removal is well tolerated, with hypotension being the limiting factor in its continued use. Additionally, the use of nondepolarizing neuromusclar blocking agents (NMBA), such as doxacurium or atracurium , have been indicated to facilitate ventilation and manage brain injuries but there are no controlled studies on the use of NMBAs in the management of increased intracranial pressure. Depolarizing neuromuscular blocking agents, most notably succinylcholine , can worsen increased ICP due to induction of muscle contraction within the body. Nutritional support is necessary in all patients with acute brain injury. Enteral feeding , or through mouth via tube, is the preferred method, unless contraindicated. Additional attention must be placed on the solute concentration of the formulations to avoid free water intake, decreased serum osmolality, and worsening of the cerebral edema. Elevated blood glucose, or hyperglycemia , is associated with increased edema in patients with cerebral ischemia and increases the risk of a hemorrhagic transformation of ischemic stroke. Maintaining a normal blood glucose level of less than 180 mg/dL is suggested. However, tight glycemic control of blood glucose under 126 mg/dL is associated with worsening of stroke size. Although cerebral edema is closely related to increased intracranial pressure (ICP) and cerebral herniation and the general treatment strategies above are useful, the treatment should ultimately be tailored to the primary cause of the symptoms. The management of individual diseases are discussed separately. The following interventions are more specific treatments for managing cerebral edema and increased ICP: The goal of osmotic therapy is to create a higher concentration of ions within the vasculature at the blood–brain barrier . This will create an osmotic pressure gradient and will cause the flow of water out of the brain and into the vasculature for drainage elsewhere. An ideal osmotic agent produces a favorable osmotic pressure gradient, is nontoxic, and is not filtered out by the blood–brain barrier. Hypertonic saline and mannitol are the main osmotic agents in use, while loop diuretics can aid in the removal of the excess fluid pulled out of the brain. Glucocorticoids , such as dexamethasone , have been shown to decrease tight-junction permeability and stabilize the blood-brain barrier. Their main use has been in the management of vasogenic cerebral edema associated with brain tumors, brain irradiation, and surgical manipulation. Glucocorticoids have not been shown to have any benefit in ischemic stroke and have been found to be harmful in traumatic brain injury. Due to the negative side effects (such as peptic ulcers, hyperglycemia, and impairment of wound healing), steroid use should be restricted to cases where they are absolutely indicated. As mentioned previously, hypoxia and hypercapnia are potent vasodilators in the cerebral vasculature, leading to increased cerebral blood flow (CBF) and worsening of cerebral edema. Conversely, therapeutic hyperventilation can be used to lower the carbon dioxide content in the blood and reduce ICP through vasoconstriction . The effects of hyperventilation, although effective, are short-lived and once removed, can often lead to a rebound elevation of ICP. Furthermore, overaggressive hyperventilation and vasoconstriction and lead to severe reduction in CBF and cause cerebral ischemia , or strokes. As a result, standard practice is to slowly reverse hyperventilation while more definitive treatments aimed at the primary cause are instituted. It is important to note that prolonged hyperventilation in those with traumatic brain injuries has been shown to worsen outcomes. Induction of a coma via the use of barbiturates , most notably pentobarbital and thiopental , after brain injury is used for secondary treatment of refractory ICP. Yet their use is not without controversy and it is not clear whether barbiturates are favored over surgical decompression. In patients with traumatic brain injuries, barbiturates are effective in reducing ICP but have failed to show benefit to clinical outcomes. Evidence is limited for their use in cerebral disease that include tumor, intracranial hypertension , and ischemic stroke . There are several adverse effects of barbiturates that limit their use, such as lowering of systemic blood pressure and cerebral perfusion pressure , cardiodepression, immunosuppression , and systemic hypothermia . As discussed previously in the treatment of fever, temperature control has been shown to decrease metabolic demand and reduce further ischemic injury. In traumatic brain injury, induced hypothermia may reduce the risks of mortality, poor neurologic outcome in adults. However, outcomes varied greatly with depth and duration of hypothermia as well as rewarming procedures. In children with traumatic brain injury, there was no benefit to therapeutic hypothermia and increased the risk of mortality and arrhythmia. The adverse effects of hypothermia are serious and require clinical monitoring including increased chance of infection, coagulopathy , and electrolyte derangement. The current consensus is that adverse effects outweigh the benefits and its use restricted to clinical trials and refractory increased ICP to other therapies. The Monroe–Kellie doctrine states that the skull is a fixed and inelastic space and the accumulation of edema will compress vital brain tissue and blood vessels. Surgical treatment of cerebral edema in the context of cerebellar or cerebral infarction is typically done by removing part of the skull to allow expansion of the dura . This will help to reduce the volume constraints inside of the skull. A decompressive hemicraniectomy is the most commonly used procedure. Multiple randomized clinical trials have shown reduced risk of death with hemicraniectomy compared with medical management. However, no individual study has shown an improvement in the percentage of survivors with good functional outcomes. Timing of decompressive craniectomy remains controversial, but is generally suggested that the surgery is best performed before there are clinical signs of brainstem compression . Postoperative complications include wound dehiscence , hydrocephalus , infection, and a substantial proportion of patients may also require tracheostomy and gastrotomy in the early phase after surgery. Finding the optimal head position in persons with cerebral edema is necessary to avoid compression of the jugular vein and obstruction of venous outflow from the skull, and for decreasing cerebrospinal fluid hydrostatic pressure . The current recommendation is to elevate the head of the bed to 30 degrees to optimize cerebral perfusion pressure and control the increase in intracranial pressure. It is also worth noting that measures should be taken to reduce restrictive neck dressings or garments as these may lead to compression of the internal jugular veins and reduce venous outflow. Decreased oxygen concentration in the blood, hypoxia , and increase in the carbon dioxide concentration in the blood, hypercapnia , are potent vasodilators in the cerebral vasculature, and should be avoided in those with cerebral edema. It is recommended that persons with decreased levels of consciousness be intubated for airway protection and maintenance of oxygen and carbon dioxide levels. However, the laryngeal instrumentation involved in the intubation process is associated with an acute, brief rise in intracranial pressure. Pretreatment with a sedative agent and neuromuscular blocking agent to induce unconsciousness and motor paralysis has been recommended as part of standard Rapid Sequence Intubation (RSI). Intravenous lidocaine prior to RSI has been suggested to reduce the rise in ICP but there is no supporting data at this time. Additionally, ventilation with use of positive pressure ( PEEP ) can improve oxygenation with the negative effect of decreasing cerebral venous drainage and increasing intracranial pressure (ICP), and thus, must be used with caution. Maintenance of cerebral perfusion pressure using appropriate fluid management is essential in patients with brain injury. Dehydration , or intravascular volume loss, and the use of hypotonic fluids, such as D5W or half normal saline , should be avoided. Blood serum ion concentration, or osmolality , should be maintained in the normo to hyperosmolar range. Judicial use of hypertonic saline can be used to increase serum osmolality and decrease cerebral edema, as discussed below. Blood pressure should be sufficient so as to sustain cerebral perfusion pressures greater than 60 mm Hg for optimal blood blow to the brain. Vasopressors may be used to achieve adequate blood pressures with minimal risk of increasing intracranial pressures. However, sharp rises in blood pressure should be avoided. Maximum blood pressures tolerated are variable and controversial depending on the clinical situation. Seizures , including subclinical seizure activity, can complicate clinical courses and increase progression of brain herniation in persons with cerebral edema and increased intracranial pressure. Anticonvulsants can be used to treat seizures caused by acute brain injuries from a variety of origins. However, there are no clear guidelines on the use of anticonvulsants for prophylactic use. Their use may be warranted on depending on the clinical scenario and studies have shown that anticonvulsants such as phenytoin can be given prophylactically without a significant increase in drug-related side effects. Fever has been demonstrated to increase metabolism and oxygen demand in the brain. The increased metabolic demand results in an increase in cerebral blood flow and can increase the intracranial pressure within the skull. Therefore, maintaining a stable body temperature within the normal range is strongly recommended. This can be achieved through the use of antipyretics such as acetaminophen ( paracetamol ) and cooling the body, as described below. Elevated blood glucose levels, known as hyperglycemia , can exacerbate brain injury and cerebral edema and has been associated with worse clinical outcomes in persons affected by traumatic brain injuries , subarachnoid hemorrhages , and ischemic strokes . Pain and agitation can worsen cerebral edema, acutely increase intracranial pressure (ICP), and should be controlled. Careful use of pain medication such as morphine or fentanyl can be used for analgesia . For those persons with decreased levels of consciousness, sedation is necessary for endotracheal intubation and maintenance of a secure airway. Sedative medication used in the intubation process, specifically propofol , have been shown to control ICP, decrease cerebral metabolic demand, and have antiseizure properties. Due to a short half-life , propofol , is a quick-acting medication whose administration and removal is well tolerated, with hypotension being the limiting factor in its continued use. Additionally, the use of nondepolarizing neuromusclar blocking agents (NMBA), such as doxacurium or atracurium , have been indicated to facilitate ventilation and manage brain injuries but there are no controlled studies on the use of NMBAs in the management of increased intracranial pressure. Depolarizing neuromuscular blocking agents, most notably succinylcholine , can worsen increased ICP due to induction of muscle contraction within the body. Nutritional support is necessary in all patients with acute brain injury. Enteral feeding , or through mouth via tube, is the preferred method, unless contraindicated. Additional attention must be placed on the solute concentration of the formulations to avoid free water intake, decreased serum osmolality, and worsening of the cerebral edema. Elevated blood glucose, or hyperglycemia , is associated with increased edema in patients with cerebral ischemia and increases the risk of a hemorrhagic transformation of ischemic stroke. Maintaining a normal blood glucose level of less than 180 mg/dL is suggested. However, tight glycemic control of blood glucose under 126 mg/dL is associated with worsening of stroke size. Finding the optimal head position in persons with cerebral edema is necessary to avoid compression of the jugular vein and obstruction of venous outflow from the skull, and for decreasing cerebrospinal fluid hydrostatic pressure . The current recommendation is to elevate the head of the bed to 30 degrees to optimize cerebral perfusion pressure and control the increase in intracranial pressure. It is also worth noting that measures should be taken to reduce restrictive neck dressings or garments as these may lead to compression of the internal jugular veins and reduce venous outflow. Decreased oxygen concentration in the blood, hypoxia , and increase in the carbon dioxide concentration in the blood, hypercapnia , are potent vasodilators in the cerebral vasculature, and should be avoided in those with cerebral edema. It is recommended that persons with decreased levels of consciousness be intubated for airway protection and maintenance of oxygen and carbon dioxide levels. However, the laryngeal instrumentation involved in the intubation process is associated with an acute, brief rise in intracranial pressure. Pretreatment with a sedative agent and neuromuscular blocking agent to induce unconsciousness and motor paralysis has been recommended as part of standard Rapid Sequence Intubation (RSI). Intravenous lidocaine prior to RSI has been suggested to reduce the rise in ICP but there is no supporting data at this time. Additionally, ventilation with use of positive pressure ( PEEP ) can improve oxygenation with the negative effect of decreasing cerebral venous drainage and increasing intracranial pressure (ICP), and thus, must be used with caution. Maintenance of cerebral perfusion pressure using appropriate fluid management is essential in patients with brain injury. Dehydration , or intravascular volume loss, and the use of hypotonic fluids, such as D5W or half normal saline , should be avoided. Blood serum ion concentration, or osmolality , should be maintained in the normo to hyperosmolar range. Judicial use of hypertonic saline can be used to increase serum osmolality and decrease cerebral edema, as discussed below. Blood pressure should be sufficient so as to sustain cerebral perfusion pressures greater than 60 mm Hg for optimal blood blow to the brain. Vasopressors may be used to achieve adequate blood pressures with minimal risk of increasing intracranial pressures. However, sharp rises in blood pressure should be avoided. Maximum blood pressures tolerated are variable and controversial depending on the clinical situation. Seizures , including subclinical seizure activity, can complicate clinical courses and increase progression of brain herniation in persons with cerebral edema and increased intracranial pressure. Anticonvulsants can be used to treat seizures caused by acute brain injuries from a variety of origins. However, there are no clear guidelines on the use of anticonvulsants for prophylactic use. Their use may be warranted on depending on the clinical scenario and studies have shown that anticonvulsants such as phenytoin can be given prophylactically without a significant increase in drug-related side effects. Fever has been demonstrated to increase metabolism and oxygen demand in the brain. The increased metabolic demand results in an increase in cerebral blood flow and can increase the intracranial pressure within the skull. Therefore, maintaining a stable body temperature within the normal range is strongly recommended. This can be achieved through the use of antipyretics such as acetaminophen ( paracetamol ) and cooling the body, as described below. Elevated blood glucose levels, known as hyperglycemia , can exacerbate brain injury and cerebral edema and has been associated with worse clinical outcomes in persons affected by traumatic brain injuries , subarachnoid hemorrhages , and ischemic strokes . Pain and agitation can worsen cerebral edema, acutely increase intracranial pressure (ICP), and should be controlled. Careful use of pain medication such as morphine or fentanyl can be used for analgesia . For those persons with decreased levels of consciousness, sedation is necessary for endotracheal intubation and maintenance of a secure airway. Sedative medication used in the intubation process, specifically propofol , have been shown to control ICP, decrease cerebral metabolic demand, and have antiseizure properties. Due to a short half-life , propofol , is a quick-acting medication whose administration and removal is well tolerated, with hypotension being the limiting factor in its continued use. Additionally, the use of nondepolarizing neuromusclar blocking agents (NMBA), such as doxacurium or atracurium , have been indicated to facilitate ventilation and manage brain injuries but there are no controlled studies on the use of NMBAs in the management of increased intracranial pressure. Depolarizing neuromuscular blocking agents, most notably succinylcholine , can worsen increased ICP due to induction of muscle contraction within the body. Nutritional support is necessary in all patients with acute brain injury. Enteral feeding , or through mouth via tube, is the preferred method, unless contraindicated. Additional attention must be placed on the solute concentration of the formulations to avoid free water intake, decreased serum osmolality, and worsening of the cerebral edema. Elevated blood glucose, or hyperglycemia , is associated with increased edema in patients with cerebral ischemia and increases the risk of a hemorrhagic transformation of ischemic stroke. Maintaining a normal blood glucose level of less than 180 mg/dL is suggested. However, tight glycemic control of blood glucose under 126 mg/dL is associated with worsening of stroke size. Although cerebral edema is closely related to increased intracranial pressure (ICP) and cerebral herniation and the general treatment strategies above are useful, the treatment should ultimately be tailored to the primary cause of the symptoms. The management of individual diseases are discussed separately. The following interventions are more specific treatments for managing cerebral edema and increased ICP: The goal of osmotic therapy is to create a higher concentration of ions within the vasculature at the blood–brain barrier . This will create an osmotic pressure gradient and will cause the flow of water out of the brain and into the vasculature for drainage elsewhere. An ideal osmotic agent produces a favorable osmotic pressure gradient, is nontoxic, and is not filtered out by the blood–brain barrier. Hypertonic saline and mannitol are the main osmotic agents in use, while loop diuretics can aid in the removal of the excess fluid pulled out of the brain. Glucocorticoids , such as dexamethasone , have been shown to decrease tight-junction permeability and stabilize the blood-brain barrier. Their main use has been in the management of vasogenic cerebral edema associated with brain tumors, brain irradiation, and surgical manipulation. Glucocorticoids have not been shown to have any benefit in ischemic stroke and have been found to be harmful in traumatic brain injury. Due to the negative side effects (such as peptic ulcers, hyperglycemia, and impairment of wound healing), steroid use should be restricted to cases where they are absolutely indicated. As mentioned previously, hypoxia and hypercapnia are potent vasodilators in the cerebral vasculature, leading to increased cerebral blood flow (CBF) and worsening of cerebral edema. Conversely, therapeutic hyperventilation can be used to lower the carbon dioxide content in the blood and reduce ICP through vasoconstriction . The effects of hyperventilation, although effective, are short-lived and once removed, can often lead to a rebound elevation of ICP. Furthermore, overaggressive hyperventilation and vasoconstriction and lead to severe reduction in CBF and cause cerebral ischemia , or strokes. As a result, standard practice is to slowly reverse hyperventilation while more definitive treatments aimed at the primary cause are instituted. It is important to note that prolonged hyperventilation in those with traumatic brain injuries has been shown to worsen outcomes. Induction of a coma via the use of barbiturates , most notably pentobarbital and thiopental , after brain injury is used for secondary treatment of refractory ICP. Yet their use is not without controversy and it is not clear whether barbiturates are favored over surgical decompression. In patients with traumatic brain injuries, barbiturates are effective in reducing ICP but have failed to show benefit to clinical outcomes. Evidence is limited for their use in cerebral disease that include tumor, intracranial hypertension , and ischemic stroke . There are several adverse effects of barbiturates that limit their use, such as lowering of systemic blood pressure and cerebral perfusion pressure , cardiodepression, immunosuppression , and systemic hypothermia . As discussed previously in the treatment of fever, temperature control has been shown to decrease metabolic demand and reduce further ischemic injury. In traumatic brain injury, induced hypothermia may reduce the risks of mortality, poor neurologic outcome in adults. However, outcomes varied greatly with depth and duration of hypothermia as well as rewarming procedures. In children with traumatic brain injury, there was no benefit to therapeutic hypothermia and increased the risk of mortality and arrhythmia. The adverse effects of hypothermia are serious and require clinical monitoring including increased chance of infection, coagulopathy , and electrolyte derangement. The current consensus is that adverse effects outweigh the benefits and its use restricted to clinical trials and refractory increased ICP to other therapies. The Monroe–Kellie doctrine states that the skull is a fixed and inelastic space and the accumulation of edema will compress vital brain tissue and blood vessels. Surgical treatment of cerebral edema in the context of cerebellar or cerebral infarction is typically done by removing part of the skull to allow expansion of the dura . This will help to reduce the volume constraints inside of the skull. A decompressive hemicraniectomy is the most commonly used procedure. Multiple randomized clinical trials have shown reduced risk of death with hemicraniectomy compared with medical management. However, no individual study has shown an improvement in the percentage of survivors with good functional outcomes. Timing of decompressive craniectomy remains controversial, but is generally suggested that the surgery is best performed before there are clinical signs of brainstem compression . Postoperative complications include wound dehiscence , hydrocephalus , infection, and a substantial proportion of patients may also require tracheostomy and gastrotomy in the early phase after surgery. The goal of osmotic therapy is to create a higher concentration of ions within the vasculature at the blood–brain barrier . This will create an osmotic pressure gradient and will cause the flow of water out of the brain and into the vasculature for drainage elsewhere. An ideal osmotic agent produces a favorable osmotic pressure gradient, is nontoxic, and is not filtered out by the blood–brain barrier. Hypertonic saline and mannitol are the main osmotic agents in use, while loop diuretics can aid in the removal of the excess fluid pulled out of the brain. Glucocorticoids , such as dexamethasone , have been shown to decrease tight-junction permeability and stabilize the blood-brain barrier. Their main use has been in the management of vasogenic cerebral edema associated with brain tumors, brain irradiation, and surgical manipulation. Glucocorticoids have not been shown to have any benefit in ischemic stroke and have been found to be harmful in traumatic brain injury. Due to the negative side effects (such as peptic ulcers, hyperglycemia, and impairment of wound healing), steroid use should be restricted to cases where they are absolutely indicated. As mentioned previously, hypoxia and hypercapnia are potent vasodilators in the cerebral vasculature, leading to increased cerebral blood flow (CBF) and worsening of cerebral edema. Conversely, therapeutic hyperventilation can be used to lower the carbon dioxide content in the blood and reduce ICP through vasoconstriction . The effects of hyperventilation, although effective, are short-lived and once removed, can often lead to a rebound elevation of ICP. Furthermore, overaggressive hyperventilation and vasoconstriction and lead to severe reduction in CBF and cause cerebral ischemia , or strokes. As a result, standard practice is to slowly reverse hyperventilation while more definitive treatments aimed at the primary cause are instituted. It is important to note that prolonged hyperventilation in those with traumatic brain injuries has been shown to worsen outcomes. Induction of a coma via the use of barbiturates , most notably pentobarbital and thiopental , after brain injury is used for secondary treatment of refractory ICP. Yet their use is not without controversy and it is not clear whether barbiturates are favored over surgical decompression. In patients with traumatic brain injuries, barbiturates are effective in reducing ICP but have failed to show benefit to clinical outcomes. Evidence is limited for their use in cerebral disease that include tumor, intracranial hypertension , and ischemic stroke . There are several adverse effects of barbiturates that limit their use, such as lowering of systemic blood pressure and cerebral perfusion pressure , cardiodepression, immunosuppression , and systemic hypothermia . As discussed previously in the treatment of fever, temperature control has been shown to decrease metabolic demand and reduce further ischemic injury. In traumatic brain injury, induced hypothermia may reduce the risks of mortality, poor neurologic outcome in adults. However, outcomes varied greatly with depth and duration of hypothermia as well as rewarming procedures. In children with traumatic brain injury, there was no benefit to therapeutic hypothermia and increased the risk of mortality and arrhythmia. The adverse effects of hypothermia are serious and require clinical monitoring including increased chance of infection, coagulopathy , and electrolyte derangement. The current consensus is that adverse effects outweigh the benefits and its use restricted to clinical trials and refractory increased ICP to other therapies. The Monroe–Kellie doctrine states that the skull is a fixed and inelastic space and the accumulation of edema will compress vital brain tissue and blood vessels. Surgical treatment of cerebral edema in the context of cerebellar or cerebral infarction is typically done by removing part of the skull to allow expansion of the dura . This will help to reduce the volume constraints inside of the skull. A decompressive hemicraniectomy is the most commonly used procedure. Multiple randomized clinical trials have shown reduced risk of death with hemicraniectomy compared with medical management. However, no individual study has shown an improvement in the percentage of survivors with good functional outcomes. Timing of decompressive craniectomy remains controversial, but is generally suggested that the surgery is best performed before there are clinical signs of brainstem compression . Postoperative complications include wound dehiscence , hydrocephalus , infection, and a substantial proportion of patients may also require tracheostomy and gastrotomy in the early phase after surgery. Cerebral edema is a severe complication of acute brain injuries, most notably ischemic stroke and traumatic brain injuries , and a significant cause of morbidity and mortality. As cerebral edema is present with many common cerebral pathologies, the epidemiology of the disease is not easily defined. The incidence of this disorder should be considered in terms of its potential causes and is present in most cases of traumatic brain injury , central nervous system tumors , brain ischemia , and intracerebral hemorrhage . The current understanding of the pathophysiology of cerebral edema after traumatic brain injury or intracerebral hemorrhage is incomplete. Current treatment therapies aimed at cerebral edema and increased intracranial pressure are effective at reducing intracranial hypertension but have unclear impacts on functional outcomes. Additionally, cerebral and ICP treatments have varied effects on individuals based on differing characteristics like age, gender, type of injury, and genetics. There are innumerable molecular pathways that contribute to cerebral edema, many of which have yet to be discovered. Researchers argue that the future treatment of cerebral edema will be based on advances in identifying the underlying pathophysiology and molecular characteristics of cerebral edema in a variety of cases. At the same time, improvement of radiographic markers, biomarkers, and analysis of clinical monitoring data is essential in treating cerebral edema. Many studies of the mechanical properties of brain edema were conducted in the 2010s, most of them based on finite element analysis (FEA), a widely used numerical method in solid mechanics. For example, Gao and Ang used the finite element method to study changes in intracranial pressure during craniotomy operations. A second line of research on the condition looks at thermal conductivity , which is related to tissue water content.

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Acute hemorrhagic fever syndrome

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

Alkhurma virus

Alkhurma virus ( ALKV ) ( Arabic : فيروس الخر٠ة ) is a zoonotic virus of the Flaviviridae virus family (class IV). ALKV causes Alkhurma hemorrhagic fever ( AHF ), or alternatively termed as Alkhurma hemorrhagic fever virus, and is mainly based in Saudi Arabia . After an incubation period lasting as short as 2–4 days or as long as 8 days, people with AHF develop symptoms including fever, headache, joint pain , muscle pain , vomiting, a loss of appetite , feeling of great discomfort , and chills. Less than 10% of people develop severe neurologic, central nervous system, and hemorrhagic symptoms, such as purpura, epitasis, hallucinations , disorientation , convulsions , and life-threatening epistaxis . Elevated liver enzymes , leukopenia, proteinuria and thrombocytopenia, which leads to hemorrhagic fever and encephalitis (which can result in death), have been found in hospitalized patients. The ALKV prototype strain 1776 was retrieved from a person in Saudi Arabia during the 1990s. It was found to contain over 10,000 nucleotides , with a single ORF encoding over 3,000 amino acid polyproteins. The AnhC, PrM, M, NS2A, NS2B, NS3, NS4A, 2K, NS4B and NS5 proteins are all of the same length. ALKV owns the largest polyprotein of all TB-flaviviruses calculated as of yet. ALKV has been found to be closely related to the Kyasanur Forest disease (KFD), with which it shares 89% nucleotide sequence homology. Close similarities indicate that these viruses diverged 700 years ago. Related viruses include Omsk hemorrhagic fever and Royal Farm virus .Laboratory diagnosis of ALKV can be performed in the early stages of the illness by molecular detection of PCR or virus isolation from the blood. Serologic testing using enzyme-linked immunosorbent serologic assay (ELISA) can be made afterward. Treatment consists of supportive therapy which balances the person's fluids and electrolytes, oxygen status and blood pressure monitored and maintained, and additional treatment for any further complications. The mortality rate of hospitalized patients ranges from 1 to 20%. Due to limited information pertaining to ALKV, no specific treatment, such as a vaccine , has been created or made readily available. The best measures for combating ALKV are basic tick bite prevention, such as using tick repellents and avoiding regions where ticks are found in abundance, and raising awareness. Limiting non-casual contact with livestock and domestic animals is also another way of prevention. Individuals should appropriately check for attached ticks and remove them as soon as possible if found. Tick collars for domestic animals and the use of acaricides are efficient in killing ticks on livestock. People working with animals or animal products in farms or slaughterhouses should refrain from making unprotected contact with the blood, tissues, or fluids (such as consuming unpasteurized milk ) of any potentially infected animal. The route of transmission for ALKV is not fully understood and is filled with huge knowledge gaps, though camels and sheep have been linked to be the natural hosts of this virus. There appears to be more than one possible route of transmission seen in people who have become infected with this virus: one or more bites by an infected tick, crushing an infected tick with unprotected fingers, ingestion of unpasteurised camel milk , or entry via a skin wound. There is evidence pointing to the sand tampan, Ornithodoros savignyi , as the vector. No cases of human-human transmission of AHF have ever been recorded. The geographic distribution of the virus has extended beyond Saudi Arabia; reports of ALKV have been documented in countries where there is no endemic vector of the disease, such as Egypt , Djibouti , and India . In a 2014 case study, researchers found that most cases of the virus have been reported from the Najran Region , where agriculture is heavily emphasised. [ citation needed ] As a response to the troubling illness, the KSA (Kingdom of Saudi Arabia) is treating ALKV as one of the nationally notifiable diseases in the country. An effective surveillance system was established by the Ministry of Health , where any suspected case of ALKV must be reported immediately. Three forms must be filled out to properly ensure the virus is being sufficiently monitored: A suspect case form, an epidemiological investigation form, and a laboratory requisition form. The hospitals and health centers, either governmental or private, report the potential ALKV case to the desk officers in charge of viral hemorrhagic fevers at the Directorate of Health Affairs in their respective region. Afterward, the desk officer forwards the report to the Directorate of Infectious Diseases at the Preventive Medicine Department at the Ministry of Health. Before entering the case into the database system, the desk officer in charge of AHFV reviews the case reports for accuracy and completion. Subsequently, the desk officer at the Ministry of Health formulates daily reports for the higher directors at the Ministry of Health and forwards them as feedback to the regions and their respective health units. In 2018, the tick species H. rufipes , another possible vector for this virus, has been found to be infecting migratory birds in Europe. This virus was first isolated from the blood of a 32-year-old male butcher at Dr. Soliman Fakeeh Hospital , Saudi Arabia during the 1990s, who became sick with an acute, fatal hemorrhagic fever after slaughtering a sheep imported from the small city of Alkhurma , Mecca province . Since then, over 40 cases of ALKV, with case fatality rates less than 1%, have been reported. ALKV is classified as a BSL-3 or BSL-4 agent, depending on the country's regulations.

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Acute hemorrhagic fever syndrome

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

Colitis

Colitis is swelling or inflammation of the large intestine ( colon ). Colitis may be acute and self-limited or long-term . It broadly fits into the category of digestive diseases . In a medical context, the label colitis (without qualification) is used if:The signs and symptoms of colitis are quite variable and dependent on the cause of the given colitis and factors that modify its course and severity. Common symptoms of colitis may include: mild to severe abdominal pains and tenderness (depending on the stage of the disease), persistent hemorrhagic diarrhea with pus either present or absent in the stools , fecal incontinence , flatulence , fatigue , loss of appetite and unexplained weight loss . More severe symptoms may include: shortness of breath , a fast or irregular heartbeat and fever . Other less common or rare non-specific symptoms that may accompany colitis include: arthritis , mouth ulcers , painful, red and swollen skin and irritated, bloodshot eyes . Signs seen on colonoscopy include: colonic mucosal erythema (redness of the colon's inner surface), ulcerations and hemorrhage . [ medical citation needed ]Symptoms suggestive of colitis are worked-up by obtaining the medical history , a physical examination and laboratory tests ( CBC , electrolytes , stool culture and sensitivity, stool ova and parasites et cetera). Additional tests may include medical imaging (e.g. abdominal computed tomography , abdominal X-rays ) and an examination with a camera inserted into the rectum ( sigmoidoscopy , colonoscopy ). An important investigation in the assessment of colitis is biopsy for histopathology . A very small piece of tissue (usually about 2mm) is removed from the bowel mucosa during endoscopy and examined under the microscope by a histopathologist. A biopsy report generally does not state the diagnosis, but should state any presence of chronic colitis, give an indication of disease activity, as well as state the presence of any epithelial damage (erosions and ulcerations). Histopathology findings generally associated with chronic colitis include: Other findings include basal plasmacytosis and mucin depletion. Histopathology findings generally associated with active colitis include: There are many types of colitis. They are usually classified by the cause. Types of colitis include: Infectious colitis A subtype of infectious colitis is Clostridioides difficile colitis , which is informally abbreviated as "C-diff colitis". It classically forms pseudomembranes and is often referred to as pseudomembranous colitis, which is its (nonspecific) histomorphologic description. Enterohemorrhagic colitis may be caused by Shiga toxin in Shigella dysenteriae or Shigatoxigenic group of Escherichia coli (STEC), which includes serotype O157:H7 and other enterohemorrhagic E. coli . Parasitic infections, like those caused by Entamoeba histolytica , can also cause colitis. Indeterminate colitis is the classification for colitis that has features of both Crohn's disease and ulcerative colitis . Indeterminate colitis' behaviour is usually closer to ulcerative colitis than Crohn's disease. Atypical colitis is a phrase that is occasionally used by physicians for a colitis that does not conform to criteria for accepted types of colitis. It is not an accepted diagnosis per se and, as such, a colitis that cannot be definitively classified. [ citation needed ] Infectious colitis A subtype of infectious colitis is Clostridioides difficile colitis , which is informally abbreviated as "C-diff colitis". It classically forms pseudomembranes and is often referred to as pseudomembranous colitis, which is its (nonspecific) histomorphologic description. Enterohemorrhagic colitis may be caused by Shiga toxin in Shigella dysenteriae or Shigatoxigenic group of Escherichia coli (STEC), which includes serotype O157:H7 and other enterohemorrhagic E. coli . Parasitic infections, like those caused by Entamoeba histolytica , can also cause colitis.Indeterminate colitis is the classification for colitis that has features of both Crohn's disease and ulcerative colitis . Indeterminate colitis' behaviour is usually closer to ulcerative colitis than Crohn's disease. Atypical colitis is a phrase that is occasionally used by physicians for a colitis that does not conform to criteria for accepted types of colitis. It is not an accepted diagnosis per se and, as such, a colitis that cannot be definitively classified. [ citation needed ]Treatment for this condition can include medications such as steroids and dietary changes. In some instances, hospitalization and surgery may be required. Moreover, several studies recently have found significant relationship between colitis and dairy allergy (including: cow milk, cow milk UHT and casein), suggesting some patients may benefit from an elimination diet . The use of oral probiotic supplements to modify the composition and behavior of the microbiome has been considered as a possible therapy for both induction and maintenance of remission in people with Crohn's disease and ulcerative colitis. A Cochrane review in 2020 did not find clear evidence of improved remission likelihood, nor lower adverse events, in people with Crohn's disease, following probiotic treatment. For ulcerative colitis, there is low-certainty evidence that probiotic supplements may increase the probability of clinical remission. People receiving probiotics were 73% more likely to experience disease remission and over 2x as likely to report improvement in symptoms compared to those receiving a placebo, with no clear difference in minor or serious adverse effects. Although there was no clear evidence of greater remission when probiotic supplements were compared with 5‐aminosalicylic acid treatment as a monotherapy , the likelihood of remission was 22% higher if probiotics were used in combination with 5-aminosalicylic acid therapy. Whereas in people who are already in remission, it is unclear whether probiotics help to prevent future relapse, either as a monotherapy or combination therapy . The use of oral probiotic supplements to modify the composition and behavior of the microbiome has been considered as a possible therapy for both induction and maintenance of remission in people with Crohn's disease and ulcerative colitis. A Cochrane review in 2020 did not find clear evidence of improved remission likelihood, nor lower adverse events, in people with Crohn's disease, following probiotic treatment. For ulcerative colitis, there is low-certainty evidence that probiotic supplements may increase the probability of clinical remission. People receiving probiotics were 73% more likely to experience disease remission and over 2x as likely to report improvement in symptoms compared to those receiving a placebo, with no clear difference in minor or serious adverse effects. Although there was no clear evidence of greater remission when probiotic supplements were compared with 5‐aminosalicylic acid treatment as a monotherapy , the likelihood of remission was 22% higher if probiotics were used in combination with 5-aminosalicylic acid therapy. Whereas in people who are already in remission, it is unclear whether probiotics help to prevent future relapse, either as a monotherapy or combination therapy . In the lab, the CRISPR-Cas systems effectively killed C. difficile bacteria. Researchers tested this approach in mice infected with C. difficile . Two days after the CRISPR treatment, the mice showed reduced C. difficile levels. Next steps include retooling the phage to prevent C. difficile from returning after the initial effective killing. In 2022, Yang et al. published a report on a successful treatment, using mesenchymal stem cells , of experimental colitis in mice. Additional research was conducted by Huang et al. that analyzed specific genes and biological markers that are associated with the risk of colon cancer development in patients with colitis. The results showed a correlation between certain biomarkers and the development of disease. Colitis is common in parts of the world where helminthic colonisation is rare, and uncommon in those areas where most people carry worms. Infections with helminths may alter the autoimmune response that causes the disease. Early trials of Trichuris suis ova (TSO) showed promising results when used in people with IBD but later trials failed at Phase 2, and most were eventually discontinued. However, the phase 2 trials had used a different formulation of TSO from the one that had been used in the earlier studies that had shown positive outcomes.

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Acute hemorrhagic fever syndrome

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Zika virus

Zika virus ( ZIKV ; pronounced / ˈ z iː k ə / or / ˈ z ɪ k ə / ) is a member of the virus family Flaviviridae . It is spread by daytime-active Aedes mosquitoes, such as A. aegypti and A. albopictus . Its name comes from the Ziika Forest of Uganda , where the virus was first isolated in 1947. Zika virus shares a genus with the dengue , yellow fever , Japanese encephalitis , and West Nile viruses. Since the 1950s, it has been known to occur within a narrow equatorial belt from Africa to Asia. From 2007 to 2016 [ update ] , the virus spread eastward, across the Pacific Ocean to the Americas, leading to the 2015–2016 Zika virus epidemic . The infection, known as Zika fever or Zika virus disease, often causes no or only mild symptoms, similar to a very mild form of dengue fever . While there is no specific treatment, paracetamol (acetaminophen) and rest may help with the symptoms. As of April 2019, no vaccines have been approved for clinical use, however a number of vaccines are currently in clinical trials. Zika can spread from a pregnant woman to her baby. This can result in microcephaly , severe brain malformations , and other birth defects. Zika infections in adults may result rarely in Guillain–Barré syndrome . In January 2016, the United States Centers for Disease Control and Prevention (CDC) issued travel guidance on affected countries, including the use of enhanced precautions, and guidelines for pregnant women including considering postponing travel. Other governments or health agencies also issued similar travel warnings, while Colombia , the Dominican Republic , Puerto Rico , Ecuador , El Salvador , and Jamaica advised women to postpone getting pregnant until more is known about the risks. Zika virus belongs to the family Flaviviridae and the genus Flavivirus , thus is related to the dengue , yellow fever , Japanese encephalitis , and West Nile viruses. Like other flaviviruses, Zika virus is enveloped and icosahedral and has a nonsegmented, single-stranded, 10 kilobase , positive-sense RNA genome . It is most closely related to the Spondweni virus and is one of the two known viruses in the Spondweni virus clade . A positive-sense RNA genome can be directly translated into viral proteins. As in other flaviviruses, such as the similarly sized West Nile virus, the RNA genome encodes seven nonstructural proteins and three structural proteins in the form of a single polyprotein ( Q32ZE1 ). One of the structural proteins encapsulates the virus. This protein is the flavivirus envelope glycoprotein, that binds to the endosomal membrane of the host cell to initiate endocytosis. The RNA genome forms a nucleocapsid along with copies of the 12-kDa capsid protein. The nucleocapsid, in turn, is enveloped within a host-derived membrane modified with two viral glycoproteins . Viral genome replication depends on the making of double-stranded RNA from the single-stranded, positive-sense RNA (ssRNA(+)) genome followed by transcription and replication to provide viral mRNAs and new ssRNA(+) genomes. A longitudinal study shows that 6 hours after cells are infected with Zika virus , the vacuoles and mitochondria in the cells begin to swell. This swelling becomes so severe, it results in cell death, also known as paraptosis. This form of programmed cell death requires gene expression. IFITM3 is a trans-membrane protein in a cell that is able to protect it from viral infection by blocking virus attachment. Cells are most susceptible to Zika infection when levels of IFITM3 are low. Once the cell has been infected, the virus restructures the endoplasmic reticulum, forming the large vacuoles, resulting in cell death. There are two Zika lineages: the African lineage and the Asian lineage. Phylogenetic studies indicate that the virus spreading in the Americas is 89% identical to African genotypes, but is most closely related to the Asian strain that circulated in French Polynesia during the 2013 – 2014 outbreak . The Asian strain appears to have first evolved around 1928. The vertebrate hosts of the virus were primarily monkeys in a so-called enzootic mosquito-monkey-mosquito cycle, with only occasional transmission to humans. Before 2007, Zika "rarely caused recognized 'spillover' infections in humans, even in highly enzootic areas". Infrequently, however, other arboviruses have become established as a human disease and spread in a mosquito–human–mosquito cycle, like the yellow fever virus and the dengue fever virus (both flaviviruses), and the chikungunya virus (a togavirus ). Though the reason for the pandemic is unknown, dengue, a related arbovirus that infects the same species of mosquito vectors , is known in particular to be intensified by urbanization and globalization . Zika is primarily spread by Aedes aegypti mosquitoes, and can also be transmitted through sexual contact or blood transfusions . The basic reproduction number ( R 0 , a measure of transmissibility) of Zika virus has been estimated to be between 1.4 and 6.6 . In 2015, news reports drew attention to the rapid spread of Zika in Latin America and the Caribbean. At that time, the Pan American Health Organization published a list of countries and territories that experienced "local Zika virus transmission" comprising Barbados, Bolivia, Brazil, Colombia, the Dominican Republic, Ecuador, El Salvador, French Guiana, Guadeloupe, Guatemala, Guyana, Haiti, Honduras, Martinique, Mexico, Panama, Paraguay, Puerto Rico, Saint Martin, Suriname, and Venezuela. By August 2016, more than 50 countries had experienced active (local) transmission of Zika virus . Zika is primarily spread by the female Aedes aegypti mosquito, which is active mostly in the daytime. The mosquitos must feed on blood to lay eggs. : 2 The virus has also been isolated from a number of arboreal mosquito species in the genus Aedes , such as A. africanus , A. apicoargenteus , A. furcifer , A. hensilli , A. luteocephalus , and A. vittatus , with an extrinsic incubation period in mosquitoes around 10 days. The true extent of the vectors is still unknown. Zika has been detected in many more species of Aedes , along with Anopheles coustani, Mansonia uniformis , and Culex perfuscus , although this alone does not incriminate them as vectors. To detect the presence of the virus usually requires genetic material to be analysed in a lab using the technique RT-PCR . A much cheaper and faster method involves shining a light at the head and thorax of the mosquito, and detecting chemical compounds characteristic of the virus using near-infrared spectroscopy . Transmission by A. albopictus , the tiger mosquito, was reported from a 2007 urban outbreak in Gabon, where it had newly invaded the country and become the primary vector for the concomitant chikungunya and dengue virus outbreaks. New outbreaks can occur if a person carrying the virus travels to another region where A. albopictus is common. The potential societal risk of Zika can be delimited by the distribution of the mosquito species that transmit it. The global distribution of the most cited carrier of Zika, A. aegypti , is expanding due to global trade and travel. A. aegypti distribution is now the most extensive ever recorded – on parts of all continents except Antarctica, including North America and even the European periphery ( Madeira , the Netherlands, and the northeastern Black Sea coast). A mosquito population capable of carrying Zika has been found in a Capitol Hill neighborhood of Washington, DC, and genetic evidence suggests they survived at least four consecutive winters in the region. The study authors conclude that mosquitos are adapting for persistence in a northern climate. Zika virus appears to be contagious via mosquitoes for around a week after infection. The virus is thought to be infectious for a longer period of time after infection (at least 2 weeks) when transmitted via semen . Research into its ecological niche suggests that Zika may be influenced to a greater degree by changes in precipitation and temperature than dengue, making it more likely to be confined to tropical areas. However, rising global temperatures would allow for the disease vector to expand its range further north, allowing Zika to follow. Zika can be transmitted from men and women to their sexual partners; most known cases involve transmission from symptomatic men to women. As of April 2016, sexual transmission of Zika has been documented in six countries – Argentina, Australia, France, Italy, New Zealand, and the United States – during the 2015 outbreak. ZIKV can persist in semen for several months, with viral RNA detected up to one year. The virus replicates in the human testis, where it infects several cell types including testicular macrophages, peritubular cells and germ cells, the spermatozoa precursors. Semen parameters can be altered in patients for several weeks post-symptoms onset, and spermatozoa can be infectious. Since October 2016, the CDC has advised men who have traveled to an area with Zika should use condoms or not have sex for at least six months after their return as the virus is still transmissible even if symptoms never develop. Zika virus can spread by vertical (or "mother-to-child") transmission , during pregnancy or at delivery. An infection during pregnancy has been linked to changes in neuronal development of the unborn child. Severe progressions of infection have been linked to the development of microcephaly in the unborn child, while mild infections potentially can lead to neurocognitive disorders later in life. Congenital brain abnormalities other than microcephaly have also been reported after a Zika outbreak. Studies in mice have suggested that maternal immunity to dengue virus may enhance fetal infection with Zika, worsen the microcephaly phenotype and/or enhance damage during pregnancy, but it is unknown whether this occurs in humans. As of April 2016 [ update ] , two cases of Zika transmission through blood transfusions have been reported globally, both from Brazil, after which the US Food and Drug Administration (FDA) recommended screening blood donors and deferring high-risk donors for 4 weeks. A potential risk had been suspected based on a blood-donor screening study during the French Polynesian Zika outbreak, in which 2.8% (42) of donors from November 2013 and February 2014 tested positive for Zika RNA and were all asymptomatic at the time of blood donation. Eleven of the positive donors reported symptoms of Zika fever after their donation, but only three of 34 samples grew in culture. Zika is primarily spread by the female Aedes aegypti mosquito, which is active mostly in the daytime. The mosquitos must feed on blood to lay eggs. : 2 The virus has also been isolated from a number of arboreal mosquito species in the genus Aedes , such as A. africanus , A. apicoargenteus , A. furcifer , A. hensilli , A. luteocephalus , and A. vittatus , with an extrinsic incubation period in mosquitoes around 10 days. The true extent of the vectors is still unknown. Zika has been detected in many more species of Aedes , along with Anopheles coustani, Mansonia uniformis , and Culex perfuscus , although this alone does not incriminate them as vectors. To detect the presence of the virus usually requires genetic material to be analysed in a lab using the technique RT-PCR . A much cheaper and faster method involves shining a light at the head and thorax of the mosquito, and detecting chemical compounds characteristic of the virus using near-infrared spectroscopy . Transmission by A. albopictus , the tiger mosquito, was reported from a 2007 urban outbreak in Gabon, where it had newly invaded the country and become the primary vector for the concomitant chikungunya and dengue virus outbreaks. New outbreaks can occur if a person carrying the virus travels to another region where A. albopictus is common. The potential societal risk of Zika can be delimited by the distribution of the mosquito species that transmit it. The global distribution of the most cited carrier of Zika, A. aegypti , is expanding due to global trade and travel. A. aegypti distribution is now the most extensive ever recorded – on parts of all continents except Antarctica, including North America and even the European periphery ( Madeira , the Netherlands, and the northeastern Black Sea coast). A mosquito population capable of carrying Zika has been found in a Capitol Hill neighborhood of Washington, DC, and genetic evidence suggests they survived at least four consecutive winters in the region. The study authors conclude that mosquitos are adapting for persistence in a northern climate. Zika virus appears to be contagious via mosquitoes for around a week after infection. The virus is thought to be infectious for a longer period of time after infection (at least 2 weeks) when transmitted via semen . Research into its ecological niche suggests that Zika may be influenced to a greater degree by changes in precipitation and temperature than dengue, making it more likely to be confined to tropical areas. However, rising global temperatures would allow for the disease vector to expand its range further north, allowing Zika to follow. Zika can be transmitted from men and women to their sexual partners; most known cases involve transmission from symptomatic men to women. As of April 2016, sexual transmission of Zika has been documented in six countries – Argentina, Australia, France, Italy, New Zealand, and the United States – during the 2015 outbreak. ZIKV can persist in semen for several months, with viral RNA detected up to one year. The virus replicates in the human testis, where it infects several cell types including testicular macrophages, peritubular cells and germ cells, the spermatozoa precursors. Semen parameters can be altered in patients for several weeks post-symptoms onset, and spermatozoa can be infectious. Since October 2016, the CDC has advised men who have traveled to an area with Zika should use condoms or not have sex for at least six months after their return as the virus is still transmissible even if symptoms never develop. Zika virus can spread by vertical (or "mother-to-child") transmission , during pregnancy or at delivery. An infection during pregnancy has been linked to changes in neuronal development of the unborn child. Severe progressions of infection have been linked to the development of microcephaly in the unborn child, while mild infections potentially can lead to neurocognitive disorders later in life. Congenital brain abnormalities other than microcephaly have also been reported after a Zika outbreak. Studies in mice have suggested that maternal immunity to dengue virus may enhance fetal infection with Zika, worsen the microcephaly phenotype and/or enhance damage during pregnancy, but it is unknown whether this occurs in humans. As of April 2016 [ update ] , two cases of Zika transmission through blood transfusions have been reported globally, both from Brazil, after which the US Food and Drug Administration (FDA) recommended screening blood donors and deferring high-risk donors for 4 weeks. A potential risk had been suspected based on a blood-donor screening study during the French Polynesian Zika outbreak, in which 2.8% (42) of donors from November 2013 and February 2014 tested positive for Zika RNA and were all asymptomatic at the time of blood donation. Eleven of the positive donors reported symptoms of Zika fever after their donation, but only three of 34 samples grew in culture. Zika virus replicates in the mosquito's midgut epithelial cells and then its salivary gland cells. After 5–10 days, the virus can be found in the mosquito's saliva. If the mosquito's saliva is inoculated into human skin, the virus can infect epidermal keratinocytes, skin fibroblasts in the skin and the Langerhans cells . The pathogenesis of the virus is hypothesized to continue with a spread to lymph nodes and the bloodstream. Flaviviruses replicate in the cytoplasm , but Zika antigens have been found in infected cell nuclei. The viral protein numbered NS4A can lead to small head size ( microcephaly ) because it disrupts brain growth by hijacking a pathway which regulates growth of new neurons. In fruit flies, both NS4A and the neighboring NS4B restrict eye growth. Zika fever (also known as Zika virus disease) is an illness caused by Zika virus . Around 80% of cases are estimated to be asymptomatic, though the accuracy of this figure is hindered by the wide variance in data quality, and figures from different outbreaks can vary significantly. Symptomatic cases are usually mild and can resemble dengue fever . Symptoms may include fever , red eyes , joint pain , headache, and a maculopapular rash . Symptoms generally last less than seven days. It has not caused any reported deaths during the initial infection. Infection during pregnancy causes microcephaly and other brain malformations in some babies. Infection in adults has been linked to Guillain–Barré syndrome (GBS) and Zika virus has been shown to infect human Schwann cells . Diagnosis is by testing the blood, urine, or saliva for the presence of Zika virus RNA when the person is sick. In 2019, an improved diagnostic test, based on research from Washington University in St. Louis , that detects Zika infection in serum was granted market authorization by the FDA . Prevention involves decreasing mosquito bites in areas where the disease occurs, and proper use of condoms. Efforts to prevent bites include the use of DEET or picaridin - based insect repellent , covering much of the body with clothing, mosquito nets , and getting rid of standing water where mosquitoes reproduce. There is no vaccine . Health officials recommended that women in areas affected by the 2015–2016 Zika outbreak consider putting off pregnancy and that pregnant women not travel to these areas. While no specific treatment exists, paracetamol (acetaminophen) and rest may help with the symptoms. Admission to a hospital is rarely necessary. It is advised, for an affected person with the zika virus, to drink a lot of water to stay hydrated, to lie down, and to treat the fever and agony with liquid solutions; taking drugs like acetaminophen or paracetamol helps to relieve fever and pain. [ according to whom? ] Referring to the US CDC it is not recommended to take anti-inflammatory and non-steroid drugs like aspirin for example. If the patient affected is already taking treatment for another medical condition it is advisable to inform your attending physician before taking any other drug or additional treatment; The World Health Organization has suggested that priority should be to develop inactivated vaccines and other nonlive vaccines, which are safe to use in pregnant women. As of March 2016 [ update ] , 18 companies and institutions were developing vaccines against Zika, but they state a vaccine is unlikely to be widely available for about 10 years. In June 2016, the FDA granted the first approval for a human clinical trial for a Zika vaccine. In March 2017, a DNA vaccine was approved for phase-2 clinical trials. This vaccine consists of a small, circular piece of DNA, known as a plasmid, that expresses the genes for the Zika virus envelope proteins. As the vaccine does not contain the full sequence of the virus, it cannot cause infection. As of April 2017, both subunit and inactivated vaccines have entered clinical trials. It is advised, for an affected person with the zika virus, to drink a lot of water to stay hydrated, to lie down, and to treat the fever and agony with liquid solutions; taking drugs like acetaminophen or paracetamol helps to relieve fever and pain. [ according to whom? ] Referring to the US CDC it is not recommended to take anti-inflammatory and non-steroid drugs like aspirin for example. If the patient affected is already taking treatment for another medical condition it is advisable to inform your attending physician before taking any other drug or additional treatment; The World Health Organization has suggested that priority should be to develop inactivated vaccines and other nonlive vaccines, which are safe to use in pregnant women. As of March 2016 [ update ] , 18 companies and institutions were developing vaccines against Zika, but they state a vaccine is unlikely to be widely available for about 10 years. In June 2016, the FDA granted the first approval for a human clinical trial for a Zika vaccine. In March 2017, a DNA vaccine was approved for phase-2 clinical trials. This vaccine consists of a small, circular piece of DNA, known as a plasmid, that expresses the genes for the Zika virus envelope proteins. As the vaccine does not contain the full sequence of the virus, it cannot cause infection. As of April 2017, both subunit and inactivated vaccines have entered clinical trials. The virus was first isolated in April 1947 from a rhesus macaque monkey placed in a cage in the Ziika Forest of Uganda , near Lake Victoria , by the scientists of the Yellow Fever Research Institute . A second isolation from the mosquito A. africanus followed at the same site in January 1948. When the monkey developed a fever, researchers isolated from its serum a "filterable transmissible agent" which was named Zika in 1948. Zika was first known to infect humans from the results of a serological survey in Uganda, published in 1952. Of 99 human blood samples tested, 6.1% had neutralizing antibodies. As part of a 1954 outbreak investigation of jaundice suspected to be yellow fever, researchers reported isolation of the virus from a patient, but the pathogen was later shown to be the closely related Spondweni virus . Spondweni was also determined to be the cause of a self-inflicted infection in a researcher reported in 1956. Subsequent serological studies in several African and Asian countries indicated the virus had been widespread within human populations in these regions. The first true case of human infection was identified by Simpson in 1964, who was himself infected while isolating the virus from mosquitoes. From then until 2007, there were only 13 further confirmed human cases of Zika infection from Africa and Southeast Asia. A study published in 2017 showed that the Zika virus, despite only a few cases were reported, has been silently circulated in West Africa for the last two decades when blood samples collected between 1992 and 2016 were tested for the ZIKV IgM antibodies. In 2017, Angola reported two cases of Zika fever. Zika was also occurring in Tanzania as of 2016. In April 2007, the first outbreak outside of Africa and Asia occurred on the island of Yap in the Federated States of Micronesia, characterized by rash, conjunctivitis, and arthralgia, which was initially thought to be dengue, chikungunya , or Ross River disease . Serum samples from patients in the acute phase of illness contained RNA of Zika. There were 49 confirmed cases, 59 unconfirmed cases, no hospitalizations, and no deaths. After October 2013 Oceania's first outbreak showed an estimated 11% population infected for French Polynesia that also presented with Guillain–Barre syndrome (GBS). The spread of ZIKV continued to New Caledonia, Easter Island, and the Cook Islands and where 1385 cases were confirmed by January 2014. During the same year, Easter Island acknowledged 51 cases. Australia began seeing cases in 2012. Research showed it was brought by travelers returning from Indonesia and other infected countries. New Zealand also experienced infections rate increases through returning foreign travelers. Oceania countries experiencing Zika today are New Caledonia, Vanuatu, Solomon Islands, Marshall Islands, American Samoa, Samoa, and Tonga. Between 2013 and 2014, further epidemics occurred in French Polynesia , Easter Island , the Cook Islands , and New Caledonia . There was an epidemic in 2015 and 2016 in the Americas . The outbreak began in April 2015 in Brazil , and spread to other countries in South America , Central America , North America , and the Caribbean . In January 2016, the WHO said the virus was likely to spread throughout most of the Americas by the end of the year; and in February 2016, the WHO declared the cluster of microcephaly and Guillain–Barré syndrome cases reported in Brazil – strongly suspected to be associated with the Zika outbreak – a Public Health Emergency of International Concern . It was estimated that 1.5 million people were infected by Zika in Brazil, with over 3,500 cases of microcephaly reported between October 2015 and January 2016. A number of countries issued travel warnings , and the outbreak was expected to significantly impact the tourism industry. Several countries have taken the unusual step of advising their citizens to delay pregnancy until more is known about the virus and its impact on fetal development. With the 2016 Summer Olympics hosted in Rio de Janeiro , health officials worldwide voiced concerns over a potential crisis, both in Brazil and when international athletes and tourists returned home and possibly would spread the virus. Some researchers speculated that only one or two tourists might be infected during the three-week period, or approximately 3.2 infections per 100,000 tourists. In November 2016, the World Health Organization declared that Zika virus was no longer a global emergency while noting that the virus still represents "a highly significant and a long-term problem". As of August 2017 the number of new Zika virus cases in the Americas had fallen dramatically. On May 15, 2017, three cases of Zika virus infection in India were reported in the state of Gujarat . By late 2018, there had been at least 159 cases in Rajasthan and 127 in Madhya Pradesh . In July 2021, the first case of Zika virus infection in the Indian state of Kerala was reported. After the first confirmed case, 19 other people who had previously presented symptoms were tested, and 13 of those had positive results, showing that Zika had been circulating in Kerala since at least May 2021. By August 6th 2021, there had been 65 reported cases in Kerala. On October 22, 2021, an officer in the Indian Air Force in Kanpur tested positive for Zika virus, making it the first reported case in the Indian state of Uttar Pradesh . On 22 March 2016, Reuters reported that Zika was isolated from a 2014 blood sample of an elderly man in Chittagong in Bangladesh as part of a retrospective study . Between August and November 2016, 455 cases of Zika virus infection were confirmed in Singapore . In 2023, 722 Zika virus cases were reported in Thailand. From 2019-2022 the Robert Koch-Institut reported 29 imported Zikavirus cases imported into Germany. Of the altogether 16 imported Zika virus cases in 2023, 10 were diagnosed after a trip to Thailand with 62% of all Zika virus cases a significant relative and absolute increase. The virus was first isolated in April 1947 from a rhesus macaque monkey placed in a cage in the Ziika Forest of Uganda , near Lake Victoria , by the scientists of the Yellow Fever Research Institute . A second isolation from the mosquito A. africanus followed at the same site in January 1948. When the monkey developed a fever, researchers isolated from its serum a "filterable transmissible agent" which was named Zika in 1948. Zika was first known to infect humans from the results of a serological survey in Uganda, published in 1952. Of 99 human blood samples tested, 6.1% had neutralizing antibodies. As part of a 1954 outbreak investigation of jaundice suspected to be yellow fever, researchers reported isolation of the virus from a patient, but the pathogen was later shown to be the closely related Spondweni virus . Spondweni was also determined to be the cause of a self-inflicted infection in a researcher reported in 1956. Subsequent serological studies in several African and Asian countries indicated the virus had been widespread within human populations in these regions. The first true case of human infection was identified by Simpson in 1964, who was himself infected while isolating the virus from mosquitoes. From then until 2007, there were only 13 further confirmed human cases of Zika infection from Africa and Southeast Asia. A study published in 2017 showed that the Zika virus, despite only a few cases were reported, has been silently circulated in West Africa for the last two decades when blood samples collected between 1992 and 2016 were tested for the ZIKV IgM antibodies. In 2017, Angola reported two cases of Zika fever. Zika was also occurring in Tanzania as of 2016. In April 2007, the first outbreak outside of Africa and Asia occurred on the island of Yap in the Federated States of Micronesia, characterized by rash, conjunctivitis, and arthralgia, which was initially thought to be dengue, chikungunya , or Ross River disease . Serum samples from patients in the acute phase of illness contained RNA of Zika. There were 49 confirmed cases, 59 unconfirmed cases, no hospitalizations, and no deaths. After October 2013 Oceania's first outbreak showed an estimated 11% population infected for French Polynesia that also presented with Guillain–Barre syndrome (GBS). The spread of ZIKV continued to New Caledonia, Easter Island, and the Cook Islands and where 1385 cases were confirmed by January 2014. During the same year, Easter Island acknowledged 51 cases. Australia began seeing cases in 2012. Research showed it was brought by travelers returning from Indonesia and other infected countries. New Zealand also experienced infections rate increases through returning foreign travelers. Oceania countries experiencing Zika today are New Caledonia, Vanuatu, Solomon Islands, Marshall Islands, American Samoa, Samoa, and Tonga. Between 2013 and 2014, further epidemics occurred in French Polynesia , Easter Island , the Cook Islands , and New Caledonia . There was an epidemic in 2015 and 2016 in the Americas . The outbreak began in April 2015 in Brazil , and spread to other countries in South America , Central America , North America , and the Caribbean . In January 2016, the WHO said the virus was likely to spread throughout most of the Americas by the end of the year; and in February 2016, the WHO declared the cluster of microcephaly and Guillain–Barré syndrome cases reported in Brazil – strongly suspected to be associated with the Zika outbreak – a Public Health Emergency of International Concern . It was estimated that 1.5 million people were infected by Zika in Brazil, with over 3,500 cases of microcephaly reported between October 2015 and January 2016. A number of countries issued travel warnings , and the outbreak was expected to significantly impact the tourism industry. Several countries have taken the unusual step of advising their citizens to delay pregnancy until more is known about the virus and its impact on fetal development. With the 2016 Summer Olympics hosted in Rio de Janeiro , health officials worldwide voiced concerns over a potential crisis, both in Brazil and when international athletes and tourists returned home and possibly would spread the virus. Some researchers speculated that only one or two tourists might be infected during the three-week period, or approximately 3.2 infections per 100,000 tourists. In November 2016, the World Health Organization declared that Zika virus was no longer a global emergency while noting that the virus still represents "a highly significant and a long-term problem". As of August 2017 the number of new Zika virus cases in the Americas had fallen dramatically. On May 15, 2017, three cases of Zika virus infection in India were reported in the state of Gujarat . By late 2018, there had been at least 159 cases in Rajasthan and 127 in Madhya Pradesh . In July 2021, the first case of Zika virus infection in the Indian state of Kerala was reported. After the first confirmed case, 19 other people who had previously presented symptoms were tested, and 13 of those had positive results, showing that Zika had been circulating in Kerala since at least May 2021. By August 6th 2021, there had been 65 reported cases in Kerala. On October 22, 2021, an officer in the Indian Air Force in Kanpur tested positive for Zika virus, making it the first reported case in the Indian state of Uttar Pradesh . On 22 March 2016, Reuters reported that Zika was isolated from a 2014 blood sample of an elderly man in Chittagong in Bangladesh as part of a retrospective study . Between August and November 2016, 455 cases of Zika virus infection were confirmed in Singapore . In 2023, 722 Zika virus cases were reported in Thailand. From 2019-2022 the Robert Koch-Institut reported 29 imported Zikavirus cases imported into Germany. Of the altogether 16 imported Zika virus cases in 2023, 10 were diagnosed after a trip to Thailand with 62% of all Zika virus cases a significant relative and absolute increase.

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Acute hemorrhagic fever syndrome

https://api.wikimedia.org/core/v1/wikipedia/en/page/Crohn's_disease/html

Crohn's disease

Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract . Symptoms often include abdominal pain , diarrhea , fever , abdominal distension , and weight loss . Complications outside of the gastrointestinal tract may include anemia , skin rashes , arthritis , inflammation of the eye , and fatigue . The skin rashes may be due to infections as well as pyoderma gangrenosum or erythema nodosum . Bowel obstruction may occur as a complication of chronic inflammation, and those with the disease are at greater risk of colon cancer and small bowel cancer . Although the precise causes of Crohn's disease (CD) are unknown, it is believed to be caused by a combination of environmental, immune , and bacterial factors in genetically susceptible individuals. It results in a chronic inflammatory disorder , in which the body's immune system defends the gastrointestinal tract, possibly targeting microbial antigens . While Crohn's is an immune-related disease, it does not seem to be an autoimmune disease (the immune system is not triggered by the body itself). The exact underlying immune problem is not clear; however, it may be an immunodeficiency state. About half of the overall risk is related to genetics, with more than 70 genes involved. Tobacco smokers are three times as likely to develop Crohn's disease as non-smokers. It often begins after gastroenteritis . Other conditions with similar symptoms include irritable bowel syndrome and Behçet's disease . There is no known cure for Crohn's disease. Treatment options are intended to help with symptoms, maintain remission , and prevent relapse . In those newly diagnosed, a corticosteroid may be used for a brief period of time to improve symptoms rapidly, alongside another medication such as either methotrexate or a thiopurine used to prevent recurrence. Cessation of smoking is recommended for people with Crohn's disease. One in five people with the disease is admitted to the hospital each year, and half of those with the disease will require surgery at some time during a ten-year period. While surgery should be used as little as possible, it is necessary to address some abscesses , certain bowel obstructions, and cancers. Checking for bowel cancer via colonoscopy is recommended every few years, starting eight years after the disease has begun. Crohn's disease affects about 3.2 per 1,000 people in Europe and North America; it is less common in Asia and Africa. It has historically been more common in the developed world . Rates have, however, been increasing, particularly in the developing world, since the 1970s. Inflammatory bowel disease resulted in 47,400 deaths in 2015, and those with Crohn's disease have a slightly reduced life expectancy . It tends to start in adolescence and young adulthood, though it can occur at any age. Males and females are equally affected. The disease was named after gastroenterologist Burrill Bernard Crohn , who in 1932, together with Leon Ginzburg (1898–1988) and Gordon D. Oppenheimer (1900–1974) at Mount Sinai Hospital in New York , described a series of patients with inflammation of the terminal ileum of the small intestine , the area most commonly affected by the illness. Why the disease was named after Crohn has controversy around it. While Crohn, in his memoir, describes his original investigation of the disease, Ginzburg provided strong evidence of how he and Oppenheimer were the first to study the disease. Many people with Crohn's disease have symptoms for years before the diagnosis. The usual onset is in the teens and twenties, but can occur at any age. Because of the 'patchy' nature of the gastrointestinal disease and the depth of tissue involvement, initial symptoms can be more subtle than those of ulcerative colitis . People with Crohn's disease experience chronic recurring periods of flare-ups and remission . The symptoms experienced can change over time as inflammation increases and spreads. Symptoms can also be different depending on which organs are involved. It is generally thought that the presentation of Crohn's disease is different for each patient due to the high variability of symptoms, organ involvement, and initial presentation. Perianal discomfort may also be prominent in Crohn's disease. Itchiness or pain around the anus may be suggestive of inflammation of the anus, or perianal complications such as anal fissures , fistulae , or abscesses around the anal area. Perianal skin tags are also common in Crohn's disease, and may appear with or without the presence of colorectal polyps . Fecal incontinence may accompany perianal Crohn's disease. The intestines, especially the colon and terminal ileum, are the areas of the body affected most commonly. Abdominal pain is a common initial symptom of Crohn's disease, especially in the lower right abdomen. Flatulence, bloating, and abdominal distension are additional symptoms and may also add to the intestinal discomfort. Pain is often accompanied by diarrhea , which may or may not be bloody. Inflammation in different areas of the intestinal tract can affect the quality of the feces . Ileitis typically results in large-volume, watery feces, while colitis may result in a smaller volume of feces of greater frequency. Fecal consistency may range from solid to watery. In severe cases, an individual may have more than 20 bowel movements per day, and may need to awaken at night to defecate. Visible bleeding in the feces is less common in Crohn's disease than in ulcerative colitis, but is not unusual. Bloody bowel movements are usually intermittent, and may be bright red, dark maroon, or even black in color. The color of bloody stool depends on the location of the bleed. In severe Crohn's colitis, bleeding may be copious. The stomach is rarely the sole or predominant site of CD. To date there are only a few documented case reports of adults with isolated gastric CD and no reports in the pediatric population. Isolated stomach involvement is very unusual presentation accounting for less than 0.07% of all gastrointestinal CD. Rarely, the esophagus and stomach may be involved in Crohn's disease. These can cause symptoms including difficulty swallowing ( dysphagia ), upper abdominal pain, and vomiting. The mouth may be affected by recurrent sores ( aphthous ulcers ). Recurrent aphthous ulcers are common; however, it is not clear whether this is due to Crohn's disease or simply that they are common in the general population. Other findings may include diffuse or nodular swelling of the mouth, a cobblestone appearance inside the mouth, granulomatous ulcers, or pyostomatitis vegetans. Medications that are commonly prescribed to treat CD, such as anti-inflammatory and sulfa-containing drugs, may cause lichenoid drug reactions in the mouth. Fungal infection such as candidiasis is also common due to the immunosuppression required in the treatment of the disease. Signs of anemia such as pallor and angular cheilitis or glossitis are also common due to nutritional malabsorption. People with Crohn's disease are also susceptible to angular stomatitis , an inflammation of the corners of the mouth, and pyostomatitis vegetans . Like many other chronic, inflammatory diseases, Crohn's disease can cause a variety of systemic symptoms . Among children, growth failure is common. Many children are first diagnosed with Crohn's disease based on inability to maintain growth . As it may manifest at the time of the growth spurt in puberty , as many as 30% of children with Crohn's disease may have retardation of growth. Fever may also be present, though fevers greater than 38.5 °C (101.3 °F) are uncommon unless there is a complication such as an abscess. Among older individuals, Crohn's disease may manifest as weight loss, usually related to decreased food intake, since individuals with intestinal symptoms from Crohn's disease often feel better when they do not eat and might lose their appetite . People with extensive small intestine disease may also have malabsorption of carbohydrates or lipids , which can further exacerbate weight loss. Crohn's disease can affect many organ systems beyond the gastrointestinal tract . Inflammation of the interior portion of the eye, known as uveitis , can cause blurred vision and eye pain, especially when exposed to light ( photophobia ). Uveitis can lead to loss of vision if untreated. Inflammation may also involve the white part of the eye ( sclera ) or the overlying connective tissue ( episclera ), which causes conditions called scleritis and episcleritis , respectively. Other very rare ophthalmological manifestations include: conjunctivitis , glaucoma , and retinal vascular disease. Crohn's disease that affects the ileum may result in an increased risk of gallstones . This is due to a decrease in bile acid resorption in the ileum , and the bile gets excreted in the stool. As a result, the cholesterol /bile ratio increases in the gallbladder , resulting in an increased risk for gallstones. Although the association is greater in the context of ulcerative colitis , Crohn's disease may also be associated with primary sclerosing cholangitis , a type of inflammation of the bile ducts . Liver involvement of Crohn's disease can include cirrhosis and steatosis . Nonalcoholic fatty liver disease (nonalcoholic steatohepatitis, NAFLD) are relatively common and can slowly progress to end-stage liver disease. NAFLD sensitizes the liver to injury and increases the risk of developing acute or chronic liver failure following another liver injury. Other rare hepatobiliary manifestations of Crohn's disease include: cholangiocarcinoma , granulomatous hepatitis, cholelithiasis, autoimmune hepatitis , hepatic abscess , and pericholangitis. Nephrolithiasis , obstructive uropathy , and fistulization of the urinary tract directly result from the underlying disease process. Nephrolithiasis is due to calcium oxalate or uric acid stones. Calcium oxalate is due to hyperoxaluria typically associated with either distal ileal CD or ileal resection. Oxalate absorption increases in the presence of unabsorbed fatty acids in the colon. The fatty acids compete with oxalate to bind calcium, displacing the oxalate, which can then be absorbed as unbound sodium oxalate across colonocytes and excreted into the urine. Because sodium oxalate only is absorbed in the colon, calcium-oxalate stones form only in patients with an intact colon. Patients with an ileostomy are prone to formation of uric-acid stones because of frequent dehydration. The sudden onset of severe abdominal, back, or flank pain in patients with IBD, particularly if different from the usual discomfort, should lead to inclusion of a renal stone in the differential diagnosis. Urological manifestations in patients with IBD may include ureteral calculi, enterovesical fistula , perivesical infection, perinephric abscess, and obstructive uropathy with hydronephrosis . Ureteral compression is associated with retroperitoneal extension of the phlegmonous inflammatory process involving the terminal ileum and cecum , and may result in hydronephrosis severe enough to cause hypertension . Immune complex glomerulonephritis presenting with proteinuria and hematuria has been described in children and adults with CD or UC. Diagnosis is by renal biopsy, and treatment parallels the underlying IBD. Amyloidosis (see endocrinological involvement) secondary to Crohn's disease has been described and is known to affect the kidneys. Pancreatitis may be associated with both UC and CD. The most common cause is iatrogenic and involves sensitivity to medications used to treat IBD (3% of patients), including sulfasalazine , mesalamine , 6-mercaptopurine , and azathioprine . Pancreatitis may present as symptomatic (in 2%) or more commonly asymptomatic (8–21%) disease in adults with IBD. Children and adults with IBD have been rarely (<1%) reported developing pleuropericarditis either at initial presentation or during active or quiescent disease. The pathogenesis of pleuropericarditis is unknown, although certain medications (e.g., sulfasalazine and mesalamine derivatives) have been implicated in some cases. The clinical presentation may include chest pain, dyspnea , or in severe cases pericardial tamponade requiring rapid drainage. Nonsteroidal anti-inflammatory drugs have been used as therapy, although this should be weighed against the hypothetical risk of exacerbating the underlying IBD. In rare cases, cardiomyopathy , endocarditis , and myocarditis have been described. Crohn's disease also increases the risk of blood clots ; painful swelling of the lower legs can be a sign of deep venous thrombosis , while difficulty breathing may be a result of pulmonary embolism . Laryngeal involvement in inflammatory bowel disease is extremely rare. Only 12 cases of laryngeal involvement in Crohn's disease have been reported as of 2019 [ update ] . Moreover, only one case of laryngeal manifestations in ulcerative colitis has been reported as of that date. Nine patients complained of difficulty in breathing due to edema and ulceration from the larynx to the hypopharynx . Hoarseness, sore throat, and odynophagia are other symptoms of laryngeal involvement of Crohn's disease. Considering extraintestinal manifestations of CD, those involving the lung are relatively rare. However, there is a wide array of lung manifestations, ranging from subclinical alterations, airway diseases and lung parenchymal diseases to pleural diseases and drug-related diseases. The most frequent manifestation is bronchial inflammation and suppuration with or without bronchiectasis. There are a number of mechanisms by which the lungs may become involved in CD. These include the same embryological origin of the lung and gastrointestinal tract by ancestral intestine, similar immune systems in the pulmonary and intestinal mucosa, the presence of circulating immune complexes and auto-antibodies, and the adverse pulmonary effects of some drugs. A complete list of known pulmonary manifestations include: fibrosing alveolitis, pulmonary vasculitis , apical fibrosis , bronchiectasis , bronchitis , bronchiolitis , tracheal stenosis , granulomatous lung disease, and abnormal pulmonary function. Crohn's disease is associated with a type of rheumatologic disease known as seronegative spondyloarthropathy . This group of diseases is characterized by inflammation of one or more joints ( arthritis ) or muscle insertions ( enthesitis ). The arthritis in Crohn's disease can be divided into two types. The first type affects larger weight-bearing joints such as the knee (most common), hips, shoulders, wrists, or elbows. The second type symmetrically involves five or more of the small joints of the hands and feet. The arthritis may also involve the spine , leading to ankylosing spondylitis if the entire spine is involved, or simply sacroiliitis if only the sacroiliac joint is involved. Crohn's disease increases the risk of osteoporosis or thinning of the bones. Individuals with osteoporosis are at increased risk of bone fractures . Crohn's disease may also involve the skin, blood, and endocrine system . Erythema nodosum is the most common type of skin problem, occurring in around 8% of people with Crohn's disease, producing raised, tender red nodules usually appearing on the shins . Erythema nodosum is due to inflammation of the underlying subcutaneous tissue , and is characterized by septal panniculitis . Pyoderma gangrenosum is a less common skin problem, occurring in under 2%, and is typically a painful ulcerating nodule. Clubbing , a deformity of the ends of the fingers, may also be a result of Crohn's disease. [ citation needed ] Other very rare dermatological manifestations include: pyostomatitis vegetans , erythema multiforme , epidermolysis bullosa acquista (described in a case report), and metastatic CD (the spread of Crohn's inflammation to the skin ). It is unknown if Sweet's syndrome is connected to Crohn's disease. Crohn's disease can also cause neurological complications (reportedly in up to 15%). The most common of these are seizures , stroke , myopathy , peripheral neuropathy , headache , and depression . Central and peripheral neurological disorders are described in patients with IBD and include peripheral neuropathies , myopathies , focal central nervous system defects, convulsions , confusional episodes, meningitis , syncope , optic neuritis , and sensorineural loss. Autoimmune mechanisms are proposed for involvement with IBD. Nutritional deficiencies associated with neurological manifestations, such as vitamin B 12 deficiency , should be investigated. Spinal abscess has been reported in both a child and an adult with initial complaints of severe back pain due to extension of a psoas abscess from the epidural space to the subarachnoid space. Crohn's disease is linked to many psychological disorders, including depression and anxiety , denial of one's disease, the need for dependence or dependent behaviors, feeling overwhelmed, and having a poor self-image. Many studies have found that patients with IBD report a higher frequency of depressive and anxiety disorders than the general population; most studies confirm that women with IBD are more likely than men to develop affective disorders and show that up to 65% of them may have depression and anxiety disorder . Autoimmune hemolytic anemia , a condition in which the immune system attacks the red blood cells , is also more common in Crohn's disease and may cause fatigue , a pale appearance, and other symptoms common in anemia . Secondary amyloidosis (AA) is another rare but serious complication of inflammatory bowel disease (IBD), generally seen in Crohn's disease. At least 1% of patients with Crohn's disease develop amyloidosis. In the literature, the time lapse between the onset of Crohn's disease and the diagnosis of amyloidosis has been reported to range from 1 to 21 years. Leukocytosis and thrombocytopenia are usually due to immunosuppressant treatments or sulfasalazine . Plasma erythropoietin levels often are lower in patients with IBD than expected, in conjunction with severe anemia . Thrombocytosis and thromboembolic events resulting from a hypercoagulable state in patients with IBD can lead to pulmonary embolism or thrombosis elsewhere in the body. Thrombosis has been reported in 1.8% of patients with UC and 3.1% of patients with CD. Thromboembolism and thrombosis are less frequently reported among pediatric patients, with three patients with UC and one with CD described in case reports. In rare cases, hypercoagulation disorders and portal vein thrombosis have been described. People with Crohn's disease may develop anemia due to vitamin B 12 , folate , iron deficiency , or due to anemia of chronic disease . The most common is iron deficiency anemia from chronic blood loss , reduced dietary intake, and persistent inflammation leading to increased hepcidin levels, restricting iron absorption in the duodenum. As Crohn's disease most commonly affects the terminal ileum where the vitamin B 12 / intrinsic factor complex is absorbed, B 12 deficiency may be seen. This is particularly common after surgery to remove the ileum. Involvement of the duodenum and jejunum can impair the absorption of many other nutrients including folate . People with Crohn's often also have issues with small bowel bacterial overgrowth syndrome , which can produce micronutrient deficiencies. Crohn's disease can lead to several mechanical complications within the intestines , including obstruction , fistulae , and abscesses . Obstruction typically occurs from strictures or adhesions that narrow the lumen , blocking the passage of the intestinal contents. A fistula can develop between two loops of bowel, between the bowel and bladder , between the bowel and vagina , and between the bowel and skin. Abscesses are walled-off concentrations of infection , which can occur in the abdomen or in the perianal area. Crohn's is responsible for 10% of vesicoenteric fistulae, and is the most common cause of ileovesical fistulae . Symptoms caused by intestinal stenosis , or the tightening and narrowing of the bowel, are also common in Crohn's disease. Abdominal pain is often most severe in areas of the bowel with stenosis . Persistent vomiting and nausea may indicate stenosis from small bowel obstruction or disease involving the stomach , pylorus , or duodenum . Intestinal granulomas are a walled-off portions of the intestine by macrophages in order to isolate infections. Granuloma formation is more often seen in younger patients, and mainly in the severe, active penetrating disease. Granuloma is considered the hallmark of microscopic diagnosis in Crohn's disease (CD), but granulomas can be detected in only 21–60% of CD patients. Crohn's disease also increases the risk of cancer in the area of inflammation. For example, individuals with Crohn's disease involving the small bowel are at higher risk for small intestinal cancer . Similarly, people with Crohn's colitis have a relative risk of 5.6 for developing colon cancer . Screening for colon cancer with colonoscopy is recommended for anyone who has had Crohn's colitis for at least eight years. Some studies suggest there is a role for chemoprotection in the prevention of colorectal cancer in Crohn's involving the colon; two agents have been suggested, folate and mesalamine preparations. Also, immunomodulators and biologic agents used to treat this disease may promote developing extra-intestinal cancers. Some cancers, such as acute myelocytic leukaemia have been described in cases of Crohn's disease. Hepatosplenic T-cell lymphoma (HSTCL) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. TNF-α Inhibitor treatments ( infliximab , adalimumab , certolizumab , natalizumab , and etanercept ) are thought to be the cause of this rare disease. Major complications of Crohn's disease include bowel obstruction , abscesses, free perforation , and hemorrhage , which in rare cases may be fatal. Individuals with Crohn's disease are at risk of malnutrition for many reasons, including decreased food intake and malabsorption . The risk increases following resection of the small bowel . Such individuals may require oral supplements to increase their caloric intake , or in severe cases, total parenteral nutrition (TPN). Most people with moderate or severe Crohn's disease are referred to a dietitian for assistance in nutrition. Small intestinal bacterial overgrowth (SIBO) is characterized by excessive proliferation of colonic bacterial species in the small bowel. Potential causes of SIBO include fistulae, strictures, or motility disturbances. Hence, patients with Crohn's disease are especially predisposed to develop SIBO. As result, CD patients may experience malabsorption and report symptoms such as weight loss, watery diarrhea, meteorism , flatulence, and abdominal pain, mimicking acute flare in these patients. Crohn's disease can be problematic during pregnancy , and some medications can cause adverse outcomes for the fetus or mother. Consultation with an obstetrician and gastroenterologist about Crohn's disease and all medications facilitates preventive measures. In some cases, remission occurs during pregnancy. Certain medications can also lower sperm count or otherwise adversely affect a man's fertility . Common complications of an ostomy (a common surgery in Crohn's disease) are: mucosal edema, peristomal dermatitis, retraction, ostomy prolapse, mucosal/skin detachment, hematoma, necrosis, parastomal hernia, and stenosis. Many people with Crohn's disease have symptoms for years before the diagnosis. The usual onset is in the teens and twenties, but can occur at any age. Because of the 'patchy' nature of the gastrointestinal disease and the depth of tissue involvement, initial symptoms can be more subtle than those of ulcerative colitis . People with Crohn's disease experience chronic recurring periods of flare-ups and remission . The symptoms experienced can change over time as inflammation increases and spreads. Symptoms can also be different depending on which organs are involved. It is generally thought that the presentation of Crohn's disease is different for each patient due to the high variability of symptoms, organ involvement, and initial presentation.Perianal discomfort may also be prominent in Crohn's disease. Itchiness or pain around the anus may be suggestive of inflammation of the anus, or perianal complications such as anal fissures , fistulae , or abscesses around the anal area. Perianal skin tags are also common in Crohn's disease, and may appear with or without the presence of colorectal polyps . Fecal incontinence may accompany perianal Crohn's disease.The intestines, especially the colon and terminal ileum, are the areas of the body affected most commonly. Abdominal pain is a common initial symptom of Crohn's disease, especially in the lower right abdomen. Flatulence, bloating, and abdominal distension are additional symptoms and may also add to the intestinal discomfort. Pain is often accompanied by diarrhea , which may or may not be bloody. Inflammation in different areas of the intestinal tract can affect the quality of the feces . Ileitis typically results in large-volume, watery feces, while colitis may result in a smaller volume of feces of greater frequency. Fecal consistency may range from solid to watery. In severe cases, an individual may have more than 20 bowel movements per day, and may need to awaken at night to defecate. Visible bleeding in the feces is less common in Crohn's disease than in ulcerative colitis, but is not unusual. Bloody bowel movements are usually intermittent, and may be bright red, dark maroon, or even black in color. The color of bloody stool depends on the location of the bleed. In severe Crohn's colitis, bleeding may be copious. The stomach is rarely the sole or predominant site of CD. To date there are only a few documented case reports of adults with isolated gastric CD and no reports in the pediatric population. Isolated stomach involvement is very unusual presentation accounting for less than 0.07% of all gastrointestinal CD. Rarely, the esophagus and stomach may be involved in Crohn's disease. These can cause symptoms including difficulty swallowing ( dysphagia ), upper abdominal pain, and vomiting. The mouth may be affected by recurrent sores ( aphthous ulcers ). Recurrent aphthous ulcers are common; however, it is not clear whether this is due to Crohn's disease or simply that they are common in the general population. Other findings may include diffuse or nodular swelling of the mouth, a cobblestone appearance inside the mouth, granulomatous ulcers, or pyostomatitis vegetans. Medications that are commonly prescribed to treat CD, such as anti-inflammatory and sulfa-containing drugs, may cause lichenoid drug reactions in the mouth. Fungal infection such as candidiasis is also common due to the immunosuppression required in the treatment of the disease. Signs of anemia such as pallor and angular cheilitis or glossitis are also common due to nutritional malabsorption. People with Crohn's disease are also susceptible to angular stomatitis , an inflammation of the corners of the mouth, and pyostomatitis vegetans . Like many other chronic, inflammatory diseases, Crohn's disease can cause a variety of systemic symptoms . Among children, growth failure is common. Many children are first diagnosed with Crohn's disease based on inability to maintain growth . As it may manifest at the time of the growth spurt in puberty , as many as 30% of children with Crohn's disease may have retardation of growth. Fever may also be present, though fevers greater than 38.5 °C (101.3 °F) are uncommon unless there is a complication such as an abscess. Among older individuals, Crohn's disease may manifest as weight loss, usually related to decreased food intake, since individuals with intestinal symptoms from Crohn's disease often feel better when they do not eat and might lose their appetite . People with extensive small intestine disease may also have malabsorption of carbohydrates or lipids , which can further exacerbate weight loss. Crohn's disease can affect many organ systems beyond the gastrointestinal tract . Inflammation of the interior portion of the eye, known as uveitis , can cause blurred vision and eye pain, especially when exposed to light ( photophobia ). Uveitis can lead to loss of vision if untreated. Inflammation may also involve the white part of the eye ( sclera ) or the overlying connective tissue ( episclera ), which causes conditions called scleritis and episcleritis , respectively. Other very rare ophthalmological manifestations include: conjunctivitis , glaucoma , and retinal vascular disease. Crohn's disease that affects the ileum may result in an increased risk of gallstones . This is due to a decrease in bile acid resorption in the ileum , and the bile gets excreted in the stool. As a result, the cholesterol /bile ratio increases in the gallbladder , resulting in an increased risk for gallstones. Although the association is greater in the context of ulcerative colitis , Crohn's disease may also be associated with primary sclerosing cholangitis , a type of inflammation of the bile ducts . Liver involvement of Crohn's disease can include cirrhosis and steatosis . Nonalcoholic fatty liver disease (nonalcoholic steatohepatitis, NAFLD) are relatively common and can slowly progress to end-stage liver disease. NAFLD sensitizes the liver to injury and increases the risk of developing acute or chronic liver failure following another liver injury. Other rare hepatobiliary manifestations of Crohn's disease include: cholangiocarcinoma , granulomatous hepatitis, cholelithiasis, autoimmune hepatitis , hepatic abscess , and pericholangitis. Nephrolithiasis , obstructive uropathy , and fistulization of the urinary tract directly result from the underlying disease process. Nephrolithiasis is due to calcium oxalate or uric acid stones. Calcium oxalate is due to hyperoxaluria typically associated with either distal ileal CD or ileal resection. Oxalate absorption increases in the presence of unabsorbed fatty acids in the colon. The fatty acids compete with oxalate to bind calcium, displacing the oxalate, which can then be absorbed as unbound sodium oxalate across colonocytes and excreted into the urine. Because sodium oxalate only is absorbed in the colon, calcium-oxalate stones form only in patients with an intact colon. Patients with an ileostomy are prone to formation of uric-acid stones because of frequent dehydration. The sudden onset of severe abdominal, back, or flank pain in patients with IBD, particularly if different from the usual discomfort, should lead to inclusion of a renal stone in the differential diagnosis. Urological manifestations in patients with IBD may include ureteral calculi, enterovesical fistula , perivesical infection, perinephric abscess, and obstructive uropathy with hydronephrosis . Ureteral compression is associated with retroperitoneal extension of the phlegmonous inflammatory process involving the terminal ileum and cecum , and may result in hydronephrosis severe enough to cause hypertension . Immune complex glomerulonephritis presenting with proteinuria and hematuria has been described in children and adults with CD or UC. Diagnosis is by renal biopsy, and treatment parallels the underlying IBD. Amyloidosis (see endocrinological involvement) secondary to Crohn's disease has been described and is known to affect the kidneys. Pancreatitis may be associated with both UC and CD. The most common cause is iatrogenic and involves sensitivity to medications used to treat IBD (3% of patients), including sulfasalazine , mesalamine , 6-mercaptopurine , and azathioprine . Pancreatitis may present as symptomatic (in 2%) or more commonly asymptomatic (8–21%) disease in adults with IBD. Children and adults with IBD have been rarely (<1%) reported developing pleuropericarditis either at initial presentation or during active or quiescent disease. The pathogenesis of pleuropericarditis is unknown, although certain medications (e.g., sulfasalazine and mesalamine derivatives) have been implicated in some cases. The clinical presentation may include chest pain, dyspnea , or in severe cases pericardial tamponade requiring rapid drainage. Nonsteroidal anti-inflammatory drugs have been used as therapy, although this should be weighed against the hypothetical risk of exacerbating the underlying IBD. In rare cases, cardiomyopathy , endocarditis , and myocarditis have been described. Crohn's disease also increases the risk of blood clots ; painful swelling of the lower legs can be a sign of deep venous thrombosis , while difficulty breathing may be a result of pulmonary embolism . Laryngeal involvement in inflammatory bowel disease is extremely rare. Only 12 cases of laryngeal involvement in Crohn's disease have been reported as of 2019 [ update ] . Moreover, only one case of laryngeal manifestations in ulcerative colitis has been reported as of that date. Nine patients complained of difficulty in breathing due to edema and ulceration from the larynx to the hypopharynx . Hoarseness, sore throat, and odynophagia are other symptoms of laryngeal involvement of Crohn's disease. Considering extraintestinal manifestations of CD, those involving the lung are relatively rare. However, there is a wide array of lung manifestations, ranging from subclinical alterations, airway diseases and lung parenchymal diseases to pleural diseases and drug-related diseases. The most frequent manifestation is bronchial inflammation and suppuration with or without bronchiectasis. There are a number of mechanisms by which the lungs may become involved in CD. These include the same embryological origin of the lung and gastrointestinal tract by ancestral intestine, similar immune systems in the pulmonary and intestinal mucosa, the presence of circulating immune complexes and auto-antibodies, and the adverse pulmonary effects of some drugs. A complete list of known pulmonary manifestations include: fibrosing alveolitis, pulmonary vasculitis , apical fibrosis , bronchiectasis , bronchitis , bronchiolitis , tracheal stenosis , granulomatous lung disease, and abnormal pulmonary function. Crohn's disease is associated with a type of rheumatologic disease known as seronegative spondyloarthropathy . This group of diseases is characterized by inflammation of one or more joints ( arthritis ) or muscle insertions ( enthesitis ). The arthritis in Crohn's disease can be divided into two types. The first type affects larger weight-bearing joints such as the knee (most common), hips, shoulders, wrists, or elbows. The second type symmetrically involves five or more of the small joints of the hands and feet. The arthritis may also involve the spine , leading to ankylosing spondylitis if the entire spine is involved, or simply sacroiliitis if only the sacroiliac joint is involved. Crohn's disease increases the risk of osteoporosis or thinning of the bones. Individuals with osteoporosis are at increased risk of bone fractures . Crohn's disease may also involve the skin, blood, and endocrine system . Erythema nodosum is the most common type of skin problem, occurring in around 8% of people with Crohn's disease, producing raised, tender red nodules usually appearing on the shins . Erythema nodosum is due to inflammation of the underlying subcutaneous tissue , and is characterized by septal panniculitis . Pyoderma gangrenosum is a less common skin problem, occurring in under 2%, and is typically a painful ulcerating nodule. Clubbing , a deformity of the ends of the fingers, may also be a result of Crohn's disease. [ citation needed ] Other very rare dermatological manifestations include: pyostomatitis vegetans , erythema multiforme , epidermolysis bullosa acquista (described in a case report), and metastatic CD (the spread of Crohn's inflammation to the skin ). It is unknown if Sweet's syndrome is connected to Crohn's disease. Crohn's disease can also cause neurological complications (reportedly in up to 15%). The most common of these are seizures , stroke , myopathy , peripheral neuropathy , headache , and depression . Central and peripheral neurological disorders are described in patients with IBD and include peripheral neuropathies , myopathies , focal central nervous system defects, convulsions , confusional episodes, meningitis , syncope , optic neuritis , and sensorineural loss. Autoimmune mechanisms are proposed for involvement with IBD. Nutritional deficiencies associated with neurological manifestations, such as vitamin B 12 deficiency , should be investigated. Spinal abscess has been reported in both a child and an adult with initial complaints of severe back pain due to extension of a psoas abscess from the epidural space to the subarachnoid space. Crohn's disease is linked to many psychological disorders, including depression and anxiety , denial of one's disease, the need for dependence or dependent behaviors, feeling overwhelmed, and having a poor self-image. Many studies have found that patients with IBD report a higher frequency of depressive and anxiety disorders than the general population; most studies confirm that women with IBD are more likely than men to develop affective disorders and show that up to 65% of them may have depression and anxiety disorder . Autoimmune hemolytic anemia , a condition in which the immune system attacks the red blood cells , is also more common in Crohn's disease and may cause fatigue , a pale appearance, and other symptoms common in anemia . Secondary amyloidosis (AA) is another rare but serious complication of inflammatory bowel disease (IBD), generally seen in Crohn's disease. At least 1% of patients with Crohn's disease develop amyloidosis. In the literature, the time lapse between the onset of Crohn's disease and the diagnosis of amyloidosis has been reported to range from 1 to 21 years. Leukocytosis and thrombocytopenia are usually due to immunosuppressant treatments or sulfasalazine . Plasma erythropoietin levels often are lower in patients with IBD than expected, in conjunction with severe anemia . Thrombocytosis and thromboembolic events resulting from a hypercoagulable state in patients with IBD can lead to pulmonary embolism or thrombosis elsewhere in the body. Thrombosis has been reported in 1.8% of patients with UC and 3.1% of patients with CD. Thromboembolism and thrombosis are less frequently reported among pediatric patients, with three patients with UC and one with CD described in case reports. In rare cases, hypercoagulation disorders and portal vein thrombosis have been described. People with Crohn's disease may develop anemia due to vitamin B 12 , folate , iron deficiency , or due to anemia of chronic disease . The most common is iron deficiency anemia from chronic blood loss , reduced dietary intake, and persistent inflammation leading to increased hepcidin levels, restricting iron absorption in the duodenum. As Crohn's disease most commonly affects the terminal ileum where the vitamin B 12 / intrinsic factor complex is absorbed, B 12 deficiency may be seen. This is particularly common after surgery to remove the ileum. Involvement of the duodenum and jejunum can impair the absorption of many other nutrients including folate . People with Crohn's often also have issues with small bowel bacterial overgrowth syndrome , which can produce micronutrient deficiencies. Inflammation of the interior portion of the eye, known as uveitis , can cause blurred vision and eye pain, especially when exposed to light ( photophobia ). Uveitis can lead to loss of vision if untreated. Inflammation may also involve the white part of the eye ( sclera ) or the overlying connective tissue ( episclera ), which causes conditions called scleritis and episcleritis , respectively. Other very rare ophthalmological manifestations include: conjunctivitis , glaucoma , and retinal vascular disease. Crohn's disease that affects the ileum may result in an increased risk of gallstones . This is due to a decrease in bile acid resorption in the ileum , and the bile gets excreted in the stool. As a result, the cholesterol /bile ratio increases in the gallbladder , resulting in an increased risk for gallstones. Although the association is greater in the context of ulcerative colitis , Crohn's disease may also be associated with primary sclerosing cholangitis , a type of inflammation of the bile ducts . Liver involvement of Crohn's disease can include cirrhosis and steatosis . Nonalcoholic fatty liver disease (nonalcoholic steatohepatitis, NAFLD) are relatively common and can slowly progress to end-stage liver disease. NAFLD sensitizes the liver to injury and increases the risk of developing acute or chronic liver failure following another liver injury. Other rare hepatobiliary manifestations of Crohn's disease include: cholangiocarcinoma , granulomatous hepatitis, cholelithiasis, autoimmune hepatitis , hepatic abscess , and pericholangitis. Nephrolithiasis , obstructive uropathy , and fistulization of the urinary tract directly result from the underlying disease process. Nephrolithiasis is due to calcium oxalate or uric acid stones. Calcium oxalate is due to hyperoxaluria typically associated with either distal ileal CD or ileal resection. Oxalate absorption increases in the presence of unabsorbed fatty acids in the colon. The fatty acids compete with oxalate to bind calcium, displacing the oxalate, which can then be absorbed as unbound sodium oxalate across colonocytes and excreted into the urine. Because sodium oxalate only is absorbed in the colon, calcium-oxalate stones form only in patients with an intact colon. Patients with an ileostomy are prone to formation of uric-acid stones because of frequent dehydration. The sudden onset of severe abdominal, back, or flank pain in patients with IBD, particularly if different from the usual discomfort, should lead to inclusion of a renal stone in the differential diagnosis. Urological manifestations in patients with IBD may include ureteral calculi, enterovesical fistula , perivesical infection, perinephric abscess, and obstructive uropathy with hydronephrosis . Ureteral compression is associated with retroperitoneal extension of the phlegmonous inflammatory process involving the terminal ileum and cecum , and may result in hydronephrosis severe enough to cause hypertension . Immune complex glomerulonephritis presenting with proteinuria and hematuria has been described in children and adults with CD or UC. Diagnosis is by renal biopsy, and treatment parallels the underlying IBD. Amyloidosis (see endocrinological involvement) secondary to Crohn's disease has been described and is known to affect the kidneys. Pancreatitis may be associated with both UC and CD. The most common cause is iatrogenic and involves sensitivity to medications used to treat IBD (3% of patients), including sulfasalazine , mesalamine , 6-mercaptopurine , and azathioprine . Pancreatitis may present as symptomatic (in 2%) or more commonly asymptomatic (8–21%) disease in adults with IBD. Children and adults with IBD have been rarely (<1%) reported developing pleuropericarditis either at initial presentation or during active or quiescent disease. The pathogenesis of pleuropericarditis is unknown, although certain medications (e.g., sulfasalazine and mesalamine derivatives) have been implicated in some cases. The clinical presentation may include chest pain, dyspnea , or in severe cases pericardial tamponade requiring rapid drainage. Nonsteroidal anti-inflammatory drugs have been used as therapy, although this should be weighed against the hypothetical risk of exacerbating the underlying IBD. In rare cases, cardiomyopathy , endocarditis , and myocarditis have been described. Crohn's disease also increases the risk of blood clots ; painful swelling of the lower legs can be a sign of deep venous thrombosis , while difficulty breathing may be a result of pulmonary embolism .Laryngeal involvement in inflammatory bowel disease is extremely rare. Only 12 cases of laryngeal involvement in Crohn's disease have been reported as of 2019 [ update ] . Moreover, only one case of laryngeal manifestations in ulcerative colitis has been reported as of that date. Nine patients complained of difficulty in breathing due to edema and ulceration from the larynx to the hypopharynx . Hoarseness, sore throat, and odynophagia are other symptoms of laryngeal involvement of Crohn's disease. Considering extraintestinal manifestations of CD, those involving the lung are relatively rare. However, there is a wide array of lung manifestations, ranging from subclinical alterations, airway diseases and lung parenchymal diseases to pleural diseases and drug-related diseases. The most frequent manifestation is bronchial inflammation and suppuration with or without bronchiectasis. There are a number of mechanisms by which the lungs may become involved in CD. These include the same embryological origin of the lung and gastrointestinal tract by ancestral intestine, similar immune systems in the pulmonary and intestinal mucosa, the presence of circulating immune complexes and auto-antibodies, and the adverse pulmonary effects of some drugs. A complete list of known pulmonary manifestations include: fibrosing alveolitis, pulmonary vasculitis , apical fibrosis , bronchiectasis , bronchitis , bronchiolitis , tracheal stenosis , granulomatous lung disease, and abnormal pulmonary function. Crohn's disease is associated with a type of rheumatologic disease known as seronegative spondyloarthropathy . This group of diseases is characterized by inflammation of one or more joints ( arthritis ) or muscle insertions ( enthesitis ). The arthritis in Crohn's disease can be divided into two types. The first type affects larger weight-bearing joints such as the knee (most common), hips, shoulders, wrists, or elbows. The second type symmetrically involves five or more of the small joints of the hands and feet. The arthritis may also involve the spine , leading to ankylosing spondylitis if the entire spine is involved, or simply sacroiliitis if only the sacroiliac joint is involved. Crohn's disease increases the risk of osteoporosis or thinning of the bones. Individuals with osteoporosis are at increased risk of bone fractures . Crohn's disease may also involve the skin, blood, and endocrine system . Erythema nodosum is the most common type of skin problem, occurring in around 8% of people with Crohn's disease, producing raised, tender red nodules usually appearing on the shins . Erythema nodosum is due to inflammation of the underlying subcutaneous tissue , and is characterized by septal panniculitis . Pyoderma gangrenosum is a less common skin problem, occurring in under 2%, and is typically a painful ulcerating nodule. Clubbing , a deformity of the ends of the fingers, may also be a result of Crohn's disease. [ citation needed ] Other very rare dermatological manifestations include: pyostomatitis vegetans , erythema multiforme , epidermolysis bullosa acquista (described in a case report), and metastatic CD (the spread of Crohn's inflammation to the skin ). It is unknown if Sweet's syndrome is connected to Crohn's disease. Crohn's disease can also cause neurological complications (reportedly in up to 15%). The most common of these are seizures , stroke , myopathy , peripheral neuropathy , headache , and depression . Central and peripheral neurological disorders are described in patients with IBD and include peripheral neuropathies , myopathies , focal central nervous system defects, convulsions , confusional episodes, meningitis , syncope , optic neuritis , and sensorineural loss. Autoimmune mechanisms are proposed for involvement with IBD. Nutritional deficiencies associated with neurological manifestations, such as vitamin B 12 deficiency , should be investigated. Spinal abscess has been reported in both a child and an adult with initial complaints of severe back pain due to extension of a psoas abscess from the epidural space to the subarachnoid space. Crohn's disease is linked to many psychological disorders, including depression and anxiety , denial of one's disease, the need for dependence or dependent behaviors, feeling overwhelmed, and having a poor self-image. Many studies have found that patients with IBD report a higher frequency of depressive and anxiety disorders than the general population; most studies confirm that women with IBD are more likely than men to develop affective disorders and show that up to 65% of them may have depression and anxiety disorder . Autoimmune hemolytic anemia , a condition in which the immune system attacks the red blood cells , is also more common in Crohn's disease and may cause fatigue , a pale appearance, and other symptoms common in anemia . Secondary amyloidosis (AA) is another rare but serious complication of inflammatory bowel disease (IBD), generally seen in Crohn's disease. At least 1% of patients with Crohn's disease develop amyloidosis. In the literature, the time lapse between the onset of Crohn's disease and the diagnosis of amyloidosis has been reported to range from 1 to 21 years. Leukocytosis and thrombocytopenia are usually due to immunosuppressant treatments or sulfasalazine . Plasma erythropoietin levels often are lower in patients with IBD than expected, in conjunction with severe anemia . Thrombocytosis and thromboembolic events resulting from a hypercoagulable state in patients with IBD can lead to pulmonary embolism or thrombosis elsewhere in the body. Thrombosis has been reported in 1.8% of patients with UC and 3.1% of patients with CD. Thromboembolism and thrombosis are less frequently reported among pediatric patients, with three patients with UC and one with CD described in case reports. In rare cases, hypercoagulation disorders and portal vein thrombosis have been described. People with Crohn's disease may develop anemia due to vitamin B 12 , folate , iron deficiency , or due to anemia of chronic disease . The most common is iron deficiency anemia from chronic blood loss , reduced dietary intake, and persistent inflammation leading to increased hepcidin levels, restricting iron absorption in the duodenum. As Crohn's disease most commonly affects the terminal ileum where the vitamin B 12 / intrinsic factor complex is absorbed, B 12 deficiency may be seen. This is particularly common after surgery to remove the ileum. Involvement of the duodenum and jejunum can impair the absorption of many other nutrients including folate . People with Crohn's often also have issues with small bowel bacterial overgrowth syndrome , which can produce micronutrient deficiencies. Crohn's disease can lead to several mechanical complications within the intestines , including obstruction , fistulae , and abscesses . Obstruction typically occurs from strictures or adhesions that narrow the lumen , blocking the passage of the intestinal contents. A fistula can develop between two loops of bowel, between the bowel and bladder , between the bowel and vagina , and between the bowel and skin. Abscesses are walled-off concentrations of infection , which can occur in the abdomen or in the perianal area. Crohn's is responsible for 10% of vesicoenteric fistulae, and is the most common cause of ileovesical fistulae . Symptoms caused by intestinal stenosis , or the tightening and narrowing of the bowel, are also common in Crohn's disease. Abdominal pain is often most severe in areas of the bowel with stenosis . Persistent vomiting and nausea may indicate stenosis from small bowel obstruction or disease involving the stomach , pylorus , or duodenum . Intestinal granulomas are a walled-off portions of the intestine by macrophages in order to isolate infections. Granuloma formation is more often seen in younger patients, and mainly in the severe, active penetrating disease. Granuloma is considered the hallmark of microscopic diagnosis in Crohn's disease (CD), but granulomas can be detected in only 21–60% of CD patients. Crohn's disease also increases the risk of cancer in the area of inflammation. For example, individuals with Crohn's disease involving the small bowel are at higher risk for small intestinal cancer . Similarly, people with Crohn's colitis have a relative risk of 5.6 for developing colon cancer . Screening for colon cancer with colonoscopy is recommended for anyone who has had Crohn's colitis for at least eight years. Some studies suggest there is a role for chemoprotection in the prevention of colorectal cancer in Crohn's involving the colon; two agents have been suggested, folate and mesalamine preparations. Also, immunomodulators and biologic agents used to treat this disease may promote developing extra-intestinal cancers. Some cancers, such as acute myelocytic leukaemia have been described in cases of Crohn's disease. Hepatosplenic T-cell lymphoma (HSTCL) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. TNF-α Inhibitor treatments ( infliximab , adalimumab , certolizumab , natalizumab , and etanercept ) are thought to be the cause of this rare disease. Major complications of Crohn's disease include bowel obstruction , abscesses, free perforation , and hemorrhage , which in rare cases may be fatal. Individuals with Crohn's disease are at risk of malnutrition for many reasons, including decreased food intake and malabsorption . The risk increases following resection of the small bowel . Such individuals may require oral supplements to increase their caloric intake , or in severe cases, total parenteral nutrition (TPN). Most people with moderate or severe Crohn's disease are referred to a dietitian for assistance in nutrition. Small intestinal bacterial overgrowth (SIBO) is characterized by excessive proliferation of colonic bacterial species in the small bowel. Potential causes of SIBO include fistulae, strictures, or motility disturbances. Hence, patients with Crohn's disease are especially predisposed to develop SIBO. As result, CD patients may experience malabsorption and report symptoms such as weight loss, watery diarrhea, meteorism , flatulence, and abdominal pain, mimicking acute flare in these patients. Crohn's disease can be problematic during pregnancy , and some medications can cause adverse outcomes for the fetus or mother. Consultation with an obstetrician and gastroenterologist about Crohn's disease and all medications facilitates preventive measures. In some cases, remission occurs during pregnancy. Certain medications can also lower sperm count or otherwise adversely affect a man's fertility . Common complications of an ostomy (a common surgery in Crohn's disease) are: mucosal edema, peristomal dermatitis, retraction, ostomy prolapse, mucosal/skin detachment, hematoma, necrosis, parastomal hernia, and stenosis. Crohn's disease can lead to several mechanical complications within the intestines , including obstruction , fistulae , and abscesses . Obstruction typically occurs from strictures or adhesions that narrow the lumen , blocking the passage of the intestinal contents. A fistula can develop between two loops of bowel, between the bowel and bladder , between the bowel and vagina , and between the bowel and skin. Abscesses are walled-off concentrations of infection , which can occur in the abdomen or in the perianal area. Crohn's is responsible for 10% of vesicoenteric fistulae, and is the most common cause of ileovesical fistulae . Symptoms caused by intestinal stenosis , or the tightening and narrowing of the bowel, are also common in Crohn's disease. Abdominal pain is often most severe in areas of the bowel with stenosis . Persistent vomiting and nausea may indicate stenosis from small bowel obstruction or disease involving the stomach , pylorus , or duodenum . Intestinal granulomas are a walled-off portions of the intestine by macrophages in order to isolate infections. Granuloma formation is more often seen in younger patients, and mainly in the severe, active penetrating disease. Granuloma is considered the hallmark of microscopic diagnosis in Crohn's disease (CD), but granulomas can be detected in only 21–60% of CD patients. Crohn's disease also increases the risk of cancer in the area of inflammation. For example, individuals with Crohn's disease involving the small bowel are at higher risk for small intestinal cancer . Similarly, people with Crohn's colitis have a relative risk of 5.6 for developing colon cancer . Screening for colon cancer with colonoscopy is recommended for anyone who has had Crohn's colitis for at least eight years. Some studies suggest there is a role for chemoprotection in the prevention of colorectal cancer in Crohn's involving the colon; two agents have been suggested, folate and mesalamine preparations. Also, immunomodulators and biologic agents used to treat this disease may promote developing extra-intestinal cancers. Some cancers, such as acute myelocytic leukaemia have been described in cases of Crohn's disease. Hepatosplenic T-cell lymphoma (HSTCL) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. TNF-α Inhibitor treatments ( infliximab , adalimumab , certolizumab , natalizumab , and etanercept ) are thought to be the cause of this rare disease. Major complications of Crohn's disease include bowel obstruction , abscesses, free perforation , and hemorrhage , which in rare cases may be fatal. Individuals with Crohn's disease are at risk of malnutrition for many reasons, including decreased food intake and malabsorption . The risk increases following resection of the small bowel . Such individuals may require oral supplements to increase their caloric intake , or in severe cases, total parenteral nutrition (TPN). Most people with moderate or severe Crohn's disease are referred to a dietitian for assistance in nutrition. Small intestinal bacterial overgrowth (SIBO) is characterized by excessive proliferation of colonic bacterial species in the small bowel. Potential causes of SIBO include fistulae, strictures, or motility disturbances. Hence, patients with Crohn's disease are especially predisposed to develop SIBO. As result, CD patients may experience malabsorption and report symptoms such as weight loss, watery diarrhea, meteorism , flatulence, and abdominal pain, mimicking acute flare in these patients. Crohn's disease can be problematic during pregnancy , and some medications can cause adverse outcomes for the fetus or mother. Consultation with an obstetrician and gastroenterologist about Crohn's disease and all medications facilitates preventive measures. In some cases, remission occurs during pregnancy. Certain medications can also lower sperm count or otherwise adversely affect a man's fertility . Common complications of an ostomy (a common surgery in Crohn's disease) are: mucosal edema, peristomal dermatitis, retraction, ostomy prolapse, mucosal/skin detachment, hematoma, necrosis, parastomal hernia, and stenosis. The etiology of Crohn's disease is unknown. Many theories have been disputed, with four main theories hypothesized to be the primary mechanism of Crohn's disease. In autoimmune diseases , antibodies and T lymphocytes are the primary mode of inflammation. These cells and bodies are part of the adaptive immune system , or the part of the immune system that learns to fight foreign bodies when first identified. Autoinflammatory diseases are diseases where the innate immune system , or the immune system we are genetically coded with, is designed to attack our own cells. Crohn's disease likely has involvement of both the adaptive and innate immune systems. Crohn's disease can be described as a multifactorial autoinflammatory disease. The etiopathogenesis of Crohn's disease is still unknown. In any event, a loss of the regulatory capacity of the immune apparatus would be implicated in the onset of the disease. In this respect interestingly enough, as for Blau's disease (a monogenic autoinflammatory disease), the NOD2 gene mutations have been linked to Crohn's disease. However, in Crohn's disease, NOD2 mutations act as a risk factor, being more common among Crohn's disease patients than the background population, while in Blau's disease NOD2 mutations are linked directly to this syndrome, as it is an autosomal-dominant disease. All this new knowledge in the pathogenesis of Crohn's disease allows us to put this multifactorial disease in the group of autoinflammatory syndromes. Some examples of how the innate immune system affects bowel inflammation have been described. A meta-analysis of CD genome -wide association studies revealed 71 distinct CD-susceptibility loci . Interestingly, three very important CD-susceptibility genes (the intracellular pathogen-recognition receptor, NOD2; the autophagy-related 16-like 1, ATG16L1 and the immunity-related GTPase M, IRGM ) are involved in innate immune responses against gut microbiota, while one (the X-box binding protein 1) is involved in regulation of the [adaptive] immune pathway via MHC class II , resulting in autoinflammatory inflammation. Studies have also found that increased ILC3 can overexpress major histocompatibility complex (MHC) II . MHC class II can induce CD4+ T cell apoptosis , thus avoiding the T cell response to normal bowel micro bacteria. Further studies of IBD patients compared with non-IBD patients found that the expression of MHC II by ILC3 was significantly reduced in IBD patients, thus causing an immune reaction against intestinal cells or normal bowel bacteria and damaging the intestines. This can also make the intestines more susceptible to environmental factors, such as food or bacteria. The thinking is that because Crohn's disease has strong innate immune system involvement and has NOD2 mutations as a predisposition, Crohn's disease is more likely an autoinflammatory disease than an autoimmune disease. A substantial body of data has emerged in recent years to suggest that the primary defect in Crohn's disease is actually one of relative immunodeficiency . This view has been bolstered recently by novel immunological and clinical studies that have confirmed gross aberrations in this early response, consistent with subsequent genetic studies that highlighted molecules important for innate immune function . The suggestion therefore is that Crohn's pathogenesis actually results from partial immunodeficiency, a theory that coincides with the frequent recognition of a virtually identical, non-infectious inflammatory bowel disease arising in patients with congenital monogenic disorders impairing phagocyte function. Crohn's disease can be described as a multifactorial autoinflammatory disease. The etiopathogenesis of Crohn's disease is still unknown. In any event, a loss of the regulatory capacity of the immune apparatus would be implicated in the onset of the disease. In this respect interestingly enough, as for Blau's disease (a monogenic autoinflammatory disease), the NOD2 gene mutations have been linked to Crohn's disease. However, in Crohn's disease, NOD2 mutations act as a risk factor, being more common among Crohn's disease patients than the background population, while in Blau's disease NOD2 mutations are linked directly to this syndrome, as it is an autosomal-dominant disease. All this new knowledge in the pathogenesis of Crohn's disease allows us to put this multifactorial disease in the group of autoinflammatory syndromes. Some examples of how the innate immune system affects bowel inflammation have been described. A meta-analysis of CD genome -wide association studies revealed 71 distinct CD-susceptibility loci . Interestingly, three very important CD-susceptibility genes (the intracellular pathogen-recognition receptor, NOD2; the autophagy-related 16-like 1, ATG16L1 and the immunity-related GTPase M, IRGM ) are involved in innate immune responses against gut microbiota, while one (the X-box binding protein 1) is involved in regulation of the [adaptive] immune pathway via MHC class II , resulting in autoinflammatory inflammation. Studies have also found that increased ILC3 can overexpress major histocompatibility complex (MHC) II . MHC class II can induce CD4+ T cell apoptosis , thus avoiding the T cell response to normal bowel micro bacteria. Further studies of IBD patients compared with non-IBD patients found that the expression of MHC II by ILC3 was significantly reduced in IBD patients, thus causing an immune reaction against intestinal cells or normal bowel bacteria and damaging the intestines. This can also make the intestines more susceptible to environmental factors, such as food or bacteria. The thinking is that because Crohn's disease has strong innate immune system involvement and has NOD2 mutations as a predisposition, Crohn's disease is more likely an autoinflammatory disease than an autoimmune disease. A substantial body of data has emerged in recent years to suggest that the primary defect in Crohn's disease is actually one of relative immunodeficiency . This view has been bolstered recently by novel immunological and clinical studies that have confirmed gross aberrations in this early response, consistent with subsequent genetic studies that highlighted molecules important for innate immune function . The suggestion therefore is that Crohn's pathogenesis actually results from partial immunodeficiency, a theory that coincides with the frequent recognition of a virtually identical, non-infectious inflammatory bowel disease arising in patients with congenital monogenic disorders impairing phagocyte function. While the exact cause or causes are unknown, Crohn's disease seems to be due to a combination of environmental factors and genetic predisposition . Crohn's is the first genetically complex disease in which the relationship between genetic risk factors and the immune system is understood in considerable detail. Each individual risk mutation makes a small contribution to the overall risk of Crohn's (approximately 1:200). The genetic data, and direct assessment of immunity, indicates a malfunction in the innate immune system . In this view, the chronic inflammation of Crohn's is caused when the adaptive immune system tries to compensate for a deficient innate immune system. Crohn's has a genetic component. Because of this, siblings of known people with Crohn's are 30 times more likely to develop Crohn's than the general population. The first mutation found to be associated with Crohn's was a frameshift in the NOD2 gene (also known as the CARD15 gene), followed by the discovery of point mutations . Over 30 genes have been associated with Crohn's; a biological function is known for most of them. For example, one association is with mutations in the XBP1 gene, which is involved in the unfolded protein response pathway of the endoplasmic reticulum . The gene variants of NOD2/CARD15 seem to be related with small-bowel involvement. Other well documented genes which increase the risk of developing Crohn's disease are ATG16L1 , IL23R , IRGM , and SLC11A1 . There is considerable overlap between susceptibility loci for IBD and mycobacterial infections. Genome -wide association studies have shown that Crohn's disease is genetically linked to coeliac disease . Crohn's has been linked to the gene LRRK2 with one variant potentially increasing the risk of developing the disease by 70%, while another lowers it by 25%. The gene is responsible for making a protein , which collects and eliminates waste product in cells, and is also associated with Parkinson's disease . There was a prevailing view that Crohn's disease is a primary T cell autoimmune disorder; however, a newer theory hypothesizes that Crohn's results from an impaired innate immunity. The later hypothesis describes impaired cytokine secretion by macrophages , which contributes to impaired innate immunity and leads to a sustained microbial-induced inflammatory response in the colon, where the bacterial load is high. Another theory is that the inflammation of Crohn's was caused by an overactive T h 1 and T h 17 cytokine response. In 2007, the ATG16L1 gene was implicated in Crohn's disease, which may induce autophagy and hinder the body's ability to attack invasive bacteria. Another study theorized that the human immune system traditionally evolved with the presence of parasites inside the body and that the lack thereof due to modern hygiene standards has weakened the immune system. Test subjects were reintroduced to harmless parasites, with positive responses. It is hypothesized that maintenance of commensal microorganism growth in the GI tract is dysregulated, either as a result or cause of immune dysregulation . There is an apparent connection between Crohn's disease, Mycobacterium , other pathogenic bacteria, and genetic markers . A number of studies have suggested a causal role for Mycobacterium avium subspecies paratuberculosis (MAP), which causes a similar disease, Johne's disease , in cattle. In many individuals, genetic factors predispose individuals to Mycobacterium avium subsp. paratuberculosis infection. This bacterium may produce certain compounds containing mannose , which may protect both itself and various other bacteria from phagocytosis , thereby possibly causing a variety of secondary infections . NOD2 is a gene involved in Crohn's genetic susceptibility. It is associated with macrophages ' diminished ability to phagocytize MAP. This same gene may reduce innate and adaptive immunity in gastrointestinal tissue and impair the ability to resist infection by the MAP bacterium. Macrophages that ingest the MAP bacterium are associated with high production of TNF-α . Other studies have linked specific strains of enteroadherent E. coli to the disease. Adherent-invasive Escherichia coli (AIEC), more common in people with CD, have the ability to make strong biofilms compared to non-AIEC strains correlating with high adhesion and invasion indices of neutrophils and the ability to block autophagy at the autolysosomal step, which allows for intracellular survival of the bacteria and induction of inflammation. Inflammation drives the proliferation of AIEC and dysbiosis in the ileum, irrespective of genotype. AIEC strains replicate extensively inside macrophages inducing the secretion of very large amounts of TNF-α. Mouse studies have suggested some symptoms of Crohn's disease, ulcerative colitis, and irritable bowel syndrome have the same underlying cause. Biopsy samples taken from the colons of all three patient groups were found to produce elevated levels of a serine protease . Experimental introduction of the serine protease into mice has been found to produce widespread pain associated with irritable bowel syndrome, as well as colitis, which is associated with all three diseases. Regional and temporal variations in those illnesses follow those associated with infection with the protozoan Blastocystis . The "cold-chain" hypothesis is that psychrotrophic bacteria such as Yersinia and Listeria species contribute to the disease. A statistical correlation was found between the advent of the use of refrigeration in the United States and various parts of Europe and the rise of the disease. There is also a tentative association between Candida colonization and Crohn's disease. Still, these relationships between specific pathogens and Crohn's disease remain unclear. The increased incidence of Crohn's in the industrialized world indicates an environmental component. Crohn's is associated with an increased intake of animal protein , milk protein , and an increased ratio of omega-6 to omega-3 polyunsaturated fatty acids . Those who consume vegetable proteins appear to have a lower incidence of Crohn's disease. Consumption of fish protein has no association. Smoking increases the risk of the return of active disease (flares). The introduction of hormonal contraception in the United States in the 1960s is associated with a dramatic increase in incidence, and one hypothesis is that these drugs work on the digestive system in ways similar to smoking. Isotretinoin is associated with Crohn's. Although stress is sometimes claimed to exacerbate Crohn's disease, there is no concrete evidence to support such claim. Still, it is well known that immune function is related to stress. Dietary microparticles , such as those found in toothpaste, have been studied as they produce effects on immunity, but they were not consumed in greater amounts in patients with Crohn's. The use of doxycycline has also been associated with increased risk of developing inflammatory bowel diseases. In one large retrospective study, patients who were prescribed doxycycline for their acne had a 2.25-fold greater risk of developing Crohn's disease. Crohn's has a genetic component. Because of this, siblings of known people with Crohn's are 30 times more likely to develop Crohn's than the general population. The first mutation found to be associated with Crohn's was a frameshift in the NOD2 gene (also known as the CARD15 gene), followed by the discovery of point mutations . Over 30 genes have been associated with Crohn's; a biological function is known for most of them. For example, one association is with mutations in the XBP1 gene, which is involved in the unfolded protein response pathway of the endoplasmic reticulum . The gene variants of NOD2/CARD15 seem to be related with small-bowel involvement. Other well documented genes which increase the risk of developing Crohn's disease are ATG16L1 , IL23R , IRGM , and SLC11A1 . There is considerable overlap between susceptibility loci for IBD and mycobacterial infections. Genome -wide association studies have shown that Crohn's disease is genetically linked to coeliac disease . Crohn's has been linked to the gene LRRK2 with one variant potentially increasing the risk of developing the disease by 70%, while another lowers it by 25%. The gene is responsible for making a protein , which collects and eliminates waste product in cells, and is also associated with Parkinson's disease . There was a prevailing view that Crohn's disease is a primary T cell autoimmune disorder; however, a newer theory hypothesizes that Crohn's results from an impaired innate immunity. The later hypothesis describes impaired cytokine secretion by macrophages , which contributes to impaired innate immunity and leads to a sustained microbial-induced inflammatory response in the colon, where the bacterial load is high. Another theory is that the inflammation of Crohn's was caused by an overactive T h 1 and T h 17 cytokine response. In 2007, the ATG16L1 gene was implicated in Crohn's disease, which may induce autophagy and hinder the body's ability to attack invasive bacteria. Another study theorized that the human immune system traditionally evolved with the presence of parasites inside the body and that the lack thereof due to modern hygiene standards has weakened the immune system. Test subjects were reintroduced to harmless parasites, with positive responses. It is hypothesized that maintenance of commensal microorganism growth in the GI tract is dysregulated, either as a result or cause of immune dysregulation . There is an apparent connection between Crohn's disease, Mycobacterium , other pathogenic bacteria, and genetic markers . A number of studies have suggested a causal role for Mycobacterium avium subspecies paratuberculosis (MAP), which causes a similar disease, Johne's disease , in cattle. In many individuals, genetic factors predispose individuals to Mycobacterium avium subsp. paratuberculosis infection. This bacterium may produce certain compounds containing mannose , which may protect both itself and various other bacteria from phagocytosis , thereby possibly causing a variety of secondary infections . NOD2 is a gene involved in Crohn's genetic susceptibility. It is associated with macrophages ' diminished ability to phagocytize MAP. This same gene may reduce innate and adaptive immunity in gastrointestinal tissue and impair the ability to resist infection by the MAP bacterium. Macrophages that ingest the MAP bacterium are associated with high production of TNF-α . Other studies have linked specific strains of enteroadherent E. coli to the disease. Adherent-invasive Escherichia coli (AIEC), more common in people with CD, have the ability to make strong biofilms compared to non-AIEC strains correlating with high adhesion and invasion indices of neutrophils and the ability to block autophagy at the autolysosomal step, which allows for intracellular survival of the bacteria and induction of inflammation. Inflammation drives the proliferation of AIEC and dysbiosis in the ileum, irrespective of genotype. AIEC strains replicate extensively inside macrophages inducing the secretion of very large amounts of TNF-α. Mouse studies have suggested some symptoms of Crohn's disease, ulcerative colitis, and irritable bowel syndrome have the same underlying cause. Biopsy samples taken from the colons of all three patient groups were found to produce elevated levels of a serine protease . Experimental introduction of the serine protease into mice has been found to produce widespread pain associated with irritable bowel syndrome, as well as colitis, which is associated with all three diseases. Regional and temporal variations in those illnesses follow those associated with infection with the protozoan Blastocystis . The "cold-chain" hypothesis is that psychrotrophic bacteria such as Yersinia and Listeria species contribute to the disease. A statistical correlation was found between the advent of the use of refrigeration in the United States and various parts of Europe and the rise of the disease. There is also a tentative association between Candida colonization and Crohn's disease. Still, these relationships between specific pathogens and Crohn's disease remain unclear. The increased incidence of Crohn's in the industrialized world indicates an environmental component. Crohn's is associated with an increased intake of animal protein , milk protein , and an increased ratio of omega-6 to omega-3 polyunsaturated fatty acids . Those who consume vegetable proteins appear to have a lower incidence of Crohn's disease. Consumption of fish protein has no association. Smoking increases the risk of the return of active disease (flares). The introduction of hormonal contraception in the United States in the 1960s is associated with a dramatic increase in incidence, and one hypothesis is that these drugs work on the digestive system in ways similar to smoking. Isotretinoin is associated with Crohn's. Although stress is sometimes claimed to exacerbate Crohn's disease, there is no concrete evidence to support such claim. Still, it is well known that immune function is related to stress. Dietary microparticles , such as those found in toothpaste, have been studied as they produce effects on immunity, but they were not consumed in greater amounts in patients with Crohn's. The use of doxycycline has also been associated with increased risk of developing inflammatory bowel diseases. In one large retrospective study, patients who were prescribed doxycycline for their acne had a 2.25-fold greater risk of developing Crohn's disease. During a colonoscopy , biopsies of the colon are often taken to confirm the diagnosis. Certain characteristic features of the pathology seen point toward Crohn's disease; it shows a transmural pattern of inflammation , meaning the inflammation may span the entire depth of the intestinal wall . Granulomas , aggregates of macrophage derivatives known as giant cells, are found in 50% of cases and are most specific for Crohn's disease. The granulomas of Crohn's disease do not show "caseation", a cheese-like appearance on microscopic examination characteristic of granulomas associated with infections, such as tuberculosis . Biopsies may also show chronic mucosal damage, as evidenced by blunting of the intestinal villi , atypical branching of the crypts, and a change in the tissue type ( metaplasia ). One example of such metaplasia, Paneth cell metaplasia , involves the development of Paneth cells (typically found in the small intestine and a key regulator of intestinal microbiota) in other parts of the gastrointestinal system. The diagnosis of Crohn's disease can sometimes be challenging, and many tests are often required to assist the physician in making the diagnosis. Even with a full battery of tests, it may not be possible to diagnose Crohn's with complete certainty; a colonoscopy is approximately 70% effective in diagnosing the disease, with further tests being less effective. Disease in the small bowel is particularly difficult to diagnose, as a traditional colonoscopy allows access to only the colon and lower portions of the small intestines; introduction of the capsule endoscopy aids in endoscopic diagnosis. Giant (multinucleate) cells , a common finding in the lesions of Crohn's disease, are less common in the lesions of lichen nitidus . Crohn's disease is one type of inflammatory bowel disease (IBD). It typically manifests in the gastrointestinal tract and can be categorized by the specific tract region affected. Gastroduodenal Crohn's disease causes inflammation in the stomach and the first part of the small intestine called the duodenum. Jejunoileitis causes spotty patches of inflammation in the top half of the small intestine, called the jejunum. The disease can attack any part of the digestive tract, from mouth to anus. However, individuals affected by the disease rarely fall outside these three classifications, with presentations in other areas. Crohn's disease may also be categorized by the behavior of disease as it progresses. These categorizations formalized in the Vienna classification of the disease. There are three categories of disease presentation in Crohn's disease: stricturing, penetrating, and inflammatory. Stricturing disease causes narrowing of the bowel that may lead to bowel obstruction or changes in the caliber of the feces . Penetrating disease creates abnormal passageways (fistulae) between the bowel and other structures, such as the skin. Inflammatory disease (or nonstricturing, nonpenetrating disease) causes inflammation without causing strictures or fistulae. A colonoscopy is the best test for making the diagnosis of Crohn's disease, as it allows direct visualization of the colon and the terminal ileum , identifying the pattern of disease involvement. On occasion, the colonoscope can travel past the terminal ileum, but it varies from person to person. During the procedure, the gastroenterologist can also perform a biopsy, taking small samples of tissue for laboratory analysis, which may help confirm a diagnosis. As 30% of Crohn's disease involves only the ileum, cannulation of the terminal ileum is required in making the diagnosis. Finding a patchy distribution of disease, with involvement of the colon or ileum, but not the rectum , is suggestive of Crohn's disease, as are other endoscopic stigmata. The utility of capsule endoscopy for this, however, is still uncertain. A small bowel follow-through may suggest the diagnosis of Crohn's disease and is useful when the disease involves only the small intestine. Because colonoscopy and gastroscopy allow direct visualization of only the terminal ileum and beginning of the duodenum , they cannot be used to evaluate the remainder of the small intestine. As a result, a barium follow-through X-ray, wherein barium sulfate suspension is ingested and fluoroscopic images of the bowel are taken over time, is useful for looking for inflammation and narrowing of the small bowel. Barium enemas, in which barium is inserted into the rectum and fluoroscopy is used to image the bowel, are rarely used in the work-up of Crohn's disease due to the advent of colonoscopy. They remain useful for identifying anatomical abnormalities when strictures of the colon are too small for a colonoscope to pass through, or in the detection of colonic fistulae (in this case contrast should be performed with iodate substances). CT and MRI scans are useful for evaluating the small bowel with enteroclysis protocols. They are also useful for looking for intra-abdominal complications of Crohn's disease, such as abscesses, small bowel obstructions, or fistulae. Magnetic resonance imaging (MRI) is another option for imaging the small bowel as well as looking for complications, though it is more expensive and less readily available. MRI techniques such as diffusion-weighted imaging and high-resolution imaging are more sensitive in detecting ulceration and inflammation compared to CT. A complete blood count may reveal anemia, which commonly is caused by blood loss leading to iron deficiency or by vitamin B 12 deficiency, usually caused by ileal disease impairing vitamin B 12 absorption. Rarely autoimmune hemolysis may occur. Ferritin levels help assess if iron deficiency is contributing to the anemia. Erythrocyte sedimentation rate (ESR) and C-reactive protein help assess the degree of inflammation, which is important as ferritin can also be raised in inflammation. Other causes of anemia include medication used in treatment of inflammatory bowel disease, like azathioprine, which can lead to cytopenia, and sulfasalazine, which can also result in folate deficiency . Testing for Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA) has been evaluated to identify inflammatory diseases of the intestine and to differentiate Crohn's disease from ulcerative colitis. Furthermore, increasing amounts and levels of serological antibodies such as ASCA, antilaminaribioside [Glc(β1,3)Glb(β); ALCA], antichitobioside [GlcNAc(β1,4)GlcNAc(β); ACCA], antimannobioside [Man(α1,3)Man(α)AMCA], antiLaminarin [(Glc(β1,3))3n(Glc(β1,6))n; anti-L] and antichitin [GlcNAc(β1,4)n; anti-C] associate with disease behavior and surgery, and may aid in the prognosis of Crohn's disease. Low serum levels of vitamin D are associated with Crohn's disease. Further studies are required to determine the significance of this association. The most common disease that mimics the symptoms of Crohn's disease is ulcerative colitis, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases, since the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis. Other conditions with similar symptoms as Crohn's disease includes intestinal tuberculosis , Behçet's disease , ulcerative colitis , nonsteroidal anti-inflammatory drug enteropathy, irritable bowel syndrome and celiac disease . Irritable bowel syndrome is excluded when there are inflammatory changes. Celiac disease cannot be excluded if specific antibodies ( anti-transglutaminase antibodies ) are negative, nor in absence of intestinal villi atrophy. Crohn's disease is one type of inflammatory bowel disease (IBD). It typically manifests in the gastrointestinal tract and can be categorized by the specific tract region affected. Gastroduodenal Crohn's disease causes inflammation in the stomach and the first part of the small intestine called the duodenum. Jejunoileitis causes spotty patches of inflammation in the top half of the small intestine, called the jejunum. The disease can attack any part of the digestive tract, from mouth to anus. However, individuals affected by the disease rarely fall outside these three classifications, with presentations in other areas. Crohn's disease may also be categorized by the behavior of disease as it progresses. These categorizations formalized in the Vienna classification of the disease. There are three categories of disease presentation in Crohn's disease: stricturing, penetrating, and inflammatory. Stricturing disease causes narrowing of the bowel that may lead to bowel obstruction or changes in the caliber of the feces . Penetrating disease creates abnormal passageways (fistulae) between the bowel and other structures, such as the skin. Inflammatory disease (or nonstricturing, nonpenetrating disease) causes inflammation without causing strictures or fistulae. A colonoscopy is the best test for making the diagnosis of Crohn's disease, as it allows direct visualization of the colon and the terminal ileum , identifying the pattern of disease involvement. On occasion, the colonoscope can travel past the terminal ileum, but it varies from person to person. During the procedure, the gastroenterologist can also perform a biopsy, taking small samples of tissue for laboratory analysis, which may help confirm a diagnosis. As 30% of Crohn's disease involves only the ileum, cannulation of the terminal ileum is required in making the diagnosis. Finding a patchy distribution of disease, with involvement of the colon or ileum, but not the rectum , is suggestive of Crohn's disease, as are other endoscopic stigmata. The utility of capsule endoscopy for this, however, is still uncertain. A small bowel follow-through may suggest the diagnosis of Crohn's disease and is useful when the disease involves only the small intestine. Because colonoscopy and gastroscopy allow direct visualization of only the terminal ileum and beginning of the duodenum , they cannot be used to evaluate the remainder of the small intestine. As a result, a barium follow-through X-ray, wherein barium sulfate suspension is ingested and fluoroscopic images of the bowel are taken over time, is useful for looking for inflammation and narrowing of the small bowel. Barium enemas, in which barium is inserted into the rectum and fluoroscopy is used to image the bowel, are rarely used in the work-up of Crohn's disease due to the advent of colonoscopy. They remain useful for identifying anatomical abnormalities when strictures of the colon are too small for a colonoscope to pass through, or in the detection of colonic fistulae (in this case contrast should be performed with iodate substances). CT and MRI scans are useful for evaluating the small bowel with enteroclysis protocols. They are also useful for looking for intra-abdominal complications of Crohn's disease, such as abscesses, small bowel obstructions, or fistulae. Magnetic resonance imaging (MRI) is another option for imaging the small bowel as well as looking for complications, though it is more expensive and less readily available. MRI techniques such as diffusion-weighted imaging and high-resolution imaging are more sensitive in detecting ulceration and inflammation compared to CT. A complete blood count may reveal anemia, which commonly is caused by blood loss leading to iron deficiency or by vitamin B 12 deficiency, usually caused by ileal disease impairing vitamin B 12 absorption. Rarely autoimmune hemolysis may occur. Ferritin levels help assess if iron deficiency is contributing to the anemia. Erythrocyte sedimentation rate (ESR) and C-reactive protein help assess the degree of inflammation, which is important as ferritin can also be raised in inflammation. Other causes of anemia include medication used in treatment of inflammatory bowel disease, like azathioprine, which can lead to cytopenia, and sulfasalazine, which can also result in folate deficiency . Testing for Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA) has been evaluated to identify inflammatory diseases of the intestine and to differentiate Crohn's disease from ulcerative colitis. Furthermore, increasing amounts and levels of serological antibodies such as ASCA, antilaminaribioside [Glc(β1,3)Glb(β); ALCA], antichitobioside [GlcNAc(β1,4)GlcNAc(β); ACCA], antimannobioside [Man(α1,3)Man(α)AMCA], antiLaminarin [(Glc(β1,3))3n(Glc(β1,6))n; anti-L] and antichitin [GlcNAc(β1,4)n; anti-C] associate with disease behavior and surgery, and may aid in the prognosis of Crohn's disease. Low serum levels of vitamin D are associated with Crohn's disease. Further studies are required to determine the significance of this association. The most common disease that mimics the symptoms of Crohn's disease is ulcerative colitis, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases, since the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis. Other conditions with similar symptoms as Crohn's disease includes intestinal tuberculosis , Behçet's disease , ulcerative colitis , nonsteroidal anti-inflammatory drug enteropathy, irritable bowel syndrome and celiac disease . Irritable bowel syndrome is excluded when there are inflammatory changes. Celiac disease cannot be excluded if specific antibodies ( anti-transglutaminase antibodies ) are negative, nor in absence of intestinal villi atrophy. There is no cure for Crohn's disease and remission may not be possible or prolonged if achieved. In cases where remission is possible, relapse can be prevented and symptoms controlled with medication, lifestyle and dietary changes, changes to eating habits (eating smaller amounts more often), reduction of stress, moderate activity, and exercise. Surgery is generally contraindicated and has not been shown to prevent relapse. Adequately controlled, Crohn's disease may not significantly restrict daily living. Treatment for Crohn's disease involves first treating the acute problem and its symptoms, then maintaining remission of the disease. Certain lifestyle changes can reduce symptoms, including dietary adjustments, elemental diet , proper hydration , and smoking cessation . Recent reviews underlined the importance to adopt diets that are best supported by evidence, even if little is known about the impact of diets on these patients. Diets that include higher levels of fiber and fruit are associated with reduced risk, while diets rich in total fats, polyunsaturated fatty acids , meat, and omega-6 fatty acids may increase the risk of Crohn's. Maintaining a balanced diet with proper portion control can help manage symptoms of the disease. Eating small meals frequently instead of big meals may also help with a low appetite. A food diary may help with identifying foods that trigger symptoms. Despite the recognized importance of dietary fiber for intestinal health, some people should follow a low residue diet to control acute symptoms especially if foods high in insoluble fiber cause symptoms, e.g., due to obstruction or irritation of the bowel. Some find relief in eliminating casein (a protein found in cow's milk) and gluten (a protein found in wheat, rye and barley) from their diets. They may have specific dietary intolerances (not allergies), for example, lactose . Fatigue can be helped with regular exercise, a healthy diet, and enough sleep, and for those with malabsorption of vitamin B 12 due to disease or surgical resection of the terminal ileum , cobalamin injections. Smoking may worsen symptoms and the course of the disease, and stopping is recommended. Alcohol consumption can also worsen symptoms, and moderation or cessation is advised. Acute treatment uses medications to treat any infection (normally antibiotics ) and to reduce inflammation (normally aminosalicylate anti-inflammatory drugs and corticosteroids ). When symptoms are in remission, treatment enters maintenance, with a goal of avoiding the recurrence of symptoms. Prolonged use of corticosteroids has significant side-effects ; as a result, they are, in general, not used for long-term treatment. Alternatives include aminosalicylates alone, though only a minority are able to maintain the treatment, and many require immunosuppressive drugs. It has been also suggested that antibiotics change the enteric flora, and their continuous use may pose the risk of overgrowth with pathogens such as Clostridium difficile . Medications used to treat the symptoms of Crohn's disease include 5-aminosalicylic acid (5-ASA) formulations, prednisone , immunomodulators such as azathioprine (given as the prodrug for 6-mercaptopurine ), methotrexate , and anti-TNF therapies and monoclonal antibodies , such as infliximab , adalimumab , certolizumab , vedolizumab , ustekinumab , natalizumab , risankizumab-rzaa , and upadacitinib Hydrocortisone should be used in severe attacks of Crohn's disease. Biological therapies are medications used to avoid long-term steroid use, decrease inflammation, and treat people who have fistulas with abscesses. The monoclonal antibody ustekinumab appears to be a safe treatment option, and may help people with moderate to severe active Crohn's disease. The long term safety and effectiveness of monoclonal antibody treatment is not known. The monoclonal antibody briakinumab is not effective for people with active Crohn's disease and it is no longer being manufactured. The gradual loss of blood from the gastrointestinal tract, as well as chronic inflammation, often leads to anemia, and professional guidelines suggest routinely monitoring for this. Many patients affected by Crohn's disease need immunosuppressant therapies, which are known to be associated with a higher risk of contracting opportunistic infectious diseases and of pre-neoplastic or neoplastic lesions such as cervical high-grade dysplasia and cancer. Many of these potentially harmful diseases, such as Hepatitis B , Influenza , chickenpox , herpes zoster virus , pneumococcal pneumonia , or human papilloma virus , can be prevented by vaccines. Each drug used in the treatment of IBD should be classified according to the degree of immunosuppression induced in the patient. Several guidelines suggest investigating patients' vaccination status before starting any treatment and performing vaccinations against Vaccine-preventable disease when required. Compared to the rest of the population, patients affected by IBD are known to be at higher risk of contracting some vaccine-preventable diseases such as flu and pneumonia. Nevertheless, despite the increased risk of infections, vaccination rates in IBD patients are known to be suboptimal and may also be lower than vaccination rates in the general population. Crohn's cannot be cured by surgery , as the disease eventually recurs, though it is used in the case of partial or full blockage of the intestine. Surgery may also be required for complications such as obstructions, fistulas, or abscesses, or if the disease does not respond to drugs. After the first surgery, Crohn's usually comes back at the site where the diseased intestine was removed and the healthy ends were rejoined; it can also come back in other locations. After a resection, scar tissue builds up, which can cause strictures , which form when the intestines become too small to allow excrement to pass through easily, which can lead to a blockage. After the first resection, another resection may be necessary within five years. For patients with an obstruction due to a stricture, two options for treatment are strictureplasty and resection of that portion of bowel. There is no statistical significance between strictureplasty alone versus strictureplasty and resection in cases of duodenal involvement. In these cases, re-operation rates were 31% and 27%, respectively, indicating that strictureplasty is a safe and effective treatment for selected people with duodenal involvement. Postsurgical recurrence of Crohn's disease is relatively common. Crohn's lesions are nearly always found at the site of the resected bowel. The join (or anastomosis ) after surgery may be inspected, usually during a colonoscopy, and disease activity graded. The "Rutgeert's score" is an endoscopic scoring system for postoperative disease recurrence in Crohn's disease. Mild postsurgical recurrences of Crohn's disease are graded i1 and i2, moderate to severe recurrences are graded i3 and i4. Fewer lesions result in a lower grade. Based on the score, treatment plans can be designed to give the patient the best chance of managing the recurrence of the disease. Short bowel syndrome (SBS, also short gut syndrome or simply short gut) is caused by the surgical removal of part of the small intestine. It usually develops in those patients who have had half or more of their small intestines removed. Diarrhea is the main symptom, but others may include weight loss, cramping, bloating, and heartburn . Short bowel syndrome is treated with changes in diet, intravenous feeding, vitamin and mineral supplements, and treatment with medications. In some cases of SBS, intestinal transplant surgery may be considered; though the number of transplant centres offering this procedure is quite small and it comes with a high risk due to the chance of infection and rejection of the transplanted intestine. Bile acid diarrhea is another complication following surgery for Crohn's disease in which the terminal ileum has been removed. This leads to the development of excessive watery diarrhea. It is usually thought to be due to an inability of the ileum to reabsorb bile acids after resection of the terminal ileum and was the first type of bile acid malabsorption recognized. The use of oral probiotic supplements to modify the composition and behaviour of the gastrointestinal microbiome has been researched to understand whether it may help to improve remission rate in people with Crohn's disease. However, only two controlled trials were available in 2020, with no clear overall evidence of higher remission nor lower adverse effects, in people with Crohn's disease receiving probiotic supplementation. Crohn's may result in anxiety or mood disorders , especially in young people who may have stunted growth or embarrassment from fecal incontinence . Counselling as well as antidepressant or anxiolytic medication may help some people manage. As of 2017 [ update ] there is a small amount of research looking at mindfulness-based therapies , hypnotherapy, and cognitive behavioural therapy . It is common for people with Crohn's disease to try complementary or alternative therapy . These include diets, probiotics , fish oil, and other herbal and nutritional supplements.Certain lifestyle changes can reduce symptoms, including dietary adjustments, elemental diet , proper hydration , and smoking cessation . Recent reviews underlined the importance to adopt diets that are best supported by evidence, even if little is known about the impact of diets on these patients. Diets that include higher levels of fiber and fruit are associated with reduced risk, while diets rich in total fats, polyunsaturated fatty acids , meat, and omega-6 fatty acids may increase the risk of Crohn's. Maintaining a balanced diet with proper portion control can help manage symptoms of the disease. Eating small meals frequently instead of big meals may also help with a low appetite. A food diary may help with identifying foods that trigger symptoms. Despite the recognized importance of dietary fiber for intestinal health, some people should follow a low residue diet to control acute symptoms especially if foods high in insoluble fiber cause symptoms, e.g., due to obstruction or irritation of the bowel. Some find relief in eliminating casein (a protein found in cow's milk) and gluten (a protein found in wheat, rye and barley) from their diets. They may have specific dietary intolerances (not allergies), for example, lactose . Fatigue can be helped with regular exercise, a healthy diet, and enough sleep, and for those with malabsorption of vitamin B 12 due to disease or surgical resection of the terminal ileum , cobalamin injections. Smoking may worsen symptoms and the course of the disease, and stopping is recommended. Alcohol consumption can also worsen symptoms, and moderation or cessation is advised. Acute treatment uses medications to treat any infection (normally antibiotics ) and to reduce inflammation (normally aminosalicylate anti-inflammatory drugs and corticosteroids ). When symptoms are in remission, treatment enters maintenance, with a goal of avoiding the recurrence of symptoms. Prolonged use of corticosteroids has significant side-effects ; as a result, they are, in general, not used for long-term treatment. Alternatives include aminosalicylates alone, though only a minority are able to maintain the treatment, and many require immunosuppressive drugs. It has been also suggested that antibiotics change the enteric flora, and their continuous use may pose the risk of overgrowth with pathogens such as Clostridium difficile . Medications used to treat the symptoms of Crohn's disease include 5-aminosalicylic acid (5-ASA) formulations, prednisone , immunomodulators such as azathioprine (given as the prodrug for 6-mercaptopurine ), methotrexate , and anti-TNF therapies and monoclonal antibodies , such as infliximab , adalimumab , certolizumab , vedolizumab , ustekinumab , natalizumab , risankizumab-rzaa , and upadacitinib Hydrocortisone should be used in severe attacks of Crohn's disease. Biological therapies are medications used to avoid long-term steroid use, decrease inflammation, and treat people who have fistulas with abscesses. The monoclonal antibody ustekinumab appears to be a safe treatment option, and may help people with moderate to severe active Crohn's disease. The long term safety and effectiveness of monoclonal antibody treatment is not known. The monoclonal antibody briakinumab is not effective for people with active Crohn's disease and it is no longer being manufactured. The gradual loss of blood from the gastrointestinal tract, as well as chronic inflammation, often leads to anemia, and professional guidelines suggest routinely monitoring for this. Many patients affected by Crohn's disease need immunosuppressant therapies, which are known to be associated with a higher risk of contracting opportunistic infectious diseases and of pre-neoplastic or neoplastic lesions such as cervical high-grade dysplasia and cancer. Many of these potentially harmful diseases, such as Hepatitis B , Influenza , chickenpox , herpes zoster virus , pneumococcal pneumonia , or human papilloma virus , can be prevented by vaccines. Each drug used in the treatment of IBD should be classified according to the degree of immunosuppression induced in the patient. Several guidelines suggest investigating patients' vaccination status before starting any treatment and performing vaccinations against Vaccine-preventable disease when required. Compared to the rest of the population, patients affected by IBD are known to be at higher risk of contracting some vaccine-preventable diseases such as flu and pneumonia. Nevertheless, despite the increased risk of infections, vaccination rates in IBD patients are known to be suboptimal and may also be lower than vaccination rates in the general population. Crohn's cannot be cured by surgery , as the disease eventually recurs, though it is used in the case of partial or full blockage of the intestine. Surgery may also be required for complications such as obstructions, fistulas, or abscesses, or if the disease does not respond to drugs. After the first surgery, Crohn's usually comes back at the site where the diseased intestine was removed and the healthy ends were rejoined; it can also come back in other locations. After a resection, scar tissue builds up, which can cause strictures , which form when the intestines become too small to allow excrement to pass through easily, which can lead to a blockage. After the first resection, another resection may be necessary within five years. For patients with an obstruction due to a stricture, two options for treatment are strictureplasty and resection of that portion of bowel. There is no statistical significance between strictureplasty alone versus strictureplasty and resection in cases of duodenal involvement. In these cases, re-operation rates were 31% and 27%, respectively, indicating that strictureplasty is a safe and effective treatment for selected people with duodenal involvement. Postsurgical recurrence of Crohn's disease is relatively common. Crohn's lesions are nearly always found at the site of the resected bowel. The join (or anastomosis ) after surgery may be inspected, usually during a colonoscopy, and disease activity graded. The "Rutgeert's score" is an endoscopic scoring system for postoperative disease recurrence in Crohn's disease. Mild postsurgical recurrences of Crohn's disease are graded i1 and i2, moderate to severe recurrences are graded i3 and i4. Fewer lesions result in a lower grade. Based on the score, treatment plans can be designed to give the patient the best chance of managing the recurrence of the disease. Short bowel syndrome (SBS, also short gut syndrome or simply short gut) is caused by the surgical removal of part of the small intestine. It usually develops in those patients who have had half or more of their small intestines removed. Diarrhea is the main symptom, but others may include weight loss, cramping, bloating, and heartburn . Short bowel syndrome is treated with changes in diet, intravenous feeding, vitamin and mineral supplements, and treatment with medications. In some cases of SBS, intestinal transplant surgery may be considered; though the number of transplant centres offering this procedure is quite small and it comes with a high risk due to the chance of infection and rejection of the transplanted intestine. Bile acid diarrhea is another complication following surgery for Crohn's disease in which the terminal ileum has been removed. This leads to the development of excessive watery diarrhea. It is usually thought to be due to an inability of the ileum to reabsorb bile acids after resection of the terminal ileum and was the first type of bile acid malabsorption recognized. The use of oral probiotic supplements to modify the composition and behaviour of the gastrointestinal microbiome has been researched to understand whether it may help to improve remission rate in people with Crohn's disease. However, only two controlled trials were available in 2020, with no clear overall evidence of higher remission nor lower adverse effects, in people with Crohn's disease receiving probiotic supplementation. Crohn's may result in anxiety or mood disorders , especially in young people who may have stunted growth or embarrassment from fecal incontinence . Counselling as well as antidepressant or anxiolytic medication may help some people manage. As of 2017 [ update ] there is a small amount of research looking at mindfulness-based therapies , hypnotherapy, and cognitive behavioural therapy . It is common for people with Crohn's disease to try complementary or alternative therapy . These include diets, probiotics , fish oil, and other herbal and nutritional supplements.Crohn's disease is a chronic condition for which there is no known cure. It is characterised by periods of improvement followed by episodes when symptoms flare up. With treatment, most people achieve a healthy weight, and the mortality rate for the disease is relatively low. It can vary from being benign to very severe, and people with CD could experience just one episode or have continuous symptoms. It usually reoccurs, although some people can remain disease-free for years or decades. Up to 80% of people with Crohn's disease are hospitalized at some point during the course of their disease, with the highest rate occurring in the first year after diagnosis. Most people with Crohn's live a normal lifespan. However, Crohn's disease is associated with a small increase in risk of small bowel and colorectal carcinoma (bowel cancer). The percentage of people with Crohn's disease has been determined in Norway and the United States and is similar at 6 to 7.1:100,000. The Crohn's & Colitis Foundation of America cites this number as approx 149:100,000; NIH cites 28 to 199 per 100,000. Crohn's disease is more common in northern countries, and with higher rates still in the northern areas of these countries. The incidence of Crohn's disease is thought to be similar in Europe but lower in Asia and Africa . It also has a higher incidence in Ashkenazi Jews and smokers. Crohn's disease begins most commonly in people in their teens and 20s, and people in their 50s through to their 70s. It is rarely diagnosed in early childhood. It usually affects female children more severely than males. However, only slightly more women than men have Crohn's disease. Parents, siblings or children of people with Crohn's disease are 3 to 20 times more likely to develop the disease. Twin studies find that if one has the disease there is a 55% chance the other will too. The incidence of Crohn's disease is increasing in Europe and in newly industrialised countries. For example, in Brazil, there has been an annual increase of 11% in the incidence of Crohn's disease since 1990. Inflammatory bowel diseases were described by Giovanni Battista Morgagni (1682–1771) and by Scottish physician Thomas Kennedy Dalziel in 1913. Ileitis terminalis was first described by Polish surgeon Antoni Leśniowski in 1904, although it was not conclusively distinguished from intestinal tuberculosis. In Poland, it is still called Leśniowski-Crohn's disease ( Polish : choroba Leśniowskiego-Crohna ). Burrill Bernard Crohn , an American gastroenterologist at New York City 's Mount Sinai Hospital , described fourteen cases in 1932, and submitted them to the American Medical Association under the rubric of "Terminal ileitis: A new clinical entity". Later that year, he, along with colleagues Leon Ginzburg and Gordon Oppenheimer, published the case series "Regional ileitis: a pathologic and clinical entity". However, due to the precedence of Crohn's name in the alphabet, it later became known in the worldwide literature as Crohn's disease.

Wiki

Acute hemorrhagic fever syndrome

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

Interstitial lung disease

Interstitial lung disease ( ILD ), or diffuse parenchymal lung disease ( DPLD ), is a group of respiratory diseases affecting the interstitium (the tissue) and space around the alveoli (air sacs) of the lungs . It concerns alveolar epithelium , pulmonary capillary endothelium , basement membrane , and perivascular and perilymphatic tissues. It may occur when an injury to the lungs triggers an abnormal healing response. Ordinarily, the body generates just the right amount of tissue to repair damage, but in interstitial lung disease, the repair process is disrupted, and the tissue around the air sacs (alveoli) becomes scarred and thickened. This makes it more difficult for oxygen to pass into the bloodstream. The disease presents itself with the following symptoms: shortness of breath, nonproductive coughing, fatigue, and weight loss, which tend to develop slowly, over several months. The average rate of survival for someone with this disease is between three and five years. The term ILD is used to distinguish these diseases from obstructive airways diseases . There are specific types in children, known as children's interstitial lung diseases . The acronym ChILD is sometimes used for this group of diseases. Prolonged ILD may result in pulmonary fibrosis , but this is not always the case. Idiopathic pulmonary fibrosis is interstitial lung disease for which no obvious cause can be identified (idiopathic) and is associated with typical findings both radiographic (basal and pleural-based fibrosis with honeycombing) and pathologic (temporally and spatially heterogeneous fibrosis, histopathologic honeycombing, and fibroblastic foci). In 2015, interstitial lung disease, together with pulmonary sarcoidosis , affected 1.9 million people. They resulted in 122,000 deaths. An ILD may be classified as to whether its cause is not known (idiopathic) or known (secondary). Idiopathic interstitial pneumonia is the term given to ILDs with an unknown cause. They represent the majority of cases of interstitial lung diseases (up to two-thirds of cases). They were subclassified by the American Thoracic Society in 2002 into 7 subgroups: Secondary ILDs are those diseases with a known etiology, including: [ citation needed ] Diffuse developmental disorders Growth abnormalities and deficient alveolarisation Infant conditions of undefined cause ILD related to alveolar surfactant regionIdiopathic interstitial pneumonia is the term given to ILDs with an unknown cause. They represent the majority of cases of interstitial lung diseases (up to two-thirds of cases). They were subclassified by the American Thoracic Society in 2002 into 7 subgroups: Secondary ILDs are those diseases with a known etiology, including: [ citation needed ] Diffuse developmental disorders Growth abnormalities and deficient alveolarisation Infant conditions of undefined cause ILD related to alveolar surfactant regionDiffuse developmental disorders Growth abnormalities and deficient alveolarisation Infant conditions of undefined cause ILD related to alveolar surfactant regionInvestigation is tailored towards the symptoms and signs. A proper and detailed history looking for the occupational exposures and for signs of conditions listed above is the first and probably the most important part of the workup in patients with interstitial lung disease. Pulmonary function tests usually show a restrictive defect with decreased diffusion capacity ( DLCO ). [ citation needed ] A lung biopsy is required if the clinical history and imaging are not clearly suggestive of a specific diagnosis or malignancy cannot otherwise be ruled out. In cases where a lung biopsy is indicated, a trans-bronchial biopsy is usually unhelpful, and a surgical lung biopsy is often required. [ citation needed ] Most patients with suspected ILD are likely to undergo complete pulmonary function testing . These tests are useful in diagnosis and determining severity of the disease. Although there is large diversity in interstitial lung disease, most follow a restrictive pattern . Restrictive defects are defined by decreased TLC (total lung capacity), RV (residual volume), FVC (forced vital capacity) and FEV1 (forced expiratory volume in one second). As both FVC and FEV1 are reduced, the FVC to FEV1 ratio remains normal or is increased. As disease progression increases and the lungs become stiffer lung volumes will continue to decrease; lower TLC, RV, FVC and FEV1 scores are associated with a more severe disease progression and poorer prognosis. Chest radiography is usually the first test to detect interstitial lung diseases, but the chest radiograph can be normal in up to 10% of patients, especially early in the disease process. High-resolution CT of the chest is the preferred modality and differs from routine CT of the chest. Conventional (regular) CT chest examines 7–10 mm slices obtained at 10 mm intervals; high resolution CT examines 1–1.5 mm slices at 10 mm intervals using a high-spatial-frequency reconstruction algorithm. The HRCT therefore provides approximately 10 times more resolution than the conventional CT chest, allowing the HRCT to elicit details that cannot otherwise be visualized. Radiologic appearance alone, however, is not adequate and should be interpreted in the clinical context, keeping in mind the temporal profile of the disease process. Interstitial lung diseases can be classified according to radiologic patterns. Acute: Alveolar hemorrhage syndromes Acute eosinophilic pneumonia Acute interstitial pneumonia Cryptogenic organizing pneumonia Chronic: Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Lymphoproliferative disorders Pulmonary alveolar proteinosis Sarcoidosis Alveolar hemorrhage syndromes Acute eosinophilic pneumonia Acute interstitial pneumonia Cryptogenic organizing pneumonia Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Lymphoproliferative disorders Pulmonary alveolar proteinosis Sarcoidosis Acute: Pulmonary edema Chronic: Idiopathic pulmonary fibrosis Connective tissue-associated interstitial lung diseases Asbestosis Sarcoidosis Hypersensitivity pneumonitis Drug-induced lung disease Pulmonary edema Idiopathic pulmonary fibrosis Connective tissue-associated interstitial lung diseases Asbestosis Sarcoidosis Hypersensitivity pneumonitis Drug-induced lung disease Acute: Hypersensitivity pneumonitis Chronic: Hypersensitivity pneumonitis Sarcoidosis Silicosis Coal workers pneumoconiosis Respiratory bronchiolitis Alveolar microlithiasis Hypersensitivity pneumonitis Hypersensitivity pneumonitis Sarcoidosis Silicosis Coal workers pneumoconiosis Respiratory bronchiolitis Alveolar microlithiasis Chronic: Pulmonary Langerhans cell histiocytosis Pulmonary lymphangioleiomyomatosis Honeycomb lung caused by idiopathic pulmonary fibrosis (IPF) or other diseases Pulmonary Langerhans cell histiocytosis Pulmonary lymphangioleiomyomatosis Honeycomb lung caused by idiopathic pulmonary fibrosis (IPF) or other diseases Acute: Alveolar hemorrhage syndromes Pulmonary edema Hypersensitivity pneumonitis Acute inhalational exposures Drug-induced lung diseases Acute interstitial pneumonia Chronic: Nonspecific interstitial pneumonia Respiratory bronchiolitis-associated interstitial lung disease Desquamative interstitial pneumonia Drug-induced lung diseases Pulmonary alveolar proteinosis Alveolar hemorrhage syndromes Pulmonary edema Hypersensitivity pneumonitis Acute inhalational exposures Drug-induced lung diseases Acute interstitial pneumonia Nonspecific interstitial pneumonia Respiratory bronchiolitis-associated interstitial lung disease Desquamative interstitial pneumonia Drug-induced lung diseases Pulmonary alveolar proteinosis Acute: Pulmonary edema Chronic: Lymphangitic carcinomatosis Pulmonary alveolar proteinosis Sarcoidosis Pulmonary veno-occlusive disease Pulmonary edema Lymphangitic carcinomatosis Pulmonary alveolar proteinosis Sarcoidosis Pulmonary veno-occlusive disease Pulmonary Langerhans cell histiocytosis Silicosis Coal workers pneumoconiosis Carmustine -related pulmonary fibrosis Respiratory broncholitis associated with interstitial lung disease Idiopathic pulmonary fibrosis Pulmonary fibrosis associated with connective tissue diseases (ILD-CTD) Asbestosis Chronic aspiration Sarcoidosis Berylliosis Idiopathic pulmonary fibrosis Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Pulmonary edema Connective tissue diseases Asbestosis Lymphangitic carcinomatosis Lymphoma Lymphangioleiomyomatosis Drug-induced lung diseases Sarcoidosis Silicosis Berylliosis Lymphangitic carcinomatosis Lymphoma Lymphocytic interstitial pneumonia For some types of paediatric ILDs and few forms adult ILDs, genetic causes have been identified. These may be identified by blood tests. For a limited number of cases, this is a definite advantage, as a precise molecular diagnosis can be done; frequently then there is no need for a lung biopsy. Testing is available for Mutations in telomerase reverse transcriptase ( TERT ) Mutations in telomerase RNA component ( TERC ) Mutations in the regulator of telomere elongation helicase 1 ( RTEL1 ) Mutations in poly(A)-specific ribonuclease ( PARN )Most patients with suspected ILD are likely to undergo complete pulmonary function testing . These tests are useful in diagnosis and determining severity of the disease. Although there is large diversity in interstitial lung disease, most follow a restrictive pattern . Restrictive defects are defined by decreased TLC (total lung capacity), RV (residual volume), FVC (forced vital capacity) and FEV1 (forced expiratory volume in one second). As both FVC and FEV1 are reduced, the FVC to FEV1 ratio remains normal or is increased. As disease progression increases and the lungs become stiffer lung volumes will continue to decrease; lower TLC, RV, FVC and FEV1 scores are associated with a more severe disease progression and poorer prognosis. Chest radiography is usually the first test to detect interstitial lung diseases, but the chest radiograph can be normal in up to 10% of patients, especially early in the disease process. High-resolution CT of the chest is the preferred modality and differs from routine CT of the chest. Conventional (regular) CT chest examines 7–10 mm slices obtained at 10 mm intervals; high resolution CT examines 1–1.5 mm slices at 10 mm intervals using a high-spatial-frequency reconstruction algorithm. The HRCT therefore provides approximately 10 times more resolution than the conventional CT chest, allowing the HRCT to elicit details that cannot otherwise be visualized. Radiologic appearance alone, however, is not adequate and should be interpreted in the clinical context, keeping in mind the temporal profile of the disease process. Interstitial lung diseases can be classified according to radiologic patterns. Acute: Alveolar hemorrhage syndromes Acute eosinophilic pneumonia Acute interstitial pneumonia Cryptogenic organizing pneumonia Chronic: Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Lymphoproliferative disorders Pulmonary alveolar proteinosis Sarcoidosis Alveolar hemorrhage syndromes Acute eosinophilic pneumonia Acute interstitial pneumonia Cryptogenic organizing pneumonia Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Lymphoproliferative disorders Pulmonary alveolar proteinosis Sarcoidosis Acute: Pulmonary edema Chronic: Idiopathic pulmonary fibrosis Connective tissue-associated interstitial lung diseases Asbestosis Sarcoidosis Hypersensitivity pneumonitis Drug-induced lung disease Pulmonary edema Idiopathic pulmonary fibrosis Connective tissue-associated interstitial lung diseases Asbestosis Sarcoidosis Hypersensitivity pneumonitis Drug-induced lung disease Acute: Hypersensitivity pneumonitis Chronic: Hypersensitivity pneumonitis Sarcoidosis Silicosis Coal workers pneumoconiosis Respiratory bronchiolitis Alveolar microlithiasis Hypersensitivity pneumonitis Hypersensitivity pneumonitis Sarcoidosis Silicosis Coal workers pneumoconiosis Respiratory bronchiolitis Alveolar microlithiasis Chronic: Pulmonary Langerhans cell histiocytosis Pulmonary lymphangioleiomyomatosis Honeycomb lung caused by idiopathic pulmonary fibrosis (IPF) or other diseases Pulmonary Langerhans cell histiocytosis Pulmonary lymphangioleiomyomatosis Honeycomb lung caused by idiopathic pulmonary fibrosis (IPF) or other diseases Acute: Alveolar hemorrhage syndromes Pulmonary edema Hypersensitivity pneumonitis Acute inhalational exposures Drug-induced lung diseases Acute interstitial pneumonia Chronic: Nonspecific interstitial pneumonia Respiratory bronchiolitis-associated interstitial lung disease Desquamative interstitial pneumonia Drug-induced lung diseases Pulmonary alveolar proteinosis Alveolar hemorrhage syndromes Pulmonary edema Hypersensitivity pneumonitis Acute inhalational exposures Drug-induced lung diseases Acute interstitial pneumonia Nonspecific interstitial pneumonia Respiratory bronchiolitis-associated interstitial lung disease Desquamative interstitial pneumonia Drug-induced lung diseases Pulmonary alveolar proteinosis Acute: Pulmonary edema Chronic: Lymphangitic carcinomatosis Pulmonary alveolar proteinosis Sarcoidosis Pulmonary veno-occlusive disease Pulmonary edema Lymphangitic carcinomatosis Pulmonary alveolar proteinosis Sarcoidosis Pulmonary veno-occlusive disease Pulmonary Langerhans cell histiocytosis Silicosis Coal workers pneumoconiosis Carmustine -related pulmonary fibrosis Respiratory broncholitis associated with interstitial lung disease Idiopathic pulmonary fibrosis Pulmonary fibrosis associated with connective tissue diseases (ILD-CTD) Asbestosis Chronic aspiration Sarcoidosis Berylliosis Idiopathic pulmonary fibrosis Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Pulmonary edema Connective tissue diseases Asbestosis Lymphangitic carcinomatosis Lymphoma Lymphangioleiomyomatosis Drug-induced lung diseases Sarcoidosis Silicosis Berylliosis Lymphangitic carcinomatosis Lymphoma Lymphocytic interstitial pneumonia Acute: Alveolar hemorrhage syndromes Acute eosinophilic pneumonia Acute interstitial pneumonia Cryptogenic organizing pneumonia Chronic: Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Lymphoproliferative disorders Pulmonary alveolar proteinosis Sarcoidosis Alveolar hemorrhage syndromes Acute eosinophilic pneumonia Acute interstitial pneumonia Cryptogenic organizing pneumonia Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Lymphoproliferative disorders Pulmonary alveolar proteinosis Sarcoidosis Acute: Pulmonary edema Chronic: Idiopathic pulmonary fibrosis Connective tissue-associated interstitial lung diseases Asbestosis Sarcoidosis Hypersensitivity pneumonitis Drug-induced lung disease Pulmonary edema Idiopathic pulmonary fibrosis Connective tissue-associated interstitial lung diseases Asbestosis Sarcoidosis Hypersensitivity pneumonitis Drug-induced lung disease Acute: Hypersensitivity pneumonitis Chronic: Hypersensitivity pneumonitis Sarcoidosis Silicosis Coal workers pneumoconiosis Respiratory bronchiolitis Alveolar microlithiasis Hypersensitivity pneumonitis Hypersensitivity pneumonitis Sarcoidosis Silicosis Coal workers pneumoconiosis Respiratory bronchiolitis Alveolar microlithiasis Chronic: Pulmonary Langerhans cell histiocytosis Pulmonary lymphangioleiomyomatosis Honeycomb lung caused by idiopathic pulmonary fibrosis (IPF) or other diseases Pulmonary Langerhans cell histiocytosis Pulmonary lymphangioleiomyomatosis Honeycomb lung caused by idiopathic pulmonary fibrosis (IPF) or other diseases Acute: Alveolar hemorrhage syndromes Pulmonary edema Hypersensitivity pneumonitis Acute inhalational exposures Drug-induced lung diseases Acute interstitial pneumonia Chronic: Nonspecific interstitial pneumonia Respiratory bronchiolitis-associated interstitial lung disease Desquamative interstitial pneumonia Drug-induced lung diseases Pulmonary alveolar proteinosis Alveolar hemorrhage syndromes Pulmonary edema Hypersensitivity pneumonitis Acute inhalational exposures Drug-induced lung diseases Acute interstitial pneumonia Nonspecific interstitial pneumonia Respiratory bronchiolitis-associated interstitial lung disease Desquamative interstitial pneumonia Drug-induced lung diseases Pulmonary alveolar proteinosis Acute: Pulmonary edema Chronic: Lymphangitic carcinomatosis Pulmonary alveolar proteinosis Sarcoidosis Pulmonary veno-occlusive disease Pulmonary edema Lymphangitic carcinomatosis Pulmonary alveolar proteinosis Sarcoidosis Pulmonary veno-occlusive disease Pulmonary Langerhans cell histiocytosis Silicosis Coal workers pneumoconiosis Carmustine -related pulmonary fibrosis Respiratory broncholitis associated with interstitial lung disease Idiopathic pulmonary fibrosis Pulmonary fibrosis associated with connective tissue diseases (ILD-CTD) Asbestosis Chronic aspiration Sarcoidosis Berylliosis Idiopathic pulmonary fibrosis Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Pulmonary edema Connective tissue diseases Asbestosis Lymphangitic carcinomatosis Lymphoma Lymphangioleiomyomatosis Drug-induced lung diseases Sarcoidosis Silicosis Berylliosis Lymphangitic carcinomatosis Lymphoma Lymphocytic interstitial pneumonia For some types of paediatric ILDs and few forms adult ILDs, genetic causes have been identified. These may be identified by blood tests. For a limited number of cases, this is a definite advantage, as a precise molecular diagnosis can be done; frequently then there is no need for a lung biopsy. Testing is available for Mutations in telomerase reverse transcriptase ( TERT ) Mutations in telomerase RNA component ( TERC ) Mutations in the regulator of telomere elongation helicase 1 ( RTEL1 ) Mutations in poly(A)-specific ribonuclease ( PARN )Mutations in telomerase reverse transcriptase ( TERT ) Mutations in telomerase RNA component ( TERC ) Mutations in the regulator of telomere elongation helicase 1 ( RTEL1 ) Mutations in poly(A)-specific ribonuclease ( PARN )ILD is not a single disease but encompasses many different pathological processes, hence treatment is different for each disease. If a specific occupational exposure cause is found, the person should avoid that environment. If a drug cause is suspected, that drug should be discontinued. [ citation needed ] Many cases due to unknown or connective tissue -based causes are treated with corticosteroids , such as prednisolone . Some people respond to immunosuppressant treatment. Oxygen therapy at home is recommended in those with significantly low oxygen levels. Pulmonary rehabilitation appears to be useful with the benefits being sustainable longer term with improvement in exercise capacity, dyspnoea , and quality of life. Lung transplantation is an option if the ILD progresses despite therapy in appropriately selected patients with no other contraindications. On October 16, 2014, the Food and Drug Administration approved a new drug for the treatment of idiopathic pulmonary fibrosis (IPF). This drug, Ofev ( nintedanib ), is marketed by Boehringer Ingelheim Pharmaceuticals, Inc. This drug has been shown to slow the decline of lung function, although the drug has not been shown to reduce mortality or improve lung function. The estimated cost of the drug per year is approximately $94,000. Oxygen therapy at home is recommended in those with significantly low oxygen levels. Pulmonary rehabilitation appears to be useful with the benefits being sustainable longer term with improvement in exercise capacity, dyspnoea , and quality of life. Lung transplantation is an option if the ILD progresses despite therapy in appropriately selected patients with no other contraindications. On October 16, 2014, the Food and Drug Administration approved a new drug for the treatment of idiopathic pulmonary fibrosis (IPF). This drug, Ofev ( nintedanib ), is marketed by Boehringer Ingelheim Pharmaceuticals, Inc. This drug has been shown to slow the decline of lung function, although the drug has not been shown to reduce mortality or improve lung function. The estimated cost of the drug per year is approximately $94,000.

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Acute hemorrhagic fever syndrome

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Pericarditis

Pericarditis is inflammation of the pericardium , the fibrous sac surrounding the heart . Symptoms typically include sudden onset of sharp chest pain , which may also be felt in the shoulders, neck, or back. The pain is typically less severe when sitting up and more severe when lying down or breathing deeply. Other symptoms of pericarditis can include fever , weakness , palpitations , and shortness of breath . The onset of symptoms can occasionally be gradual rather than sudden. The cause of pericarditis often remains unknown but is believed to be most often due to a viral infection . Other causes include bacterial infections such as tuberculosis , uremic pericarditis , heart attack , cancer , autoimmune disorders , and chest trauma . Diagnosis is based on the presence of chest pain, a pericardial rub , specific electrocardiogram (ECG) changes, and fluid around the heart . A heart attack may produce similar symptoms to pericarditis. Treatment in most cases is with NSAIDs and possibly the anti-inflammatory medication colchicine . Steroids may be used if these are not appropriate. Symptoms usually improve in a few days to weeks but can occasionally last months. Complications can include cardiac tamponade , myocarditis , and constrictive pericarditis . Pericarditis is an uncommon cause of chest pain. About 3 per 10,000 people are affected per year. Those most commonly affected are males between the ages of 20 and 50. Up to 30% of those affected have more than one episode. Substernal or left precordial pleuritic chest pain with radiation to the trapezius ridge (the bottom portion of scapula on the back) is the characteristic pain of pericarditis. The pain is usually relieved by sitting up or bending forward, and worsened by lying down (both recumbent and supine positions ) or by inspiration (taking a breath in). The pain may resemble that of angina but differs in that pericarditis pain changes with body position, where heart attack pain is generally constant and pressure-like. Other symptoms of pericarditis may include dry cough , fever , fatigue, and anxiety . [ citation needed ] Due to its similarity to the pain of myocardial infarction (heart attack), pericarditis can be misdiagnosed as a heart attack. Acute myocardial infarction can also cause pericarditis, but the presenting symptoms often differ enough to warrant diagnosis. The following table organizes the clinical presentation of pericarditis differential to myocardial infarction: The classic sign of pericarditis is a friction rub heard with a stethoscope on the cardiovascular examination, usually on the lower left sternal border . Other physical signs include a person in distress, positional chest pain, diaphoresis (excessive sweating); possibility of heart failure in form of pericardial tamponade causing pulsus paradoxus , and the Beck's triad of low blood pressure (due to decreased cardiac output ), distant (muffled) heart sounds, and distension of the jugular vein (JVD). [ citation needed ] Pericarditis can progress to pericardial effusion and eventually cardiac tamponade . This can be seen in people who are experiencing the classic signs of pericarditis but then show signs of relief, and progress to show signs of cardiac tamponade which include decreased alertness and lethargy, pulsus paradoxus (decrease of at least 10 mmHg of the systolic blood pressure upon inspiration ), low blood pressure (due to decreased cardiac index ), (jugular vein distention from right sided heart failure and fluid overload), distant heart sounds on auscultation, and equilibration of all the diastolic blood pressures on cardiac catheterization due to the constriction of the pericardium by the fluid. [ citation needed ] In such cases of cardiac tamponade, EKG or Holter monitor will then depict electrical alternans indicating wobbling of the heart in the fluid filled pericardium, and the capillary refill might decrease, as well as severe vascular collapse and altered mental status due to hypoperfusion of body organs by a heart that can not pump out blood effectively. [ citation needed ] The diagnosis of tamponade can be confirmed with trans-thoracic echocardiography (TTE), which should show a large pericardial effusion and diastolic collapse of the right ventricle and right atrium. Chest X-ray usually shows an enlarged cardiac silhouette ("water bottle" appearance) and clear lungs. Pulmonary congestion is typically not seen because equalization of diastolic pressures constrains the pulmonary capillary wedge pressure to the intra-pericardial pressure (and all other diastolic pressures). [ citation needed ]The classic sign of pericarditis is a friction rub heard with a stethoscope on the cardiovascular examination, usually on the lower left sternal border . Other physical signs include a person in distress, positional chest pain, diaphoresis (excessive sweating); possibility of heart failure in form of pericardial tamponade causing pulsus paradoxus , and the Beck's triad of low blood pressure (due to decreased cardiac output ), distant (muffled) heart sounds, and distension of the jugular vein (JVD). [ citation needed ]Pericarditis can progress to pericardial effusion and eventually cardiac tamponade . This can be seen in people who are experiencing the classic signs of pericarditis but then show signs of relief, and progress to show signs of cardiac tamponade which include decreased alertness and lethargy, pulsus paradoxus (decrease of at least 10 mmHg of the systolic blood pressure upon inspiration ), low blood pressure (due to decreased cardiac index ), (jugular vein distention from right sided heart failure and fluid overload), distant heart sounds on auscultation, and equilibration of all the diastolic blood pressures on cardiac catheterization due to the constriction of the pericardium by the fluid. [ citation needed ] In such cases of cardiac tamponade, EKG or Holter monitor will then depict electrical alternans indicating wobbling of the heart in the fluid filled pericardium, and the capillary refill might decrease, as well as severe vascular collapse and altered mental status due to hypoperfusion of body organs by a heart that can not pump out blood effectively. [ citation needed ] The diagnosis of tamponade can be confirmed with trans-thoracic echocardiography (TTE), which should show a large pericardial effusion and diastolic collapse of the right ventricle and right atrium. Chest X-ray usually shows an enlarged cardiac silhouette ("water bottle" appearance) and clear lungs. Pulmonary congestion is typically not seen because equalization of diastolic pressures constrains the pulmonary capillary wedge pressure to the intra-pericardial pressure (and all other diastolic pressures). [ citation needed ]Pericarditis may be caused by viral , bacterial , or fungal infection. In the developing world the bacterial disease tuberculosis is a common cause, whereas in the developed world viruses are believed to be the cause of about 85% of cases. Viral causes include coxsackievirus , herpesvirus , mumps virus , and HIV among others. Pneumococcus or tuberculous pericarditis are the most common bacterial forms. Anaerobic bacteria can also be a rare cause. Fungal pericarditis is usually due to histoplasmosis , or in immunocompromised hosts Aspergillus , Candida , and Coccidioides . [ citation needed ] The most common cause of pericarditis worldwide is infectious pericarditis with tuberculosis. [ citation needed ]Pericarditis may be caused by viral , bacterial , or fungal infection. In the developing world the bacterial disease tuberculosis is a common cause, whereas in the developed world viruses are believed to be the cause of about 85% of cases. Viral causes include coxsackievirus , herpesvirus , mumps virus , and HIV among others. Pneumococcus or tuberculous pericarditis are the most common bacterial forms. Anaerobic bacteria can also be a rare cause. Fungal pericarditis is usually due to histoplasmosis , or in immunocompromised hosts Aspergillus , Candida , and Coccidioides . [ citation needed ] The most common cause of pericarditis worldwide is infectious pericarditis with tuberculosis. [ citation needed ]Laboratory values can show increased blood urea nitrogen ( BUN ), or increased blood creatinine in cases of uremic pericarditis . Generally, however, laboratory values are normal, but if there is a concurrent myocardial infarction (heart attack) or great stress to the heart, laboratory values may show increased cardiac markers like Troponin (I, T), CK-MB , Myoglobin , and LDH 1 (lactase dehydrogenase isotype 1). [ citation needed ] The preferred initial diagnostic testing is the ECG, which may demonstrate a 12-lead electrocardiogram with diffuse, non-specific, concave ("saddle-shaped"), ST-segment elevations in all leads except aVR and V1 and PR-segment depression possible in any lead except aVR ; sinus tachycardia, and low-voltage QRS complexes can also be seen if there is subsymptomatic levels of pericardial effusion. The PR depression is often seen early in the process as the thin atria are affected more easily than the ventricles by the inflammatory process of the pericardium. [ citation needed ] Since the mid-19th century, retrospective diagnosis of pericarditis has been made upon the finding of adhesions of the pericardium. When pericarditis is diagnosed clinically, the underlying cause is often never known; it may be discovered in only 16–22 percent of people with acute pericarditis. [ citation needed ] On MRI T2-weighted spin-echo images, inflamed pericardium will show high signal intensity. Late gadolinium contrast will show uptake of contrast by the inflamed pericardium. Normal pericardium will not show any contrast enhancement. Pericarditis can be classified according to the composition of the fluid that accumulates around the heart. Types of pericarditis include the following: [ citation needed ] Depending on the time of presentation and duration, pericarditis is divided into "acute" and "chronic" forms. Acute pericarditis is more common than chronic pericarditis, and can occur as a complication of infections, immunologic conditions, or even as a result of a heart attack (myocardial infarction), as Dressler's syndrome . Chronic pericarditis however is less common, a form of which is constrictive pericarditis . The following is the clinical classification of acute vs. chronic: [ citation needed ] Clinically : Acute (6 months)Laboratory values can show increased blood urea nitrogen ( BUN ), or increased blood creatinine in cases of uremic pericarditis . Generally, however, laboratory values are normal, but if there is a concurrent myocardial infarction (heart attack) or great stress to the heart, laboratory values may show increased cardiac markers like Troponin (I, T), CK-MB , Myoglobin , and LDH 1 (lactase dehydrogenase isotype 1). [ citation needed ] The preferred initial diagnostic testing is the ECG, which may demonstrate a 12-lead electrocardiogram with diffuse, non-specific, concave ("saddle-shaped"), ST-segment elevations in all leads except aVR and V1 and PR-segment depression possible in any lead except aVR ; sinus tachycardia, and low-voltage QRS complexes can also be seen if there is subsymptomatic levels of pericardial effusion. The PR depression is often seen early in the process as the thin atria are affected more easily than the ventricles by the inflammatory process of the pericardium. [ citation needed ] Since the mid-19th century, retrospective diagnosis of pericarditis has been made upon the finding of adhesions of the pericardium. When pericarditis is diagnosed clinically, the underlying cause is often never known; it may be discovered in only 16–22 percent of people with acute pericarditis. [ citation needed ]On MRI T2-weighted spin-echo images, inflamed pericardium will show high signal intensity. Late gadolinium contrast will show uptake of contrast by the inflamed pericardium. Normal pericardium will not show any contrast enhancement. Pericarditis can be classified according to the composition of the fluid that accumulates around the heart. Types of pericarditis include the following: [ citation needed ] Depending on the time of presentation and duration, pericarditis is divided into "acute" and "chronic" forms. Acute pericarditis is more common than chronic pericarditis, and can occur as a complication of infections, immunologic conditions, or even as a result of a heart attack (myocardial infarction), as Dressler's syndrome . Chronic pericarditis however is less common, a form of which is constrictive pericarditis . The following is the clinical classification of acute vs. chronic: [ citation needed ] Clinically : Acute (6 months)Depending on the time of presentation and duration, pericarditis is divided into "acute" and "chronic" forms. Acute pericarditis is more common than chronic pericarditis, and can occur as a complication of infections, immunologic conditions, or even as a result of a heart attack (myocardial infarction), as Dressler's syndrome . Chronic pericarditis however is less common, a form of which is constrictive pericarditis . The following is the clinical classification of acute vs. chronic: [ citation needed ] Clinically : Acute (6 months)The treatment in viral or idiopathic pericarditis is with aspirin , or non-steroidal anti-inflammatory drugs (NSAIDs such as ibuprofen ). Colchicine may be added to the above as it decreases the risk of further episodes of pericarditis. Severe cases may require one or more of the following: [ citation needed ] Recurrent pericarditis resistant to colchicine and anti-inflammatory steroids may benefit from a number of medicines that affect the action of interleukin 1 ; they cannot be taken in tablet form. These are anakinra , canakinumab and rilonacept . Rilonacept has been specifically approved as an orphan drug for use in this situation. Immunosuppressive agents, such as Azathioprine and intravenous immunoglobulins, are a novel therapeutic agent which have been effective in treating and preventing recurrent pericarditis, though research on these therapies is limited. Surgical removal of the pericardium, pericardiectomy , may be used in severe cases and where the pericarditis is causing constriction, impairing cardiac function. It is less effective if the pericarditis is a consequence of trauma, in elderly patients, and if the procedure is done incompletely. It carries a risk of death between 5 and 10%. About 30% of people with viral pericarditis or pericarditis of an unknown cause have one or several recurrent episodes.

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Acute hemorrhagic fever syndrome

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

Acute liver failure

Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice ) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complications are hepatic encephalopathy and impaired protein synthesis (as measured by the levels of serum albumin and the prothrombin time in the blood). The 1993 classification defines hyperacute as within 1 week, acute as 8–28 days, and subacute as 4–12 weeks; both the speed with which the disease develops and the underlying cause strongly affect outcomes. The main features of acute liver failure are rapid-onset jaundice, weakness, and eventually, changes in mental status that can begin as mild confusion but progress to coma, known as hepatic encephalopathy. In ALF, hepatic encephalopathy leads to cerebral edema , coma , brain herniation , and eventually death. Detection of encephalopathy is central to the diagnosis of ALF. It may vary from subtle deficit in higher brain function (e.g. mood, concentration in grade I) to deep coma (grade IV). Patients presenting as acute and hyperacute liver failure are at greater risk of developing cerebral edema and grade IV encephalopathy. The pathogenesis remains unclear, but is likely to be a consequence of several phenomena. There is a buildup of toxic substances like ammonia , mercaptan , serotonin and tryptophan in the brain. This affects neurotransmitter level and neuroreceptor activation. Autoregulation of cerebral blood flow is impaired, and is associated with anaerobic glycolysis and oxidative stress . Neuronal cell astrocytes are susceptible to these changes, and they swell up, resulting in increased intracranial pressure. Inflammatory mediators also play important role. Unfortunately, signs of elevated intracranial pressure , such as papilledema and loss of pupillary reflexes, are not reliable, and occur late in the disease process. CT imaging of the brain is also unhelpful in detecting early cerebral oedema, but is often performed to rule out intra-cerebral bleeding . Invasive intracranial pressure monitoring via subdural route is often recommended; however, the risk of complications must be weighed against the possible benefit (1% fatal haemorrhage). The aim is to maintain intracranial pressures below 25 mm Hg, and cerebral perfusion pressures above 50 mm Hg. Coagulopathy is another cardinal feature of ALF. The liver has the central role in the synthesis of almost all coagulation factors and some inhibitors of coagulation and fibrinolysis . Hepatocellular necrosis leads to impaired synthesis of many coagulation factors and their inhibitors. The former produces a prolongation in prothrombin time which is widely used to monitor the severity of hepatic injury. There is significant platelet dysfunction (with both quantitative and qualitative platelet defects). Progressive thrombocytopenia with the loss of larger and more active platelets is almost universal. Thrombocytopenia with or without DIC increases risk of intracerebral bleeding. Kidney failure is common, present in more than 50% of ALF patients, either due to original insult such as paracetamol resulting in acute tubular necrosis or from hyperdynamic circulation leading to hepatorenal syndrome or functional kidney failure. Because of impaired production of urea, blood urea does not represent the degree of kidney impairment. [ citation needed ] About 60% of all ALF patients fulfil the criteria for systemic inflammatory syndrome irrespective of presence or absence of infection. This often contributes towards multi organ failure . Impaired host defence mechanism, due to impaired opsonization , chemotaxis and intracellular killing, substantially increases risk of sepsis. Bacterial sepsis mostly due to gram positive organisms and fungal sepsis are observed in up to 80% and 30% patients, respectively. Hyponatraemia is an almost universal finding due to water retention and a shift in intracellular sodium transport from inhibition of Na/K ATPase [ citation needed ] . Hypoglycaemia (due to depleted hepatic glycogen store and hyperinsulinaemia ), hypokalaemia , hypophosphataemia and metabolic alkalosis are often present, independent of renal function. Lactic acidosis occurs predominantly in paracetamol (also known as acetaminophen) overdose . Hyperdynamic circulation , with peripheral vasodilatation from low systemic vascular resistance , leads to hypotension . There is a compensatory increase in cardiac output . Adrenal insufficiency has been documented in 60% of ALF cases, and is likely to contribute in haemodynamic compromise. There is also abnormal oxygen transport and utilization. Although delivery of oxygen to the tissues is adequate, there is a decrease in tissue oxygen uptake, resulting in tissue hypoxia and lactic acidosis. Pulmonary complications occur in up to 50% of patients. Severe lung injury and hypoxemia result in high mortality. Most cases of severe lung injury are due to ARDS , with or without sepsis . Pulmonary haemorrhage , pleural effusions , atelectasis , and intrapulmonary shunts also contribute to respiratory difficulty. In late pregnancy liver function decreases significantly, which can be easily monitored by blood tests. Early clinical manifestations of ALF in late pregnancy include hypodynamia, decrease in appetite, dark amber urine, deep jaundice, nausea, vomiting, and abdominal distention. Among patients whose deaths were attributed to ALF in late pregnancy, the majority had experienced vaginal deliveries. In ALF, hepatic encephalopathy leads to cerebral edema , coma , brain herniation , and eventually death. Detection of encephalopathy is central to the diagnosis of ALF. It may vary from subtle deficit in higher brain function (e.g. mood, concentration in grade I) to deep coma (grade IV). Patients presenting as acute and hyperacute liver failure are at greater risk of developing cerebral edema and grade IV encephalopathy. The pathogenesis remains unclear, but is likely to be a consequence of several phenomena. There is a buildup of toxic substances like ammonia , mercaptan , serotonin and tryptophan in the brain. This affects neurotransmitter level and neuroreceptor activation. Autoregulation of cerebral blood flow is impaired, and is associated with anaerobic glycolysis and oxidative stress . Neuronal cell astrocytes are susceptible to these changes, and they swell up, resulting in increased intracranial pressure. Inflammatory mediators also play important role. Unfortunately, signs of elevated intracranial pressure , such as papilledema and loss of pupillary reflexes, are not reliable, and occur late in the disease process. CT imaging of the brain is also unhelpful in detecting early cerebral oedema, but is often performed to rule out intra-cerebral bleeding . Invasive intracranial pressure monitoring via subdural route is often recommended; however, the risk of complications must be weighed against the possible benefit (1% fatal haemorrhage). The aim is to maintain intracranial pressures below 25 mm Hg, and cerebral perfusion pressures above 50 mm Hg. Coagulopathy is another cardinal feature of ALF. The liver has the central role in the synthesis of almost all coagulation factors and some inhibitors of coagulation and fibrinolysis . Hepatocellular necrosis leads to impaired synthesis of many coagulation factors and their inhibitors. The former produces a prolongation in prothrombin time which is widely used to monitor the severity of hepatic injury. There is significant platelet dysfunction (with both quantitative and qualitative platelet defects). Progressive thrombocytopenia with the loss of larger and more active platelets is almost universal. Thrombocytopenia with or without DIC increases risk of intracerebral bleeding. Kidney failure is common, present in more than 50% of ALF patients, either due to original insult such as paracetamol resulting in acute tubular necrosis or from hyperdynamic circulation leading to hepatorenal syndrome or functional kidney failure. Because of impaired production of urea, blood urea does not represent the degree of kidney impairment. [ citation needed ]About 60% of all ALF patients fulfil the criteria for systemic inflammatory syndrome irrespective of presence or absence of infection. This often contributes towards multi organ failure . Impaired host defence mechanism, due to impaired opsonization , chemotaxis and intracellular killing, substantially increases risk of sepsis. Bacterial sepsis mostly due to gram positive organisms and fungal sepsis are observed in up to 80% and 30% patients, respectively. Hyponatraemia is an almost universal finding due to water retention and a shift in intracellular sodium transport from inhibition of Na/K ATPase [ citation needed ] . Hypoglycaemia (due to depleted hepatic glycogen store and hyperinsulinaemia ), hypokalaemia , hypophosphataemia and metabolic alkalosis are often present, independent of renal function. Lactic acidosis occurs predominantly in paracetamol (also known as acetaminophen) overdose .Hyperdynamic circulation , with peripheral vasodilatation from low systemic vascular resistance , leads to hypotension . There is a compensatory increase in cardiac output . Adrenal insufficiency has been documented in 60% of ALF cases, and is likely to contribute in haemodynamic compromise. There is also abnormal oxygen transport and utilization. Although delivery of oxygen to the tissues is adequate, there is a decrease in tissue oxygen uptake, resulting in tissue hypoxia and lactic acidosis. Pulmonary complications occur in up to 50% of patients. Severe lung injury and hypoxemia result in high mortality. Most cases of severe lung injury are due to ARDS , with or without sepsis . Pulmonary haemorrhage , pleural effusions , atelectasis , and intrapulmonary shunts also contribute to respiratory difficulty.In late pregnancy liver function decreases significantly, which can be easily monitored by blood tests. Early clinical manifestations of ALF in late pregnancy include hypodynamia, decrease in appetite, dark amber urine, deep jaundice, nausea, vomiting, and abdominal distention. Among patients whose deaths were attributed to ALF in late pregnancy, the majority had experienced vaginal deliveries. Common causes for acute liver failure are paracetamol (acetaminophen) overdose , idiosyncratic reaction to medication (e.g. tetracycline , troglitazone ), excessive alcohol consumption (severe alcoholic hepatitis ), viral hepatitis ( hepatitis A or B —it is extremely uncommon in hepatitis C ), acute fatty liver of pregnancy , and idiopathic (without an obvious cause). Reye syndrome is acute liver failure in a child with a viral infection (e.g. chickenpox ); it appears that aspirin use may play a significant role. Wilson's disease (hereditary copper accumulation) may infrequently present with acute liver failure. Acute liver failure also results from poisoning by the death cap mushroom ( Amanita phalloides ) as well as other amatoxin -producing fungus species. Certain strains of Bacillus cereus —a common species of bacterium implicated as a frequent cause of food poisoning —can cause fulminant liver failure through the production of cereulide , a toxin which destroys the mitochondria in affected hepatocytes , resulting in cell death. While most instances of B. cereus infection are resolved by the body's immune system and do not affect the liver, severe cases resulting in liver damage can be fatal without immediate treatment or liver transplantation .In the majority of acute liver failure (ALF) there is widespread hepatocellular necrosis beginning in the centrizonal distribution and progressing towards portal tracts . The degree of parenchymal inflammation is variable and is proportional to duration of disease . Zone 1 (periportal) occurs in phosphorus poisoning or eclampsia. Zone 2 (mid-zonal), although rare, is seen in yellow fever . Zone 3 (centrilobular) occurs with ischemic injury, toxic effects, carbon tetrachloride exposure, or chloroform ingestion. In acute acetaminophen overdose, toxification occurs, mostly in Zone III which has the highest level of P450 micro-enzymes. That fact along with Zone III's decreased oxygen level helps to explain why it is preferentially one of the initial sites of damage.All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have an immediate measurement of prothrombin time and careful evaluation of mental status. If the prothrombin time is prolonged by ≈ 4–6 seconds or more (INR ≥ 1.5), and there is any evidence of altered sensorium , the diagnosis of ALF should be strongly suspected, and hospital admission is mandatory. Initial laboratory examination must be extensive in order to evaluate both the etiology and severity. History taking should include a careful review of possible exposures to viral infection and drugs or other toxins. From history and clinical examination, the possibility of underlying chronic disease should be ruled out as it may require different management. A liver biopsy done via the transjugular route because of coagulopathy is not usually necessary, other than in occasional malignancies. As the evaluation continues, several important decisions have to be made; such as whether to admit the patient to an ICU, or whether to transfer the patient to a transplant facility. Consultation with the transplant center as early as possible is critical due to the possibility of rapid progression of ALF. Acute liver failure is defined as "the rapid development of hepatocellular dysfunction, specifically coagulopathy and mental status changes (encephalopathy) in a patient without known prior liver disease". page 1557 The diagnosis of acute liver failure is based on physical exam, laboratory findings, patient history, and past medical history to establish mental status changes, coagulopathy, rapidity of onset, and absence of known prior liver disease respectively. page 1557 The exact definition of "rapid" is somewhat questionable, and different sub-divisions exist which are based on the time from onset of first hepatic symptoms to onset of encephalopathy. One scheme defines "acute hepatic failure" as the development of encephalopathy within 26 weeks of the onset of any hepatic symptoms. This is sub-divided into "fulminant hepatic failure", which requires onset of encephalopathy within 8 weeks, and "subfulminant", which describes onset of encephalopathy after 8 weeks but before 26 weeks. Another scheme defines "hyperacute" as onset within 7 days, "acute" as onset between 7 and 28 days, and "subacute" as onset between 28 days and 24 weeks. page 1557Acute liver failure is defined as "the rapid development of hepatocellular dysfunction, specifically coagulopathy and mental status changes (encephalopathy) in a patient without known prior liver disease". page 1557 The diagnosis of acute liver failure is based on physical exam, laboratory findings, patient history, and past medical history to establish mental status changes, coagulopathy, rapidity of onset, and absence of known prior liver disease respectively. page 1557 The exact definition of "rapid" is somewhat questionable, and different sub-divisions exist which are based on the time from onset of first hepatic symptoms to onset of encephalopathy. One scheme defines "acute hepatic failure" as the development of encephalopathy within 26 weeks of the onset of any hepatic symptoms. This is sub-divided into "fulminant hepatic failure", which requires onset of encephalopathy within 8 weeks, and "subfulminant", which describes onset of encephalopathy after 8 weeks but before 26 weeks. Another scheme defines "hyperacute" as onset within 7 days, "acute" as onset between 7 and 28 days, and "subacute" as onset between 28 days and 24 weeks. page 1557for liver transplantation in acute liver failure pH 100 seconds and serum creatinine level > 3.4 mg/dL (> 300 μmol/L) if in grade III or IV encephalopathy Prothrombin time > 100 seconds or Three of the following variables : Age 40 years Cause: Hepatitis C or E halothane hepatitis idiosyncratic drug reaction Duration of jaundice before encephalopathy > 7 days Prothrombin time > 50 seconds Serum bilirubin level > 17.6 mg/dL (> 300 μmol/L) Because ALF often involves the rapid deterioration of mental status and the potential for multiorgan failure, patients should be managed in the intensive care unit. For patients not at a transplant center, the possibility of rapid progression of ALF makes early consultation with a transplant facility critical. Accordingly, plans for transfer to a transplant center should begin in patients with any abnormal mentation. Early institution of antidotes or specific therapy may prevent the need for liver transplantation and reduce the likelihood of poor outcome. Measures appropriate for specific causes of ALF are described in detail later in this chapter. Patients with grade I–II encephalopathy should be transferred to a liver transplant facility and listed for transplantation. Consider a brain computed tomography (CT) scan to rule out other causes of altered or impaired mental status. Stimulation and overhydration can cause elevations in intracranial pressure (ICP) and should be avoided. Unmanageable agitation may be treated with short-acting benzodiazepines in small doses. Lactulose can be considered at this stage. A preliminary report from the ALFSG on 117 patients suggests that use of lactulose in the first 7 days after diagnosis is associated with a small increase in survival time, but with no difference in severity of encephalopathy or in the overall outcome. For patients who progress to grade III–IV encephalopathy, intubation for airway protection is generally required. Many centers use propofol for sedation because it may reduce cerebral blood. The head of the bed should be elevated to 30 degrees, and electrolytes, blood gasses, glucose, and neurologic status monitored frequently. Increased cardiac output and low systemic vascular resistance are characteristic of ALF. Pulmonary artery catheterization should be considered. Hypotension should be treated preferentially with fluids, but systemic vasopressor support with agents such as epinephrine, norepinephrine, or dopamine should be used if fluid replacement fails to maintain mean arterial pressure of 50–60 mm Hg. Vasoconstrictive agents (especially vasopressin) should be avoided. Pulmonary edema and pulmonary infections are commonly seen in patients with ALF. Mechanical ventilation may be required. However, positive end-expiratory pressure can worsen cerebral edema. Impaired liver synthesis of clotting factors, low-grade fibrinolysis, and intravascular coagulation are typical of ALF. Thrombocytopenia is common and may also be dysfunctional. Replacement therapy is recommended only in the setting of bleeding or prior to an invasive procedure. Vitamin K can be given to treat an abnormal prothrombin time, regardless of whether there is poor nutritional status. Administration of recombinant factor VIIa has shown promise; however, this treatment approach requires further study. The use of gastrointestinal hemorrhage prophylaxis with a histamine-2 (H2) blocker , proton pump inhibitor , or sucralfate is recommended. In patients with grade I or II encephalopathy, enteral feeding should be initiated early. Parenteral nutrition should be used only if enteral feeding is contraindicated as it increases the risk of infection. Severe restriction of protein is not beneficial; 60 g/day of protein is generally reasonable. Fluid replacement with colloid (e.g. albumin) is preferred rather than crystalloid (e.g. saline); all solutions should contain dextrose to maintain euglycemia. Multiple electrolyte abnormalities are common in ALF. Correction of hypokalemia is essential as hypokalemia increases the kidneys' ammonia production, potentially exacerbating encephalopathy. Hypophosphatemia is especially common in patients with acetaminophen-induced ALF and in those with intact renal function. Hypoglycemia occurs in many patients with ALF and is often due to depletion of hepatic glycogen stores and impaired gluconeogenesis. Plasma glucose concentration should be monitored and hypertonic glucose administered as needed. Bacterial and fungal infections are common in ALF, with one study demonstrating culture-proven infection in 80% of ALF patients. Defective cellular and humoral immunity as well as presence of indwelling catheters, coma, broad-spectrum antibiotics, and medications that suppress immunity all predispose to infection. Localizing symptoms of infection such as fever and sputum production are frequently absent and the only clues to an underlying infectious process may be worsening of encephalopathy or renal function. There must be a low threshold for obtaining frequent cultures (blood, urine, and sputum), chest radiographs, and paracentesis. Bacteria that enter through the skin, such as streptococci and staphylococci, tend to predominate. Aggressive surveillance is essential as prophylactic antibiotics have shown little benefit. Fungal infections, particularly in the setting of broad-spectrum antibiotics, are also common, and disseminated fungemia is a poor prognostic sign. The advent of transplantation has changed survival from as low as 15% in the pretransplant era to more than 60% today. Liver transplantation is indicated for many patients with ALF, and survival rates of 56–90% can be achieved. In addition to transplantation, better critical care and the trend toward more benign causes, such as acetaminophen, all contribute to improved survival rates. Spontaneous survival is now around 40%. The application of transplantation among patients with ALF remains low, suggesting that the full potential of this modality may not be realized. Timely availability of an allograft is one of the major factors determining transplant outcomes. In the largest U.S. study, only 29% of patients received a liver graft, while 10% of the overall group (one fourth of patients listed for transplantation) died on the waiting list. Other series have reported death rates of those listed for transplant as high as 40%. In the ALFSG, the transplantation rate was higher in the groups with lower short-term spontaneous survival, making overall survival similar in all groups: acetaminophen, 73%; drug induced, 70%; indeterminate group, 64%; and other causes, 61%. Causes of death for the 101 patients who died within the 3-week period included cerebral edema, multiorgan failure, sepsis, cardiac arrhythmia or arrest and respiratory failure. The median time to death after admission was 5 days. Intravenous N-acetylcysteine has been found to be beneficial in acetaminophen toxicity but not in non-acetaminophen-related acute liver failure. Because ALF often involves the rapid deterioration of mental status and the potential for multiorgan failure, patients should be managed in the intensive care unit. For patients not at a transplant center, the possibility of rapid progression of ALF makes early consultation with a transplant facility critical. Accordingly, plans for transfer to a transplant center should begin in patients with any abnormal mentation. Early institution of antidotes or specific therapy may prevent the need for liver transplantation and reduce the likelihood of poor outcome. Measures appropriate for specific causes of ALF are described in detail later in this chapter. Patients with grade I–II encephalopathy should be transferred to a liver transplant facility and listed for transplantation. Consider a brain computed tomography (CT) scan to rule out other causes of altered or impaired mental status. Stimulation and overhydration can cause elevations in intracranial pressure (ICP) and should be avoided. Unmanageable agitation may be treated with short-acting benzodiazepines in small doses. Lactulose can be considered at this stage. A preliminary report from the ALFSG on 117 patients suggests that use of lactulose in the first 7 days after diagnosis is associated with a small increase in survival time, but with no difference in severity of encephalopathy or in the overall outcome. For patients who progress to grade III–IV encephalopathy, intubation for airway protection is generally required. Many centers use propofol for sedation because it may reduce cerebral blood. The head of the bed should be elevated to 30 degrees, and electrolytes, blood gasses, glucose, and neurologic status monitored frequently. Increased cardiac output and low systemic vascular resistance are characteristic of ALF. Pulmonary artery catheterization should be considered. Hypotension should be treated preferentially with fluids, but systemic vasopressor support with agents such as epinephrine, norepinephrine, or dopamine should be used if fluid replacement fails to maintain mean arterial pressure of 50–60 mm Hg. Vasoconstrictive agents (especially vasopressin) should be avoided. Pulmonary edema and pulmonary infections are commonly seen in patients with ALF. Mechanical ventilation may be required. However, positive end-expiratory pressure can worsen cerebral edema. Impaired liver synthesis of clotting factors, low-grade fibrinolysis, and intravascular coagulation are typical of ALF. Thrombocytopenia is common and may also be dysfunctional. Replacement therapy is recommended only in the setting of bleeding or prior to an invasive procedure. Vitamin K can be given to treat an abnormal prothrombin time, regardless of whether there is poor nutritional status. Administration of recombinant factor VIIa has shown promise; however, this treatment approach requires further study. The use of gastrointestinal hemorrhage prophylaxis with a histamine-2 (H2) blocker , proton pump inhibitor , or sucralfate is recommended. In patients with grade I or II encephalopathy, enteral feeding should be initiated early. Parenteral nutrition should be used only if enteral feeding is contraindicated as it increases the risk of infection. Severe restriction of protein is not beneficial; 60 g/day of protein is generally reasonable. Fluid replacement with colloid (e.g. albumin) is preferred rather than crystalloid (e.g. saline); all solutions should contain dextrose to maintain euglycemia. Multiple electrolyte abnormalities are common in ALF. Correction of hypokalemia is essential as hypokalemia increases the kidneys' ammonia production, potentially exacerbating encephalopathy. Hypophosphatemia is especially common in patients with acetaminophen-induced ALF and in those with intact renal function. Hypoglycemia occurs in many patients with ALF and is often due to depletion of hepatic glycogen stores and impaired gluconeogenesis. Plasma glucose concentration should be monitored and hypertonic glucose administered as needed. Bacterial and fungal infections are common in ALF, with one study demonstrating culture-proven infection in 80% of ALF patients. Defective cellular and humoral immunity as well as presence of indwelling catheters, coma, broad-spectrum antibiotics, and medications that suppress immunity all predispose to infection. Localizing symptoms of infection such as fever and sputum production are frequently absent and the only clues to an underlying infectious process may be worsening of encephalopathy or renal function. There must be a low threshold for obtaining frequent cultures (blood, urine, and sputum), chest radiographs, and paracentesis. Bacteria that enter through the skin, such as streptococci and staphylococci, tend to predominate. Aggressive surveillance is essential as prophylactic antibiotics have shown little benefit. Fungal infections, particularly in the setting of broad-spectrum antibiotics, are also common, and disseminated fungemia is a poor prognostic sign. The advent of transplantation has changed survival from as low as 15% in the pretransplant era to more than 60% today. Liver transplantation is indicated for many patients with ALF, and survival rates of 56–90% can be achieved. In addition to transplantation, better critical care and the trend toward more benign causes, such as acetaminophen, all contribute to improved survival rates. Spontaneous survival is now around 40%. The application of transplantation among patients with ALF remains low, suggesting that the full potential of this modality may not be realized. Timely availability of an allograft is one of the major factors determining transplant outcomes. In the largest U.S. study, only 29% of patients received a liver graft, while 10% of the overall group (one fourth of patients listed for transplantation) died on the waiting list. Other series have reported death rates of those listed for transplant as high as 40%. In the ALFSG, the transplantation rate was higher in the groups with lower short-term spontaneous survival, making overall survival similar in all groups: acetaminophen, 73%; drug induced, 70%; indeterminate group, 64%; and other causes, 61%. Causes of death for the 101 patients who died within the 3-week period included cerebral edema, multiorgan failure, sepsis, cardiac arrhythmia or arrest and respiratory failure. The median time to death after admission was 5 days. Intravenous N-acetylcysteine has been found to be beneficial in acetaminophen toxicity but not in non-acetaminophen-related acute liver failure. Historically mortality has been high, being in excess of 80%. In recent years the advent of liver transplantation and multidisciplinary intensive care support have improved survival significantly. At present overall short-term survival with transplant is more than 65%. Several prognostic scoring systems have been devised to predict mortality and to identify who will require an early liver transplant. These include King's College Hospital criteria , MELD score , and Clichy criteria . To date, no universally accepted nomenclature has been adopted. Trey and Davidson introduced the phrase fulminant hepatic failure in 1970, which they described as a "... potentially reversible condition, the consequence of severe liver injury, with an onset of encephalopathy within 8 weeks of the appearance of the first symptoms and in the absence of pre-existing liver disease". Later, it was suggested that the term fulminant should be confined to patients who develop jaundice to encephalopathy within 2 weeks. Phrases subfulminant hepatic failure and late onset hepatic failure were coined for onset between 2 weeks to 3 months and for 8 weeks to 24 weeks, respectively. The umbrella phrase of acute liver failure was proposed by King's College group, which has been adopted in this article. Paradoxically, in this classification, the best prognosis is in the hyperacute group.

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Acute hemorrhagic fever syndrome

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Vasculitis

Vasculitis is a group of disorders that destroy blood vessels by inflammation . Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels ) is sometimes considered a type of vasculitis. Vasculitis is primarily caused by leukocyte migration and resultant damage. Although both occur in vasculitis, inflammation of veins ( phlebitis ) or arteries ( arteritis ) on their own are separate entities.Possible signs and symptoms include: There are several different etiologies for vasculitides. Although infections usually involve vessels as a component of more extensive tissue damage, they can also directly or indirectly cause vasculitic syndromes through immune-mediated secondary events. Simple vascular thrombosis usually only affects the luminal process, but through the process of thrombus organization, it can also occasionally cause a more chronic vasculitic syndrome. The autoimmune etiologies, a particular family of diseases characterized by dysregulated immune responses that produce particular pathophysiologic signs and symptoms, are more prevalent. Primary systemic, secondary, and single-organ vasculitis are distinguished using the highest classification level in the 2012 Chapel Hill Consensus Conference nomenclature. Primary systemic vasculitis is catogized by the size of the vessels mainly involved. Primary systemic vasculitis includes large-vessel vasculitis, medium-vessel vasculitis, small-vessel vasculitis, and variable-vessel vasculitis. The 2012 Chapel Hill Consensus Conference defines large vessel vasculitis (LVV) as a type of vasculitis that can affect any size artery, but it usually affects the aorta and its major branches more frequently than other vasculitides. Takayasu arteritis (TA) and giant cell arteritis (GCA) are the two main forms of LVV. Medium vessel vasculitis (MVV) is a type of vasculitis that mostly affects the medium arteries, which are the major arteries that supply the viscera and their branches. Any size artery could be impacted, though. The two primary types are polyarteritis nodosa (PAN) and Kawasaki disease (KD). Small vessel vasculitis (SVV) is separated into immune complex SVV and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a necrotizing vasculitis linked to MPO-ANCA or PR3-ANCA that primarily affects small vessels and has few or no immune deposits. AAV is further classified as eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), granulomatosis with polyangiitis (Wegener's) (GPA), and microscopic polyangiitis (MPA). Immune complex small vessel vasculitis (SVV) is vasculitis that primarily affects small vessels and has moderate to significant immunoglobulin and complement component deposits on the vessel wall. Normocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis), cryoglobulinemic vasculitis (CV), IgA vasculitis (Henoch-Schönlein) (IgAV), and anti-glomerular basement membrane (anti-GBM) disease are the categories of immune complex SVV. Variable vessel vasculitis (VVV) is a kind of vasculitis that may impact vessels of all sizes (small, medium, and large) and any type (arteries, veins, and capillaries), with no particular type of vessel being predominantly affected. This category includes Behcet's disease (BD) and Cogan's syndrome (CS). The subset of illnesses known as secondary vasculitis are those believed to be brought on by an underlying ailment or exposure. Systemic illnesses (such as rheumatoid arthritis ), cancer, drug exposure, and infection are the primary causes of vasculitis; however, there are still few factors that have a conclusively shown pathogenic relationship to the condition. Vasculitis frequently coexists with infections, and several infections, including hepatitis B and C , HIV , infective endocarditis , and tuberculosis , are significant secondary causes of vasculitis. Except for rheumatoid vasculitis , the majority of secondary vasculitis forms are exceedingly rare. Single-organ vasculitis, formerly known as "localized," "limited," "isolated," or "nonsystemic" vasculitis, refers to vasculitis that is limited to one organ or organ system. Examples of this type of vasculitis include gastrointestinal, cutaneous, and peripheral nerve vasculitis. Primary systemic vasculitis is catogized by the size of the vessels mainly involved. Primary systemic vasculitis includes large-vessel vasculitis, medium-vessel vasculitis, small-vessel vasculitis, and variable-vessel vasculitis. The 2012 Chapel Hill Consensus Conference defines large vessel vasculitis (LVV) as a type of vasculitis that can affect any size artery, but it usually affects the aorta and its major branches more frequently than other vasculitides. Takayasu arteritis (TA) and giant cell arteritis (GCA) are the two main forms of LVV. Medium vessel vasculitis (MVV) is a type of vasculitis that mostly affects the medium arteries, which are the major arteries that supply the viscera and their branches. Any size artery could be impacted, though. The two primary types are polyarteritis nodosa (PAN) and Kawasaki disease (KD). Small vessel vasculitis (SVV) is separated into immune complex SVV and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a necrotizing vasculitis linked to MPO-ANCA or PR3-ANCA that primarily affects small vessels and has few or no immune deposits. AAV is further classified as eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), granulomatosis with polyangiitis (Wegener's) (GPA), and microscopic polyangiitis (MPA). Immune complex small vessel vasculitis (SVV) is vasculitis that primarily affects small vessels and has moderate to significant immunoglobulin and complement component deposits on the vessel wall. Normocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis), cryoglobulinemic vasculitis (CV), IgA vasculitis (Henoch-Schönlein) (IgAV), and anti-glomerular basement membrane (anti-GBM) disease are the categories of immune complex SVV. Variable vessel vasculitis (VVV) is a kind of vasculitis that may impact vessels of all sizes (small, medium, and large) and any type (arteries, veins, and capillaries), with no particular type of vessel being predominantly affected. This category includes Behcet's disease (BD) and Cogan's syndrome (CS). The 2012 Chapel Hill Consensus Conference defines large vessel vasculitis (LVV) as a type of vasculitis that can affect any size artery, but it usually affects the aorta and its major branches more frequently than other vasculitides. Takayasu arteritis (TA) and giant cell arteritis (GCA) are the two main forms of LVV. Medium vessel vasculitis (MVV) is a type of vasculitis that mostly affects the medium arteries, which are the major arteries that supply the viscera and their branches. Any size artery could be impacted, though. The two primary types are polyarteritis nodosa (PAN) and Kawasaki disease (KD). Small vessel vasculitis (SVV) is separated into immune complex SVV and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a necrotizing vasculitis linked to MPO-ANCA or PR3-ANCA that primarily affects small vessels and has few or no immune deposits. AAV is further classified as eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), granulomatosis with polyangiitis (Wegener's) (GPA), and microscopic polyangiitis (MPA). Immune complex small vessel vasculitis (SVV) is vasculitis that primarily affects small vessels and has moderate to significant immunoglobulin and complement component deposits on the vessel wall. Normocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis), cryoglobulinemic vasculitis (CV), IgA vasculitis (Henoch-Schönlein) (IgAV), and anti-glomerular basement membrane (anti-GBM) disease are the categories of immune complex SVV. Variable vessel vasculitis (VVV) is a kind of vasculitis that may impact vessels of all sizes (small, medium, and large) and any type (arteries, veins, and capillaries), with no particular type of vessel being predominantly affected. This category includes Behcet's disease (BD) and Cogan's syndrome (CS). The subset of illnesses known as secondary vasculitis are those believed to be brought on by an underlying ailment or exposure. Systemic illnesses (such as rheumatoid arthritis ), cancer, drug exposure, and infection are the primary causes of vasculitis; however, there are still few factors that have a conclusively shown pathogenic relationship to the condition. Vasculitis frequently coexists with infections, and several infections, including hepatitis B and C , HIV , infective endocarditis , and tuberculosis , are significant secondary causes of vasculitis. Except for rheumatoid vasculitis , the majority of secondary vasculitis forms are exceedingly rare. Single-organ vasculitis, formerly known as "localized," "limited," "isolated," or "nonsystemic" vasculitis, refers to vasculitis that is limited to one organ or organ system. Examples of this type of vasculitis include gastrointestinal, cutaneous, and peripheral nerve vasculitis. In this table: ANA = antinuclear antibodies, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, ds DNA = double-stranded DNA, ENA = extractable nuclear antigens, RNP = ribonucleoproteins; VDRL = Venereal Disease Research LaboratoryTreatments are generally directed toward stopping the inflammation and suppressing the immune system. Typically, corticosteroids such as prednisone are used. Additionally, other immune suppression medications, such as cyclophosphamide and others, are considered. In case of an infection, antimicrobial agents including cephalexin may be prescribed. Affected organs (such as the heart or lungs) may require specific medical treatment intended to improve their function during the active phase of the disease. [ citation needed ]

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Acute hemorrhagic fever syndrome

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List of diseases (A)

This is a list of diseases starting with the letter "A".

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Acute hemorrhagic fever syndrome

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Scrub typhus

Scrub typhus or bush typhus is a form of typhus caused by the intracellular parasite Orientia tsutsugamushi , a Gram-negative α-proteobacterium of family Rickettsiaceae first isolated and identified in 1930 in Japan. Although the disease is similar in presentation to other forms of typhus , its pathogen is no longer included in genus Rickettsia with the typhus bacteria proper, but in Orientia . The disease is thus frequently classified separately from the other typhi.Signs and symptoms include fever , headache , muscle pain, cough , and gastrointestinal symptoms . More virulent strains of O. tsutsugamushi can cause hemorrhaging and intravascular coagulation . Morbilliform rash, eschar , splenomegaly , and lymphadenopathies are typical signs. Leukopenia and abnormal liver function tests are commonly seen in the early phase of the illness. Pneumonitis , encephalitis , and myocarditis occur in the late phase of illness. It has particularly been shown to be the most common cause of acute encephalitis syndrome in Bihar, India. Scrub typhus is transmitted by some species of trombiculid mites (" chiggers ", particularly Leptotrombidium deliense ), which are found in areas of heavy scrub vegetation. The mites feed on infected rodent hosts and subsequently transmit the parasite to other rodents and humans. The bite of this mite leaves a characteristic black eschar that is useful to the doctor for making the diagnosis. Scrub typhus is endemic to a part of the world known as the tsutsugamushi triangle (after O. tsutsugamushi ). This extends from northern Japan and far-eastern Russia in the north, to the territories around the Solomon Sea into northern Australia in the south, and to Pakistan and Afghanistan in the west. It may also be endemic in parts of South America. The precise incidence of the disease is unknown, as diagnostic facilities are not available in much of its large native range, which spans vast regions of equatorial jungle to the subtropics. In rural Thailand and Laos, murine and scrub typhus account for around a quarter of all adults presenting to hospital with fever and negative blood cultures. The incidence in Japan has fallen over the past few decades, probably due to land development driving decreasing exposure, and many prefectures report fewer than 50 cases per year. It affects females more than males in Korea, but not in Japan, which may be because sex-differentiated cultural roles have women tending garden plots more often, thus being exposed to vegetation inhabited by chiggers. The incidence is increasing in the southern part of the Indian subcontinent and in northern areas around Darjeeling. [ citation needed ]In endemic areas, diagnosis is generally made on clinical grounds alone. However, overshadowing of the diagnosis is quite often as the clinical symptoms overlap with other infectious diseases such as dengue fever , paratyphoid , and pyrexia of unknown origin (PUO). If the eschar can be identified, it is quite diagnostic of scrub typhus, but this can be unreliable on dark skin, and moreover, the site of eschar which is usually where the mite bites is often located in covered areas. Unless it is actively searched for, the eschar can easily be missed. History of mite bite is often absent since the bite does not inflict pain and the mites are almost too small to be seen by the naked eye. Usually, scrub typhus is often labelled as PUO in remote endemic areas, since blood culture is often negative, yet it can be treated effectively with chloramphenicol. Where doubt exists, the diagnosis may be confirmed by a laboratory test such as serology . Again, this is often unavailable in most endemic areas, since the serological test involved is not included in the routine screening tests for PUO, especially in Burma (Myanmar). [ citation needed ] The choice of laboratory test is not straightforward, and all currently available tests have their limitations. The cheapest and most easily available serological test is the Weil-Felix test , but this is notoriously unreliable. The best test is indirect immunofluorescence , but the main limitation of this method is the availability of fluorescent microscopes, which are not often available in resource-poor settings where scrub typhus is endemic. Indirect immunoperoxidase, a modification of the standard IFA method, can be used with a light microscope, and the results of these tests are comparable to those from IFA. Rapid bedside kits have been described that produce a result within one hour, but the availability of these tests is severely limited by their cost. Serological methods are most reliable when a four-fold rise in antibody titre is found. If the patient is from a nonendemic area, then diagnosis can be made from a single acute serum sample. In patients from endemic areas, this is not possible because antibodies may be found in up to 18% of healthy individuals. Other methods include culture and polymerase chain reaction , but these are not routinely available and the results do not always correlate with serological testing, and are affected by prior antibiotic treatment. The currently available diagnostic methods have been summarised. Without treatment, the disease is often fatal. Since the use of antibiotics, case fatalities have decreased from 4–40% to less than 2%. [ citation needed ] The drug most commonly used is doxycycline or tetracycline , but chloramphenicol is an alternative. Strains that are resistant to doxycycline and chloramphenicol have been reported in northern Thailand. Rifampicin and azithromycin are alternatives. Azithromycin is an alternative in children and pregnant women with scrub typhus, and when doxycycline resistance is suspected. Ciprofloxacin cannot be used safely in pregnancy and is associated with stillbirths and miscarriage . Combination therapy with doxycycline and rifampicin is not recommended due to possible antagonism. No licensed vaccines are available. An early attempt to create a scrub typhus vaccine occurred in the United Kingdom in 1937 (with the Wellcome Foundation infecting around 300,000 cotton rats in a classified project called "Operation Tyburn"), but the vaccine was not used. The first known batch of scrub typhus vaccine actually used to inoculate human subjects was dispatched to India for use by Allied Land Forces, South-East Asia Command in June 1945. By December 1945, 268,000 cc had been dispatched. The vaccine was produced at Wellcome's laboratory at Ely Grange, Frant, Sussex. An attempt to verify the efficacy of the vaccine by using a placebo group for comparison was vetoed by the military commanders, who objected to the experiment. Enormous antigenic variation in Orientia tsutsugamushi strains is now recognized, and immunity to one strain does not confer immunity to another. Any scrub typhus vaccine should give protection to all the strains present locally, to give an acceptable level of protection. A vaccine developed for one locality may not be protective in another, because of antigenic variation. This complexity continues to hamper efforts to produce a viable vaccine. Dora Lush , an Australian bacteriologist , died after accidentally pricking her finger with a needle containing scrub typhus while inoculating a mouse in an attempt to develop a vaccine. Severe epidemics of the disease occurred among troops in Burma and Ceylon during World War II . Several members of the U.S. Army's 5307th Composite Unit ( Merrill's Marauders ) died of the disease, as well as many soldiers in the Burma theatre ; and before 1944, no effective antibiotics or vaccines were available. World War II provides some indicators that the disease is endemic to undeveloped areas in all of Oceania in the Pacific theater , although war records frequently lack definitive diagnoses, and many records of "high fever" evacuations were also likely to be other tropical illnesses. In the chapter entitled "The Green War", General MacArthur 's biographer William Manchester identifies that the disease was one of a number of debilitating afflictions affecting both sides on New Guinea in the running bloody Kokoda battles over extremely harsh terrains under intense hardships— fought during a six-month span all along the Kokoda Track in 1942–43, and mentions that to be hospital-evacuated, Allied soldiers (who cycled forces) had to run a fever of 102 °F (39 °C) , and that sickness casualties outnumbered weapons-inflicted casualties 5:1. Similarly, the illness was a casualty producer in all the jungle fighting of the land battles of the New Guinea campaign and the Guadalcanal campaign . Where the Allies had bases, they could remove and cut back vegetation, or use DDT as a prophylaxis area barrier treatment, so mite- and tick-induced sickness rates in forces off the front lines were diminished. [ citation needed ] The disease was also a problem for US troops stationed in Japan after WWII, and was variously known as "Shichitō fever" (by troops stationed in the Izu Seven Islands ) or "Hatsuka fever" (Chiba prefecture). Scrub typhus was first reported in Chile in 2006. This is likely the result of underdiagnosis and underreporting and not of a recent spread to Chile. In January 2020 the disease was for the first time reported in Chile's southernmost region .

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Acute hemorrhagic fever syndrome

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Legionnaires' disease

Legionnaires' disease is a form of atypical pneumonia caused by any species of Legionella bacteria, quite often Legionella pneumophila . Signs and symptoms include cough, shortness of breath , high fever , muscle pains , and headaches. Nausea, vomiting, and diarrhea may also occur. This often begins 2–10 days after exposure. A legionellosis is any disease caused by Legionella , including Legionnaires' disease (a pneumonia) and Pontiac fever (a related upper respiratory tract infection), but Legionnaires' disease is the most common, so mentions of legionellosis often refer to Legionnaires' disease. The bacterium is found naturally in fresh water . It can contaminate hot water tanks, hot tubs, and cooling towers of large air conditioners . It is usually spread by breathing in mist that contains the bacteria. It can also occur when contaminated water is aspirated . It typically does not spread directly between people, and most people who are exposed do not become infected. Risk factors for infection include older age, a history of smoking, chronic lung disease , and poor immune function . Those with severe pneumonia and those with pneumonia and a recent travel history should be tested for the disease. Diagnosis is by a urinary antigen test and sputum culture . No vaccine is available. Prevention depends on good maintenance of water systems . Treatment of Legionnaires' disease is with antibiotics . Recommended agents include fluoroquinolones , azithromycin , or doxycycline . Hospitalization is often required. The fatality rate is around 10% for healthy persons and 25% for those with underlying conditions. The number of cases that occur globally is not known. Legionnaires' disease is the cause of an estimated 2–9% of pneumonia cases that are acquired outside of a hospital. An estimated 8,000 to 18,000 cases a year in the United States require hospitalization. Outbreaks of disease account for a minority of cases. While it can occur any time of the year, it is more common in the summer and fall. The disease is named after the outbreak where it was first identified , at a 1976 American Legion convention in Philadelphia . The length of time between exposure to the bacteria and the appearance of symptoms ( incubation period ) is generally 2–10 days, but can more rarely extend to as long as 20 days. For the general population, among those exposed, between 0.1 and 5.0% develop the disease, while among those in hospital, between 0.4 and 14% develop the disease. Those with Legionnaires' disease usually have fever, chills, and a cough, which may be dry or may produce sputum . Almost all experience fever, while around half have cough with sputum, and one-third cough up blood or bloody sputum . Some also have muscle aches, headache , tiredness, loss of appetite , loss of coordination ( ataxia ), chest pain, or diarrhea and vomiting . Up to half of those with Legionnaires' disease have gastrointestinal symptoms, and almost half have neurological symptoms, including confusion and impaired cognition. "Relative bradycardia " may also be present, which is low to normal heart rate despite the presence of a fever. Laboratory tests may show that kidney functions, liver functions, and electrolyte levels are abnormal, which may include low sodium in the blood . Chest X-rays often show pneumonia with consolidation in the bottom portion of both lungs. Distinguishing Legionnaires' disease from other types of pneumonia by symptoms or radiologic findings alone is difficult; other tests are required for definitive diagnosis. [ medical citation needed ] People with Pontiac fever, a much milder illness caused by the same bacterium, experience fever and muscle aches without pneumonia. They generally recover in 2–5 days without treatment. For Pontiac fever, the time between exposure and symptoms is generally a few hours to two days. [ medical citation needed ]Over 90% of cases of Legionnaires' disease are caused by Legionella pneumophila . Other types include L. longbeachae , L. feeleii , L. micdadei , and L. anisa . [ citation needed ] Legionnaires' disease is usually spread by the breathing in of aerosolized water or soil contaminated with the Legionella bacteria. Experts have stated that Legionnaires' disease is not transmitted from person to person. In 2014, one case of possible spread from someone sick to the caregiver occurred. Rarely, it has been transmitted by direct contact between contaminated water and surgical wounds. The bacteria grow best at warm temperatures and thrive at water temperatures between 25 and 45 °C (77 and 113 °F) , with an optimum temperature of 35 °C (95 °F) . Temperatures above 60 °C (140 °F) kill the bacteria. Sources where temperatures allow the bacteria to thrive include hot water tanks, cooling towers, and evaporative condensers of large air conditioning systems, such as those commonly found in hotels and large office buildings. Pre-1988, energy conservation programs from the late 1970s and early 1980s still mandated a maximum hot water generation, storage and distribution temperature of 110 °F (43 °C) , unknowingly, legionella bacteria's ideal breeding temperature. To minimize risks of bacterial growth, the American Society of Heating, Refrigerating and Air-Conditioning Engineers' 1988 ASHRAE Standard 188 and subsequent ASHRAE Guideline 12-2000 increased recommended hot water generation and storage temperatures to 135–140 °F (57–60 °C) with minimum distribution temperatures of 124 °F (51 °C) . Though the first known outbreak was in Philadelphia, cases of legionellosis have occurred throughout the world. L. pneumophila thrives in aquatic systems, where it is established within amoebae in a symbiotic relationship . Legionella bacteria survive in water as intracellular parasites of water-dwelling protozoa, such as amoebae . Amoebae are often part of biofilms , and once Legionella and infected amoebae are protected within a biofilm, they are particularly difficult to destroy. In the built environment, central air conditioning systems in office buildings, hotels, and hospitals are sources of contaminated water. Other places the bacteria can dwell include cooling towers used in industrial cooling systems, evaporative coolers , nebulizers , humidifiers , whirlpool spas , hot water systems, showers, windshield washers, fountains, room-air humidifiers, ice-making machines, and misting systems typically found in grocery-store produce sections. The bacteria may also be transmitted from contaminated aerosols generated in hot tubs if the disinfection and maintenance programs are not followed rigorously. Freshwater ponds, creeks, and ornamental fountains are potential sources of Legionella . The disease is particularly associated with hotels, fountains, cruise ships , and hospitals with complex potable water systems and cooling systems. Respiratory-care devices such as humidifiers and nebulizers used with contaminated tap water may contain Legionella species, so using sterile water is very important. Other sources include exposure to potting mix and compost. Legionnaires' disease is usually spread by the breathing in of aerosolized water or soil contaminated with the Legionella bacteria. Experts have stated that Legionnaires' disease is not transmitted from person to person. In 2014, one case of possible spread from someone sick to the caregiver occurred. Rarely, it has been transmitted by direct contact between contaminated water and surgical wounds. The bacteria grow best at warm temperatures and thrive at water temperatures between 25 and 45 °C (77 and 113 °F) , with an optimum temperature of 35 °C (95 °F) . Temperatures above 60 °C (140 °F) kill the bacteria. Sources where temperatures allow the bacteria to thrive include hot water tanks, cooling towers, and evaporative condensers of large air conditioning systems, such as those commonly found in hotels and large office buildings. Pre-1988, energy conservation programs from the late 1970s and early 1980s still mandated a maximum hot water generation, storage and distribution temperature of 110 °F (43 °C) , unknowingly, legionella bacteria's ideal breeding temperature. To minimize risks of bacterial growth, the American Society of Heating, Refrigerating and Air-Conditioning Engineers' 1988 ASHRAE Standard 188 and subsequent ASHRAE Guideline 12-2000 increased recommended hot water generation and storage temperatures to 135–140 °F (57–60 °C) with minimum distribution temperatures of 124 °F (51 °C) . Though the first known outbreak was in Philadelphia, cases of legionellosis have occurred throughout the world. L. pneumophila thrives in aquatic systems, where it is established within amoebae in a symbiotic relationship . Legionella bacteria survive in water as intracellular parasites of water-dwelling protozoa, such as amoebae . Amoebae are often part of biofilms , and once Legionella and infected amoebae are protected within a biofilm, they are particularly difficult to destroy. In the built environment, central air conditioning systems in office buildings, hotels, and hospitals are sources of contaminated water. Other places the bacteria can dwell include cooling towers used in industrial cooling systems, evaporative coolers , nebulizers , humidifiers , whirlpool spas , hot water systems, showers, windshield washers, fountains, room-air humidifiers, ice-making machines, and misting systems typically found in grocery-store produce sections. The bacteria may also be transmitted from contaminated aerosols generated in hot tubs if the disinfection and maintenance programs are not followed rigorously. Freshwater ponds, creeks, and ornamental fountains are potential sources of Legionella . The disease is particularly associated with hotels, fountains, cruise ships , and hospitals with complex potable water systems and cooling systems. Respiratory-care devices such as humidifiers and nebulizers used with contaminated tap water may contain Legionella species, so using sterile water is very important. Other sources include exposure to potting mix and compost. Legionella spp. enter the lungs either by aspiration of contaminated water or inhalation of aerosolized contaminated water or soil. In the lung, the bacteria are consumed by macrophages , a type of white blood cell , inside of which the Legionella bacteria multiply, causing the death of the macrophage. Once the macrophage dies, the bacteria are released from the dead cell to infect other macrophages. Virulent strains of Legionella kill macrophages by blocking the fusion of phagosomes with lysosomes inside the host cell; normally, the bacteria are contained inside the phagosome, which merges with a lysosome, allowing enzymes and other chemicals to break down the invading bacteria. People of any age may develop Legionnaires' disease, but the illness most often affects middle-aged and older people, particularly those who smoke cigarettes or have chronic lung disease. Immunocompromised people are also at higher risk. Pontiac fever most commonly occurs in those who are otherwise healthy. [ citation needed ] The most useful diagnostic tests detect the bacteria in coughed-up mucus , find Legionella antigens in urine samples, or allow comparison of Legionella antibody levels in two blood samples taken 3–6 weeks apart. A urine antigen test is simple, quick, and very reliable, but only detects L. pneumophila serogroup 1, which accounts for 70% of disease caused by L. pneumophila , which means use of the urine antigen test alone may miss as many as 30% of cases. This test was developed by Richard Kohler in 1982. When dealing with L. pneumophila serogroup 1, the urine antigen test is useful for early detection of Legionnaire's disease and initiation of treatment, and has been helpful in early detection of outbreaks. However, it does not identify the specific subtypes, so it cannot be used to match the person with the environmental source of infection. The Legionella bacteria can be cultured from sputum or other respiratory samples. Legionella spp. stain poorly with Gram stain, stain positive with silver, and are cultured on charcoal yeast extract with iron and cysteine ( CYE agar ). [ citation needed ] A significant under-reporting problem occurs with legionellosis. Even in countries with effective health services and readily available diagnostic testing, about 90% of cases of Legionnaires' disease are missed. This is partly due to the disease being a relatively rare form of pneumonia, which many clinicians may not have encountered before, thus may misdiagnose. A further issue is that people with legionellosis can present with a wide range of symptoms, some of which (such as diarrhea) may distract clinicians from making a correct diagnosis. Although the risk of Legionnaires' disease being spread by large-scale water systems cannot be eliminated, it can be greatly reduced by writing and enforcing a highly detailed, systematic water safety plan appropriate for the specific facility involved (office building, hospital, hotel, spa, cruise ship, etc.) Some of the elements that such a plan may include are: An effective water safety plan also covers such matters as training, record-keeping, communication among staff, contingency plans, and management responsibilities. The format and content of the plan may be prescribed by public health laws or regulations. To inform the water safety plan, the undertaking of a site specific legionella risk assessment is often recommended in the first instance. The legionella risk assessment identifies the hazards, the level of risk they pose and provides recommendations of control measures to put place within the overarching water safety plan .Effective antibiotics include most macrolides , tetracyclines , ketolides , and quinolones . Legionella spp. multiply within the cell, so any effective treatment must have excellent intracellular penetration. Current treatments of choice are the respiratory tract quinolones ( levofloxacin , moxifloxacin , gemifloxacin ) or newer macrolides ( azithromycin , clarithromycin , roxithromycin ). The antibiotics used most frequently have been levofloxacin, doxycycline , and azithromycin. [ citation needed ] Macrolides (azithromycin) are used in all age groups, while tetracyclines (doxycycline) are prescribed for children above the age of 12 and quinolones (levofloxacin) above the age of 18. Rifampicin can be used in combination with a quinolone or macrolide. Whether rifampicin is an effective antibiotic to take for treatment is uncertain. The Infectious Diseases Society of America does not recommend the use of rifampicin with added regimens. Tetracyclines and erythromycin led to improved outcomes compared to other antibiotics in the original American Legion outbreak. These antibiotics are effective because they have excellent intracellular penetration in Legionella -infected cells. The recommended treatment is 5–10 days of levofloxacin or 3–5 days of azithromycin, but in people who are immunocompromised, have severe disease, or other pre-existing health conditions, longer antibiotic use may be necessary. During outbreaks, prophylactic antibiotics have been used to prevent Legionnaires' disease in high-risk individuals who have possibly been exposed. The mortality at the original American Legion convention in 1976 was high (29 deaths in 182 infected individuals ) because the antibiotics used (including penicillins , cephalosporins , and aminoglycosides ) had poor intracellular penetration. Mortality has plunged to less than 5% if therapy is started quickly. Delay in giving the appropriate antibiotic leads to higher mortality. [ medical citation needed ]The fatality rate of Legionnaires' disease has ranged from 5–30% during various outbreaks and approaches 50% for nosocomial infections , especially when treatment with antibiotics is delayed. Hospital-acquired Legionella pneumonia has a fatality rate of 28%, and the principal source of infection in such cases is the drinking-water distribution system . Legionnaires' disease acquired its name in July 1976, when an outbreak of pneumonia occurred among people attending a convention of the American Legion at the Bellevue-Stratford Hotel in Philadelphia. Of the 182 reported cases, mostly men, 29 died. On 18 January 1977, the causative agent was identified as a previously unknown strain of bacteria, subsequently named Legionella , and the species that caused the outbreak was named Legionella pneumophila . Following this discovery, unexplained outbreaks of severe respiratory disease from the 1950s were retrospectively attributed to Legionella . Legionnaires' disease also became a prominent historical example of an emerging infectious disease . Outbreaks of Legionnaires' disease receive significant media attention, but this disease usually occurs in single, isolated cases not associated with any recognized outbreak. When outbreaks do occur, they are usually in the summer and early autumn, though cases may occur at any time of year. Most infections occur in those who are middle-aged or older. National surveillance systems and research studies were established early, and in recent years, [ when? ] improved ascertainment and changes in clinical methods of diagnosis have contributed to an upsurge in reported cases in many countries. Environmental studies continue to identify novel sources of infection, leading to regular revisions of guidelines and regulations. About 8,000 to 18,000 cases of Legionnaires' disease occur each year in the United States, according to the Bureau of Communicable Disease Control. Between 1995 and 2005, over 32,000 cases of Legionnaires' disease and more than 600 outbreaks were reported to the European Working Group for Legionella Infections . The data on Legionella are limited in developing countries, and Legionella -related illnesses likely are underdiagnosed worldwide. Improvements in diagnosis and surveillance in developing countries would be expected to reveal far higher levels of morbidity and mortality than are currently recognised. Similarly, improved diagnosis of human illness related to Legionella species and serogroups other than Legionella pneumophila would improve knowledge about their incidence and spread. [ citation needed ] A 2011 study successfully used modeling to predict the likely number of cases during Legionnaires' outbreaks based on symptom onset dates from past outbreaks. In this way, the eventual likely size of an outbreak can be predicted, enabling efficient and effective use of public-health resources in managing an outbreak. During the COVID-19 pandemic , some researchers and organisations raised concerns about the impact of the COVID-19 lockdowns on Legionnaire's disease outbreaks. Additionally, at least two people in England died from a co-infection of Legionella and SARS-CoV-2 . An outbreak is defined as two or more cases where the onset of illness is closely linked in time (weeks rather than months) and space, where a suspicion or evidence exists of a common source of infection, with or without microbiological support ( i.e. common spatial location of cases from travel history). An outbreak is defined as two or more cases where the onset of illness is closely linked in time (weeks rather than months) and space, where a suspicion or evidence exists of a common source of infection, with or without microbiological support ( i.e. common spatial location of cases from travel history).

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Acute hemorrhagic fever syndrome

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Behçet's disease

Behçet disease Behçet's syndrome Morbus Behçet Silk Road disease Behçet's disease ( BD ) is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful sores on the mucous membranes of the mouth and other parts of the body, inflammation of parts of the eye, and arthritis . The sores can last from a few days, up to a week or more. Less commonly there may be inflammation of the brain or spinal cord, blood clots , aneurysms , or blindness . Often, the symptoms come and go. The cause is unknown. It is believed to be partly genetic . Behçet's is not contagious . Diagnosis is based on at least three episodes of mouth sores in a year, together with at least two of the following: genital sores, eye inflammation, skin sores, a positive skin prick test . There is no cure. Treatments may include immunosuppressive medication such as corticosteroids and lifestyle changes. Lidocaine mouthwash may help with the pain. Colchicine may decrease the frequency of attacks. While rare in the United States and Europe, it is more common in the Middle East and Asia. In Turkey , for example, about 2 per 1,000 are affected. Onset is usually in a person's twenties or forties. The disease was initially described by Turkish dermatologist Hulusi Behçet in 1937. Nearly all people with Behçet's disease present with some form of painful ulcerations inside the mouth. They are a form of aphthous ulcers or non-scarring oral lesions. The oral lesions are similar to those found in inflammatory bowel disease and can be relapsing. Painful genital ulcerations usually develop around the anus, vulva, or scrotum and cause scarring in 75 percent of the patients. Additionally, patients may present with erythema nodosum , cutaneous pustular vasculitis, and lesions similar to pyoderma gangrenosum . Inflammatory eye disease can develop early in the disease course and lead to permanent vision loss in 20 percent of cases. Ocular involvement can be in the form of posterior uveitis , anterior uveitis , or retinal vasculitis . Anterior uveitis presents with painful eyes, conjuctival redness, hypopyon , and decreased visual acuity, while posterior uveitis presents with painless decreased visual acuity and visual field floaters. A rare form of ocular (eye) involvement in this syndrome is retinal vasculitis which presents with painless decrease of vision with the possibility of floaters or visual field defects. Optic nerve involvement in Behçet's disease is rare, typically presenting as progressive optic atrophy and visual loss. However, cases of acute optic neuropathy (specifically anterior ischemic optic neuropathy ) have also been reported to occur. Optic nerve atrophy has been identified as the most common cause of visual impairment. Behçet's disease may result in primary or secondary optic nerve involvement. Papilledema as a result of dural sinus thrombosis and atrophy resulting from retinal disease, have been characterized as secondary causes of optic nerve atrophy in Behçet's disease. Signs and symptoms of acute optic neuropathy include painless loss of vision which may affect either one or both eyes, reduced visual acuity, reduced color vision, relative afferent pupillary defect , central scotoma , swollen optic disc, macular edema , or retrobulbar pain. When these symptoms occur with concurrent mucocutaneous ulcerations, they raise suspicion of acute optic neuropathy in Behçet's Disease. Progressive optic atrophy may result in decreased visual acuity or color vision. Intracranial hypertension with papilledema may be present. Episcleritis may occur, which causes eye redness and mild pain, without a significant impact on vision. Gastrointestinal (GI) manifestations include abdominal pain, nausea, and diarrhea with or without blood, and they often involve the terminal ileum and ileocecal valve . Some patients with BD experience abdominal tenderness, bloating, and general abdominal discomfort. When mild this can resemble irritable bowel syndrome; more severe cases bear similarities to inflammatory bowel diseases such as ulcerative colitis or Crohn's. Behçet's disease causes ulcers in the terminal ileum and ileocecal valve . The ulcers may be aphthous or have a classic punched out appearance with undermining. Linear and fissuring ulcers up to 5cm may be present. Biopsies show vasculitis (phlebitis or venulitis) with a neutrophilic inflammatory infiltrate. Involvement of the oesophagus, stomach and large intestine is rare. [ citation needed ] Lung involvement is typically in the form of hemoptysis , pleuritis , cough, or fever, and in severe cases can be life-threatening if the outlet pulmonary artery develops an aneurysm which ruptures causing severe vascular collapse and death from bleeding in the lungs. Pulmonary artery thrombosis may occur. Arthritis is seen in up to half of people, and is usually a non-erosive poly or oligoarthritis primarily of the large joints of the lower extremities. Behçet's disease can rarely result in renal involvement. This can manifest in the following: Small vessel vascular disease results in renal vasculitis, whereas large vessel involvement causes aneurysms (bulging) and thrombosis (blockages). Serious kidney problems are more common in men typically with a history of large vessel involvement in other parts of the body. Bladder and urethral involvement is rare in Behçet's disease. Central nervous system (CNS) involvement most often occurs as a chronic meningoencephalitis. Lesions tend to occur in the brainstem, the basal ganglia and deep hemispheric white matter and may resemble those of multiple sclerosis (MS). Brainstem atrophy is seen in chronic cases. [ citation needed ] Neurological involvements range from aseptic meningitis to vascular thrombosis such as dural sinus thrombosis and organic brain syndrome manifesting with confusion, seizures, and memory loss. Sudden hearing loss (sensorineural) is often associated with it. They often appear late in the progression of the disease but are associated with a poor prognosis. [ citation needed ] Chronic aortic regurgitation due to aortic root disease may also be seen. Although infrequent, myocardial infarction (heart attack) with angiographically identified acute coronary artery thrombosis has been reported, including one case with a pathologically demonstrable lesion due to arteritis found at autopsy. Blood vessel problems are observed in 7–29% of people with arterial lesions representing 15% of vascular lesions. Arterial lesions pose a greater risk. Most common arterial lesions are occlusions or stenosis and aneurysms or pseudoaneurysms. [ citation needed ]Nearly all people with Behçet's disease present with some form of painful ulcerations inside the mouth. They are a form of aphthous ulcers or non-scarring oral lesions. The oral lesions are similar to those found in inflammatory bowel disease and can be relapsing. Painful genital ulcerations usually develop around the anus, vulva, or scrotum and cause scarring in 75 percent of the patients. Additionally, patients may present with erythema nodosum , cutaneous pustular vasculitis, and lesions similar to pyoderma gangrenosum . Inflammatory eye disease can develop early in the disease course and lead to permanent vision loss in 20 percent of cases. Ocular involvement can be in the form of posterior uveitis , anterior uveitis , or retinal vasculitis . Anterior uveitis presents with painful eyes, conjuctival redness, hypopyon , and decreased visual acuity, while posterior uveitis presents with painless decreased visual acuity and visual field floaters. A rare form of ocular (eye) involvement in this syndrome is retinal vasculitis which presents with painless decrease of vision with the possibility of floaters or visual field defects. Optic nerve involvement in Behçet's disease is rare, typically presenting as progressive optic atrophy and visual loss. However, cases of acute optic neuropathy (specifically anterior ischemic optic neuropathy ) have also been reported to occur. Optic nerve atrophy has been identified as the most common cause of visual impairment. Behçet's disease may result in primary or secondary optic nerve involvement. Papilledema as a result of dural sinus thrombosis and atrophy resulting from retinal disease, have been characterized as secondary causes of optic nerve atrophy in Behçet's disease. Signs and symptoms of acute optic neuropathy include painless loss of vision which may affect either one or both eyes, reduced visual acuity, reduced color vision, relative afferent pupillary defect , central scotoma , swollen optic disc, macular edema , or retrobulbar pain. When these symptoms occur with concurrent mucocutaneous ulcerations, they raise suspicion of acute optic neuropathy in Behçet's Disease. Progressive optic atrophy may result in decreased visual acuity or color vision. Intracranial hypertension with papilledema may be present. Episcleritis may occur, which causes eye redness and mild pain, without a significant impact on vision. Gastrointestinal (GI) manifestations include abdominal pain, nausea, and diarrhea with or without blood, and they often involve the terminal ileum and ileocecal valve . Some patients with BD experience abdominal tenderness, bloating, and general abdominal discomfort. When mild this can resemble irritable bowel syndrome; more severe cases bear similarities to inflammatory bowel diseases such as ulcerative colitis or Crohn's. Behçet's disease causes ulcers in the terminal ileum and ileocecal valve . The ulcers may be aphthous or have a classic punched out appearance with undermining. Linear and fissuring ulcers up to 5cm may be present. Biopsies show vasculitis (phlebitis or venulitis) with a neutrophilic inflammatory infiltrate. Involvement of the oesophagus, stomach and large intestine is rare. [ citation needed ]Lung involvement is typically in the form of hemoptysis , pleuritis , cough, or fever, and in severe cases can be life-threatening if the outlet pulmonary artery develops an aneurysm which ruptures causing severe vascular collapse and death from bleeding in the lungs. Pulmonary artery thrombosis may occur.Arthritis is seen in up to half of people, and is usually a non-erosive poly or oligoarthritis primarily of the large joints of the lower extremities. Behçet's disease can rarely result in renal involvement. This can manifest in the following: Small vessel vascular disease results in renal vasculitis, whereas large vessel involvement causes aneurysms (bulging) and thrombosis (blockages). Serious kidney problems are more common in men typically with a history of large vessel involvement in other parts of the body. Bladder and urethral involvement is rare in Behçet's disease.Central nervous system (CNS) involvement most often occurs as a chronic meningoencephalitis. Lesions tend to occur in the brainstem, the basal ganglia and deep hemispheric white matter and may resemble those of multiple sclerosis (MS). Brainstem atrophy is seen in chronic cases. [ citation needed ] Neurological involvements range from aseptic meningitis to vascular thrombosis such as dural sinus thrombosis and organic brain syndrome manifesting with confusion, seizures, and memory loss. Sudden hearing loss (sensorineural) is often associated with it. They often appear late in the progression of the disease but are associated with a poor prognosis. [ citation needed ]Chronic aortic regurgitation due to aortic root disease may also be seen. Although infrequent, myocardial infarction (heart attack) with angiographically identified acute coronary artery thrombosis has been reported, including one case with a pathologically demonstrable lesion due to arteritis found at autopsy. Blood vessel problems are observed in 7–29% of people with arterial lesions representing 15% of vascular lesions. Arterial lesions pose a greater risk. Most common arterial lesions are occlusions or stenosis and aneurysms or pseudoaneurysms. [ citation needed ]The cause is not well-defined, but it is primarily characterized by auto-inflammation of the blood vessels. Although sometimes erroneously referred to as a diagnosis of exclusion, the diagnosis can sometimes be reached by pathologic examination of the affected areas. The primary mechanism of the damage is autoimmune, which by definition is an overactive immune system that targets the patient's own body. The involvement of a subset of T cells ( Th17 ) seems to be important. The primary cause is not well known. In fact, no one knows yet why the immune system starts to behave this way in Behçet's disease. There does however seem to be a genetic component involved, as first degree relatives of the affected patients are often affected in more than the expected proportion for the general population. [ citation needed ] Research suggests that previous infections may provoke the autoimmune responses present in Behçet's disease. Heat shock proteins (HSPs) are present in some bacteria and serve as a "danger signal" to the immune system. However, some HSPs share a similarity in bacteria and humans. The anti- HSP60 and anti-HSP65 antibodies that target HSPs produced by Streptococci (including S. sanguinis and S. pyogenes ) and Mycobacterium tuberculosis can also target human HSPs, leading to immune responses linked to uveitis and various symptoms shown in parenchymal neuro-Behçet's disease. An association with the GIMAP (" GTPase of the immunity-associated protein") family of genes on the long arm of chromosome 7 (7q36.1) has been reported. Gene locations of single-nucleotide polymorphisms associated with Behçet's disease included GIMAP1 , GIMAP2 and GIMAP4 . Behçet's disease is considered more prevalent in the areas surrounding the old silk trading routes in the Middle East and in Central Asia . Thus, it is sometimes known as Silk Road disease . However, this disease is not restricted to people from these regions. A large number of serological studies show a linkage between the disease and HLA-B51 . HLA-B51 is more frequently found from the Middle East to South Eastern Siberia, but the incidence of B51 in some studies was 3 fold higher than the normal population. However, B51 tends not to be found in disease when a certain SUMO4 gene variant is involved, and symptoms appear to be milder when HLA-B27 is present. At the current time, a similar infectious origin has not yet been confirmed that leads to Behçet's disease, but certain strains of S. sanguinis has been found to have a homologous antigenicity. Vasculitis resulting in occlusion of the vessels supplying the optic nerve may be the cause of acute optic neuropathy and progressive optic atrophy in Behçet's disease. Histological evaluation in a reported case of acute optic neuropathy demonstrated substitution of the axonal portion of the optic nerve with fibrous astrocytes without retinal changes. CNS involvement in Behçet's disease may lead to intracranial hypertension most commonly due to dural venous sinus thrombosis and subsequent secondary optic atrophy.There is no specific pathological testing or technique available for the diagnosis of the disease, although the International Study Group criteria for the disease are highly sensitive and specific, involving clinical criteria and a pathergy test. Behçet's disease has a high degree of resemblance to diseases that cause mucocutaneous lesions such as Herpes simplex labialis, and therefore clinical suspicion should be maintained until all the common causes of oral lesions are ruled out from the differential diagnosis . [ citation needed ] Visual acuity, or color vision loss with concurrent mucocutaneous lesions or systemic Behçet's disease symptoms should raise suspicion of optic nerve involvement in Behçet's disease and prompt a work-up for Behçet's disease if not previously diagnosed in addition to an ocular work-up. Diagnosis of Behçet's disease is based on clinical findings including oral and genital ulcers, skin lesions such as erythema nodosum, acne, or folliculitis, ocular inflammatory findings and a pathergy reaction. Inflammatory markers such ESR, and CRP may be elevated. A complete ophthalmic examination may include a slit lamp examination, optical coherence tomography to detect nerve loss, visual field examinations, fundoscopic examination to assess optic disc atrophy and retinal disease, fundoscopic angiography, and visual evoked potentials, which may demonstrate increased latency. Optic nerve enhancement may be identified on Magnetic Resonance Imaging (MRI) in some patients with acute optic neuropathy. However, a normal study does not rule out optic neuropathy. Cerebrospinal fluid (CSF) analysis may demonstrate elevated protein level with or without pleocytosis. Imaging including angiography may be indicated to identify dural venous sinus thrombosis as a cause of intracranial hypertension and optic atrophy. [ citation needed ] According to the International Study Group guidelines, for a patient to be diagnosed with Behçet's disease, the patient must have oral ( aphthous ) ulcers (any shape, size, or number at least three times in any twelve-month period) along with two of the following four hallmark symptoms: [ citation needed ] Despite the inclusive criteria set forth by the International Study Group, there are cases where not all the criteria can be met and therefore a diagnosis cannot readily be made. There is, however, a set of clinical findings that a physician can rely upon in making a tentative diagnosis of the disease; essentially, Behçet's disease does not always follow the International Study Group guidelines and so a high degree of suspicion for a patient who presents having any number of the following findings is necessary: [ citation needed ]According to the International Study Group guidelines, for a patient to be diagnosed with Behçet's disease, the patient must have oral ( aphthous ) ulcers (any shape, size, or number at least three times in any twelve-month period) along with two of the following four hallmark symptoms: [ citation needed ] Despite the inclusive criteria set forth by the International Study Group, there are cases where not all the criteria can be met and therefore a diagnosis cannot readily be made. There is, however, a set of clinical findings that a physician can rely upon in making a tentative diagnosis of the disease; essentially, Behçet's disease does not always follow the International Study Group guidelines and so a high degree of suspicion for a patient who presents having any number of the following findings is necessary: [ citation needed ]Current treatment is aimed at easing the symptoms, reducing inflammation, and controlling the immune system. The quality of the evidence for treating the oral ulcers associated with Behçet's disease, however, is poor. High-dose corticosteroid therapy is often used for severe disease manifestations. Anti-TNF therapy such as infliximab has shown promise in treating the uveitis associated with the disease. Another Anti-TNF agent, etanercept , may be useful in people with mainly skin and mucosal symptoms. Apremilast may also be used to treat oral ulcers associated with Behçet's disease. Interferon alpha-2a may also be an effective alternative treatment, particularly for the genital and oral ulcers as well as ocular lesions. Azathioprine , when used in combination with interferon alpha-2b also shows promise, and colchicine can be useful for treating some genital ulcers, erythema nodosum , and arthritis. Benzathine‐penicillin may also reduce new arthritic attacks. Thalidomide has also been used due to its immune-modifying effect. Dapsone and rebamipide have been shown, in small studies, to have beneficial results for mucocutaneous lesions. Given its rarity, the optimal treatment for acute optic neuropathy in Behçet's disease has not been established. Early identification and treatment are essential. Response to ciclosporin , periocular triamcinolone, and IV methylprednisone followed by oral prednisone has been reported although relapses leading to irreversible visual loss may occur even with treatment. Immunosuppressants such as interferon-alpha and tumour necrosis factor antagonists may improve though not completely reverse symptoms of ocular Behçet's disease, which may progress over time despite treatment. When symptoms are limited to the anterior chamber of the eye prognosis is improved. Posterior involvement, particularly optic nerve involvement, is a poor prognostic indicator. Secondary optic nerve atrophy is frequently irreversible. Lumbar puncture or surgical treatment may be required to prevent optic atrophy in cases of intracranial hypertension refractory to treatment with immunomodulators and steroids. [ citation needed ] Intravenous immunoglobulin therapy (IVIg) could be a treatment for severe or complicated cases. Surgical treatment of arterial manifestations of BD bears many pitfalls since the obliterative endarteritis of vasa vasorum causes thickening of the medial layer and splitting of elastin fibers. Therefore, anastomotic pseudoaneurysms are likely to form, as well as pseudoaneurysms at the site of the puncture in case of angiography or endovascular treatment; furthermore, early graft occlusion may occur. [ citation needed ] For these reasons, invasive treatment should not be performed in the acute and active phases of the disease when inflammation is at its peak. The evaluation of disease's activity is usually based on relapsing symptoms, ESR (erythrocyte sedimentation rate), and serum levels of CRP (C‐reactive protein). [ citation needed ] Endovascular treatment can be an effective and safe alternative to open surgery, with less postoperative complications, faster recovery time, and reduced need for intensive care, while offering patency rates and procedural success rates comparable with those of surgery. This notwithstanding, long‐term results of endovascular treatment in BD are still to be determined. [ citation needed ]Surgical treatment of arterial manifestations of BD bears many pitfalls since the obliterative endarteritis of vasa vasorum causes thickening of the medial layer and splitting of elastin fibers. Therefore, anastomotic pseudoaneurysms are likely to form, as well as pseudoaneurysms at the site of the puncture in case of angiography or endovascular treatment; furthermore, early graft occlusion may occur. [ citation needed ] For these reasons, invasive treatment should not be performed in the acute and active phases of the disease when inflammation is at its peak. The evaluation of disease's activity is usually based on relapsing symptoms, ESR (erythrocyte sedimentation rate), and serum levels of CRP (C‐reactive protein). [ citation needed ] Endovascular treatment can be an effective and safe alternative to open surgery, with less postoperative complications, faster recovery time, and reduced need for intensive care, while offering patency rates and procedural success rates comparable with those of surgery. This notwithstanding, long‐term results of endovascular treatment in BD are still to be determined. [ citation needed ]The syndrome is rare in the United States, Africa and South America, but is common in Asia, suggesting a possible cause endemic to those areas. A theory suggested that past exposure to lethal infectious agents might have fixed the genetic susceptibility factors to Behçet's disease in those area. An estimated 15,000 to 20,000 Americans have been diagnosed with this disease. In the UK, it is estimated to have about 1 case for every 100,000 people. Globally, males are affected more frequently than females. In an epidemiologic study, 56 percent of patients with Behçet's disease developed ocular involvement at a mean age of 30. Ocular involvement was the first manifestation of Behçet's disease in 8.6 percent of patients. Ocular Behçet's disease with involvement of the optic nerve is rarely reported. Among patients with ocular Behçet's disease funduscopic findings of optic atrophy, and optic disc paleness have been identified with a frequency of 17.9 percent and 7.4 percent, respectively. Other fundoscopic findings include vascular sheathing (23.7%), retinal hemorrhage (9%), macular edema (11.3%), branch retinal vein occlusion (5.8%), and retinal edema (6.6%). However, optic atrophy was the most significant cause of visual impairment identified in 54 percent of patients with ocular Behçet's disease and permanent visual impairment. With Behçet's disease as a pre-existing disease in pregnancy or acquired, the pregnancy does not have an adverse effect on the course of Behçet's disease and may possibly ameliorate its course. Still, there is a substantial variability in clinical course between patients and even for different pregnancies in the same patient. Also, the other way around, Behçet's disease confers an increased risk of pregnancy complications , miscarriage and Cesarean section . Behçet's can cause male infertility , either as a result of the condition itself or of a side effect of concomitant medication such as colchicine , which is known to lower sperm count . The first modern formal description of the symptoms was made by H. Planner and F. Remenovsky and published in 1922 in the Archiv für Dermatologie und Syphilis . Behçet's disease is named after Hulusi Behçet (1889–1948), the Turkish dermatologist and scientist who first recognized the three main symptoms of the syndrome in one of his patients in 1924 and reported his research on the disease in Journal of Skin and Venereal Diseases in 1936. The name ( Morbus Behçet ) was formally adopted at the International Congress of Dermatology in Geneva in September 1947. Symptoms of this disease may have been described by Hippocrates in the 5th century BC, in his Epidemion (book 3, case 7). Some sources use the term "Adamantiades's syndrome" or "Adamantiades–Behçet syndrome", for the work done by Benediktos Adamantiades . However, the current World Health Organization / ICD-10 standard is "Behçet's disease". In 1991, Saudi Arabian medical researchers described neuro-Behçet's disease , a neurological involvement in Behçet's disease, considered one of the most devastating manifestations of the disease. The mechanism can be immune-mediated or thrombotic. The term dates back to at least 1990.

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Acute hemorrhagic fever syndrome

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Councilman body

In pathology , a Councilman body , also known as a Councilman hyaline body or apoptotic body , is an eosinophilic globule of apoptotic hepatocyte cell fragments. Ultimately, the fragments are taken up by macrophages or adjacent parenchymal cells. They are found in the liver of individuals suffering from acute viral hepatitis, yellow fever , and other viral syndromes. Councilman bodies were first identified in yellow fever, which characteristically shows a midzonal hepatic necrosis on biopsy. Similar inclusions are observed in other viral hemorrhagic fevers and all of the viral hepatitides. Liver biopsy of acute viral hepatitis shows panlobular lymphocytic infiltrates with ballooning hepatocytes.Councilman bodies are named after American pathologist William Thomas Councilman (1854–1933), who discovered them.

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Acute hemorrhagic fever syndrome

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Oropouche fever

Oropouche fever is a tropical viral infection transmitted by biting midges and mosquitoes from the blood of sloths to humans . This disease is named after the region where it was first discovered and isolated at the Trinidad Regional Virus Laboratory in 1955 by the Oropouche River in Trinidad and Tobago . Oropouche fever is caused by a specific arbovirus , the Oropouche virus (OROV), of the Bunyaviridae family. Large epidemics are common and very swift, one of the earliest largest having occurred at the city of Belém , in the Brazilian Amazon state of Pará , with 11,000 recorded cases. In the Brazilian Amazon, oropouche is the second most frequent viral disease, after dengue fever. Several epidemics have generated more than 263,000 cases, of which 130,000 alone occurred in the period from 1978 to 1980. Presently, in Brazil alone it is estimated that more than half a million cases have occurred. Nevertheless, clinics in Brazil may not have adequate testing reliability as they rely on symptoms rather than PCR viral sequencing, which is expensive and time consuming, in many cases there may be co-infection with other similar mosquito-borne viruses. Oropouche fever is characterized as an acute febrile illness, meaning that it begins with a sudden onset of a fever followed by severe clinical symptoms. It typically takes 4 to 8 days from the incubation period to first start noticing signs of infection , beginning from the bite of the infected mosquito or midge. Fevers are the most common symptom with temperatures as high as 40 °C (104 °F) . Clinical symptoms include chills, headache, myalgia, arthralgia, dizziness, photophobia, vomiting, joint pains, epigastric pain , and rashes. There also have been some cases where rashes resembles rubella and patients presented systematic symptoms including nausea , vomiting , diarrhea , conjunctive congestion , epigastric pain, and retro-orbitial pain. The initial febrile episode typically passes after a few days, but it is very common to have a reoccurrence of these symptoms with a lesser intensity. Studies have shown this typically happens in about 60% of cases. The oropouche virus is an emerging infectious agent that causes the illness oropouche fever. This virus is an arbovirus and is transmitted among sloths, marsupials, primates, and birds through the mosquitoes Aedes serratus and Culex quinquefaciatus . The oropouche virus has evolved to an urban cycle infecting humans though midges as its main transporting vector. OROV was first described in Trinidad in 1955 when the prototype strain was isolated from the blood of a febrile human patient and from Coquillettidia venezuelensis mosquitoes . In Brazil, OROV was first described in 1960 when it was isolated from a three-toed sloth ( Bradypus tridactylus ) and Ochlerotatus serratus mosquitoes captured nearby during the construction of the Belém-Brasilia Highway . The oropouche virus is responsible for causing massive, explosive outbreaks in Latin American countries, making oropouche fever the second most common arboviral infection seen in Brazil. So far the only reported cases of Oropouche fever have been in Brazil, Panama, Peru, and Trinidad and Tobago. ORO fever occurs mainly during the rainy seasons because there is an increase in breeding sites in the vector populations. There has also been reports of the oropouche epidemics during the dry season but this is most likely due to the high population density of mosquitoes from the past rainy season. Moreover, during the dry season there is a deceased chance of outbreaks which decreases the amount of midges this is because the amount of outbreaks is related to the number of human population that has not yet been exposed to this virus. Oropouche fever is caused by the oropouche virus (OROV) that belongs to the Peribunyaviridae family of arboviruses. This virus is a single-stranded, negative sense RNA virus which is the cause of this disease. There are no specific ultrastructural studies of the oropouche virus in human tissues that have been recorded to this date. It is likely that this viral agent shares similar morphological characteristics with other members of the Orthobunyavirus genus. Members of the Orthobunyavirus genus have a three part, single-stranded, negative sense RNA genome of small (S), medium (M) and large (L) RNA segments. These segments function to encode nucleocapsids , glycoproteins and the RNA polymerase in that sequential order. Through phylogenetic analysis of nucleocapsid genes in different oropouche virus strains, it has been revealed that there are three unique genotypes (I, II, III) that are currently spreading through Central and South America. Genetic reassortment is said to be one of the most important mechanisms in explaining the viral biodiversity in orthobunyaviruses. This occurs when two genetically related viruses infect the same cell at the same time forming a progeny virus and this virus holds various components of genetic L, M and S segments from the two parental viruses. In reassortment, the S and L segments are the ones that are usually exchanged between species further, the S segment, that is coded by the nucleocapsid protein, and the L polymerase function together to create a replication of the viral genome. Due to this, one segment will restrict the molecular evolution of another segment and this is said to be inherited as a pair. On the contrary, the M segment codes for viral glycoproteins and these could be more prone to mutations due to a higher selective pressure in their coding region because these proteins are major host range determinants. There is not a significant amount of information about regarding the natural pathogenesis of OROV infections because there have been no recorded fatalities to date. It is known that within 2–4 days from the initial onset of systematic symptoms in humans, the presence of this virus is detected in the blood. In some cases this virus has also been recovered from the cerebrospinal fluid, but the route of invasion to the central nervous system remains unclear. To further understand the pathogenesis of how this virus manifests in the body experimental studies using murine models have been performed. BALB/c neonate mice were treated with this virus subcutaneously and presented clinical symptoms five days after inoculation . The mice revealed a high concentration of the replicating virus in the brain along with inflammation of the meninges and apoptosis of neurons without encephalitis, which is inflammation of the brain due to an infection. These findings confirmed the neurotropism of this virus, which means that this virus is capable of infecting nerve cells. Immunohistochemistry was used to reveal how this virus had access to the central nervous system. The findings indicated that the OROV infection starts from the posterior parts of the brain and progresses toward the forebrain. The oropouche virus spreads through the neural routes during early stages of the infection, reaching the spinal cord and traveling upward to the brain through brainstem with little inflammation. As the infection progresses, the virus crosses the blood-brain barrier and spreads to the brain parenchyma leading to severe manifestations of encephalitis . Damage to the brain parenchyma can result in the loss of cognitive ability or death. Genetic reassortment is said to be one of the most important mechanisms in explaining the viral biodiversity in orthobunyaviruses. This occurs when two genetically related viruses infect the same cell at the same time forming a progeny virus and this virus holds various components of genetic L, M and S segments from the two parental viruses. In reassortment, the S and L segments are the ones that are usually exchanged between species further, the S segment, that is coded by the nucleocapsid protein, and the L polymerase function together to create a replication of the viral genome. Due to this, one segment will restrict the molecular evolution of another segment and this is said to be inherited as a pair. On the contrary, the M segment codes for viral glycoproteins and these could be more prone to mutations due to a higher selective pressure in their coding region because these proteins are major host range determinants. There is not a significant amount of information about regarding the natural pathogenesis of OROV infections because there have been no recorded fatalities to date. It is known that within 2–4 days from the initial onset of systematic symptoms in humans, the presence of this virus is detected in the blood. In some cases this virus has also been recovered from the cerebrospinal fluid, but the route of invasion to the central nervous system remains unclear. To further understand the pathogenesis of how this virus manifests in the body experimental studies using murine models have been performed. BALB/c neonate mice were treated with this virus subcutaneously and presented clinical symptoms five days after inoculation . The mice revealed a high concentration of the replicating virus in the brain along with inflammation of the meninges and apoptosis of neurons without encephalitis, which is inflammation of the brain due to an infection. These findings confirmed the neurotropism of this virus, which means that this virus is capable of infecting nerve cells. Immunohistochemistry was used to reveal how this virus had access to the central nervous system. The findings indicated that the OROV infection starts from the posterior parts of the brain and progresses toward the forebrain. The oropouche virus spreads through the neural routes during early stages of the infection, reaching the spinal cord and traveling upward to the brain through brainstem with little inflammation. As the infection progresses, the virus crosses the blood-brain barrier and spreads to the brain parenchyma leading to severe manifestations of encephalitis . Damage to the brain parenchyma can result in the loss of cognitive ability or death. BALB/c neonate mice were treated with this virus subcutaneously and presented clinical symptoms five days after inoculation . The mice revealed a high concentration of the replicating virus in the brain along with inflammation of the meninges and apoptosis of neurons without encephalitis, which is inflammation of the brain due to an infection. These findings confirmed the neurotropism of this virus, which means that this virus is capable of infecting nerve cells. Immunohistochemistry was used to reveal how this virus had access to the central nervous system. The findings indicated that the OROV infection starts from the posterior parts of the brain and progresses toward the forebrain. The oropouche virus spreads through the neural routes during early stages of the infection, reaching the spinal cord and traveling upward to the brain through brainstem with little inflammation. As the infection progresses, the virus crosses the blood-brain barrier and spreads to the brain parenchyma leading to severe manifestations of encephalitis . Damage to the brain parenchyma can result in the loss of cognitive ability or death. Diagnosis of the oropouche infection is done through classic and molecular virology techniques. These include: Clinical diagnosis of oropouche fever is hard to perform due to the nonspecific nature of the disease, in many causes it can be confused with dengue fever or other arbovirus illness. Prevention strategies include reducing the breeding of midges through source reduction (removal and modification of breeding sites) and reducing contact between midges and people. This can be accomplished by reducing the number of natural and artificial water-filled habitats and encourage the midge larvae to grow. Oropouche fever is present in epidemics so the chances of one contracting it after being exposed to areas of midgets or mosquitoes is rare. Oropouche Fever has no cure or specific therapy so treatment is done by relieving the pain of the symptoms through symptomatic treatment . Certain oral analgesic and anti-inflammatory agents can help treat headaches and body pains. In extreme cases of oropouche fever the drug Ribavirin is recommended to help against the virus. This is called antiviral therapy . Treatments also consist of drinking plenty of fluids to prevent dehydration. Aspirin is not a recommended choice of drug because it can reduce blood clotting and may aggravate the hemorrhagic effects and prolong recovery time. [ citation needed ]The infection is usually self-limiting and complications are rare. This illness usually lasts for about a week but in extreme cases can be prolonged. Patients usually recover fully with no long term ill effects. There have been no recorded fatalities resulting from oropouche fever. One study has focused on identifying OROV through the use of RNA extraction from reverse transcription-polymerase chain reaction. This study revealed that OROV caused central nervous system infections in three patients. The three patients all had meningoencephalitis and also showed signs of clear lympho-monocytic cellular pattern in CSF , high protein, and normal to slightly decreased glucose levels indicating they had viral infections. Two of the patients already had underlying infections that can effect the CNS and immune system and in particular one of these patients has HIV/AIDS and the third patient has neurocysticercosis . Two patients were infected with OROV developed meningitis and it was theorized that this is due to them being immunocompromised. Through this it was revealed that it's possible that the invasion of the central nervous system by the oropouche virus can be performed by a previous blood-brain barrier damage.

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Acute hemorrhagic fever syndrome

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Arbovirus

Arbovirus is an informal name for any virus that is transmitted by arthropod vectors . The term arbovirus is a portmanteau word ( ar thropod- bo rne virus ). Tibovirus ( ti ck- bo rne virus ) is sometimes used to more specifically describe viruses transmitted by ticks , a superorder within the arthropods. Arboviruses can affect both animals (including humans) and plants. In humans, symptoms of arbovirus infection generally occur 3–15 days after exposure to the virus and last three or four days. The most common clinical features of infection are fever , headache , and malaise , but encephalitis and viral hemorrhagic fever may also occur. The incubation period – the time between when infection occurs and when symptoms appear – varies from virus to virus, but is usually limited between 2 and 15 days for arboviruses. The majority of infections, however, are asymptomatic. Among cases in which symptoms do appear, symptoms tend to be non-specific, resembling a flu-like illness , and are not indicative of a specific causative agent. These symptoms include fever, headache, malaise, rash and fatigue. Rarely, vomiting and hemorrhagic fever may occur. The central nervous system can also be affected by infection, as encephalitis and meningitis are sometimes observed. Prognosis is good for most people, but is poor in those who develop severe symptoms, with up to a 20% mortality rate in this population depending on the virus. The very young, elderly, pregnant women, and people with immune deficiencies are more likely to develop severe symptoms. [ citation needed ]Arboviruses maintain themselves in nature by going through a cycle between a host , an organism that carries the virus, and a vector , an organism that carries and transmits the virus to other organisms. For arboviruses, vectors are commonly mosquitoes, ticks, sandflies and other arthropods that consume the blood of vertebrates for nutritious or developmental purposes. Vertebrates which have their blood consumed act as the hosts, with each vector generally having an affinity for the blood of specific species, making those species the hosts. Transmission between the vector and the host occurs when the vector feeds on the blood of the vertebrate, wherein the virus that has established an infection in the salivary glands of the vector comes into contact with the host's blood. While the virus is inside the host, it undergoes a process called amplification, where the virus replicates at sufficient levels to induce viremia , a condition in which there are large numbers of virions present in the blood. The abundance of virions in the host's blood allows the host to transmit the virus to other organisms if its blood is consumed by them. When uninfected vectors become infected from feeding, they are then capable of transmitting the virus to uninfected hosts, resuming amplification of virus populations. If viremia is not achieved in a vertebrate, the species can be called a "dead-end host", as the virus cannot be transmitted back to the vector. An example of this vector-host relationship can be observed in the transmission of the West Nile virus. Female mosquitoes of the genus Culex prefer to consume the blood of passerine birds, making them the hosts of the virus. When these birds are infected, the virus amplifies, potentially infecting multiple mosquitoes that feed on its blood. These infected mosquitoes may go on to further transmit the virus to more birds. If the mosquito is unable to find its preferred food source, it will choose another. Human blood is sometimes consumed, but since the West Nile virus does not replicate that well in mammals , humans are considered a dead-end host. Person-to-person transmission of arboviruses is not common, but can occur. Blood transfusions , organ transplantation , and the use of blood products can transmit arboviruses if the virus is present in the donor's blood or organs. Because of this, blood and organs are often screened for viruses before being administered. Rarely, vertical transmission , or mother-to-child transmission, has been observed in infected pregnant and breastfeeding women. Exposure to used needles may also transmit arboviruses if they have been used by an infected person or animal. This puts intravenous drug users and healthcare workers at risk for infection in regions where the arbovirus may be spreading in human populations. Arboviruses are a polyphyletic group , belonging to various viral genera and therefore exhibiting different virologic characteristics.Arboviruses maintain themselves in nature by going through a cycle between a host , an organism that carries the virus, and a vector , an organism that carries and transmits the virus to other organisms. For arboviruses, vectors are commonly mosquitoes, ticks, sandflies and other arthropods that consume the blood of vertebrates for nutritious or developmental purposes. Vertebrates which have their blood consumed act as the hosts, with each vector generally having an affinity for the blood of specific species, making those species the hosts. Transmission between the vector and the host occurs when the vector feeds on the blood of the vertebrate, wherein the virus that has established an infection in the salivary glands of the vector comes into contact with the host's blood. While the virus is inside the host, it undergoes a process called amplification, where the virus replicates at sufficient levels to induce viremia , a condition in which there are large numbers of virions present in the blood. The abundance of virions in the host's blood allows the host to transmit the virus to other organisms if its blood is consumed by them. When uninfected vectors become infected from feeding, they are then capable of transmitting the virus to uninfected hosts, resuming amplification of virus populations. If viremia is not achieved in a vertebrate, the species can be called a "dead-end host", as the virus cannot be transmitted back to the vector. An example of this vector-host relationship can be observed in the transmission of the West Nile virus. Female mosquitoes of the genus Culex prefer to consume the blood of passerine birds, making them the hosts of the virus. When these birds are infected, the virus amplifies, potentially infecting multiple mosquitoes that feed on its blood. These infected mosquitoes may go on to further transmit the virus to more birds. If the mosquito is unable to find its preferred food source, it will choose another. Human blood is sometimes consumed, but since the West Nile virus does not replicate that well in mammals , humans are considered a dead-end host. Person-to-person transmission of arboviruses is not common, but can occur. Blood transfusions , organ transplantation , and the use of blood products can transmit arboviruses if the virus is present in the donor's blood or organs. Because of this, blood and organs are often screened for viruses before being administered. Rarely, vertical transmission , or mother-to-child transmission, has been observed in infected pregnant and breastfeeding women. Exposure to used needles may also transmit arboviruses if they have been used by an infected person or animal. This puts intravenous drug users and healthcare workers at risk for infection in regions where the arbovirus may be spreading in human populations. Arboviruses are a polyphyletic group , belonging to various viral genera and therefore exhibiting different virologic characteristics.Preliminary diagnosis of arbovirus infection is usually based on clinical presentations of symptoms, places and dates of travel, activities, and epidemiological history of the location where infection occurred. Definitive diagnosis is typically made in a laboratory by employing some combination of blood tests , particularly immunologic , serologic and/or virologic techniques such as ELISA , complement fixation , polymerase chain reaction , neutralization test , and hemagglutination-inhibition test . In the past, arboviruses were organized into one of four groups: A, B, C, and D. Group A denoted members of the genus Alphavirus , Group B were members of the genus Flavivirus , and Group C remains as the Group C serogroup of the genus Orthobunyavirus . Group D was renamed in the mid-1950s to the Guama group and is currently the Guama serogroup in the genus Orthobunyavirus . Currently, viruses are jointly classified according to Baltimore classification and a virus-specific system based on standard biological classification . With the exception of the African swine fever virus , which belongs to the Asfarviridae family of viruses, all major clinically important arboviruses belong to one of the following four groups: [ citation needed ]In the past, arboviruses were organized into one of four groups: A, B, C, and D. Group A denoted members of the genus Alphavirus , Group B were members of the genus Flavivirus , and Group C remains as the Group C serogroup of the genus Orthobunyavirus . Group D was renamed in the mid-1950s to the Guama group and is currently the Guama serogroup in the genus Orthobunyavirus . Currently, viruses are jointly classified according to Baltimore classification and a virus-specific system based on standard biological classification . With the exception of the African swine fever virus , which belongs to the Asfarviridae family of viruses, all major clinically important arboviruses belong to one of the following four groups: [ citation needed ]Vector control measures, especially mosquito control , are essential to reducing the transmission of disease by arboviruses. Habitat control involves draining swamps and removal of other pools of stagnant water (such as old tires, large outdoor potted plants, empty cans, etc.) that often serve as breeding grounds for mosquitoes. Insecticides can be applied in rural and urban areas, inside houses and other buildings, or in outdoor environments. They are often quite effective for controlling arthropod populations, though use of some of these chemicals is controversial, and some organophosphates and organochlorides (such as DDT ) have been banned in many countries. Infertile male mosquitoes have been introduced in some areas in order to reduce the breeding rate of relevant mosquito species. Larvicides are also used worldwide in mosquito abatement programs. Temefos is a common mosquito larvicide. People can also reduce the risk of getting bitten by arthropods by employing personal protective measures such as sleeping under mosquito nets , wearing protective clothing , applying insect repellents such as permethrin and DEET to clothing and exposed skin, and (where possible) avoiding areas known to harbor high arthropod populations. Arboviral encephalitis can be prevented in two major ways: personal protective measures and public health measures to reduce the population of infected mosquitoes. Personal measures include reducing time outdoors particularly in early evening hours, wearing long pants and long sleeved shirts and applying mosquito repellent to exposed skin areas. Public health measures often require spraying of insecticides to kill juvenile (larvae) and adult mosquitoes. Vaccines are available for the following arboviral diseases: Vaccines are in development for the following arboviral diseases:Vaccines are available for the following arboviral diseases: Vaccines are in development for the following arboviral diseases:Because the arboviral encephalitides are viral diseases, antibiotics are not an effective form of treatment and no effective antiviral drugs have yet been discovered. Treatment is supportive, attempting to deal with problems such as swelling of the brain, loss of the automatic breathing activity of the brain and other treatable complications like bacterial pneumonia . The WHO caution against the use of aspirin and ibuprofen as they can increase the risk of bleeding. Most arboviruses are located in tropical areas, however as a group they have a global distribution. The warm climate conditions found in tropical areas allows for year-round transmission by the arthropod vectors. Other important factors determining geographic distribution of arthropod vectors include rainfall, humidity, and vegetation. Mapping methods such as GIS and GPS have allowed for spatial and temporal analyses of arboviruses. Tagging cases or breeding sites geographically has allowed for deeper examination of vector transmission. To see the epidemiology of specific arboviruses, the following resources hold maps, fact sheets, and reports on arboviruses and arboviral epidemics. The WHO also hosts DengueNet, a database which can be queried about Dengue cases. Arboviruses were not known to exist until the rise of modern medicine , with the germ theory and an understanding that viruses were distinct from other microorganisms . The connection between arthropods and disease was not postulated until 1881 when Cuban doctor and scientist Carlos Finlay proposed that yellow fever may be transmitted by mosquitoes instead of human contact, a reality that was verified by Major Walter Reed in 1901. The primary vector, Aedes aegypti , had spread globally from the 15th to the 19th centuries as a result of globalization and the slave trade . This geographic spreading caused dengue fever epidemics throughout the 18th and 19th centuries, and later, in 1906, transmission by the Aedes mosquitoes was confirmed, making yellow fever and dengue fever the first two diseases known to be caused by viruses. Thomas Milton Rivers published the first clear description of a virus as distinct from a bacterium in 1927. The discovery of the West Nile virus came in 1937, and has since been found in Culex populations causing epidemics throughout Africa , the Middle East , and Europe . The virus was introduced into the Western Hemisphere in 1999, sparking a series of epidemics. During the latter half of the 20th century, Dengue fever reemerged as a global disease, with the virus spreading geographically due to urbanization , population growth , increased international travel, and global warming , and continues to cause at least 50 million infections per year, making Dengue fever the most common and clinically important arboviral disease. Yellow fever , alongside malaria , was a major obstacle in the construction of the Panama Canal . French supervision of the project in the 1880s was unsuccessful because of these diseases, forcing the abandonment of the project in 1889. During the American effort to construct the canal in the early 1900s, William C. Gorgas , the Chief Sanitary Officer of Havana , was tasked with overseeing the health of the workers. He had past success in eradicating the disease in Florida and Havana by reducing mosquito populations through draining nearby pools of water, cutting grass, applying oil to the edges of ponds and swamps to kill larvae , and capturing adult mosquitoes that remained indoors during the daytime. Joseph Augustin LePrince , the Chief Sanitary Inspector of the Canal Zone , invented the first commercial larvicide , a mixture of carbolic acid , resin , and caustic soda , to be used throughout the Canal Zone . The combined implementation of these sanitation measures led to a dramatic decline in the number of workers dying and the eventual eradication of yellow fever in the Canal Zone as well as the containment of malaria during the 10-year construction period. Because of the success of these methods at preventing disease, they were adopted and improved upon in other regions of the world.

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Acute hemorrhagic fever syndrome

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Respiratory disease

Respiratory diseases , or lung diseases , are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea , bronchi , bronchioles , alveoli , pleurae , pleural cavity , the nerves and muscles of respiration . Respiratory diseases range from mild and self-limiting, such as the common cold , influenza , and pharyngitis to life-threatening diseases such as bacterial pneumonia , pulmonary embolism , tuberculosis , acute asthma , lung cancer , and severe acute respiratory syndromes , such as COVID-19 . Respiratory diseases can be classified in many different ways, including by the organ or tissue involved, by the type and pattern of associated signs and symptoms, or by the cause of the disease. The study of respiratory disease is known as pulmonology . A physician who specializes in respiratory disease is known as a pulmonologist, a chest medicine specialist, a respiratory medicine specialist, a respirologist or a thoracic medicine specialist.Asthma , chronic bronchitis , bronchiectasis and chronic obstructive pulmonary disease (COPD) are all obstructive lung diseases characterised by airway obstruction . This limits the amount of air that is able to enter alveoli because of constriction of the bronchial tree, due to inflammation. Obstructive lung diseases are often identified because of symptoms and diagnosed with pulmonary function tests such as spirometry . Many obstructive lung diseases are managed by avoiding triggers (such as dust mites or smoking ), with symptom control such as bronchodilators , and with suppression of inflammation (such as through corticosteroids ) in severe cases. One common cause of COPD including emphysema , and chronic bronchitis, is tobacco smoking , and common causes of bronchiectasis include severe infections and cystic fibrosis . The definitive cause of asthma is not yet known. Restrictive lung diseases are a category of respiratory disease characterized by a loss of lung compliance , causing incomplete lung expansion and increased lung stiffness, such as in infants with respiratory distress syndrome. Restrictive lung diseases can be divided into two categories: those caused by intrinsic factors and those caused by extrinsic factors. Restrictive lung diseases yielding from intrinsic factors occur within the lungs themselves, such as tissue death due to inflammation or toxins. Conversely, restrictive lung diseases caused by extrinsic factors result from conditions originating from outside the lungs such as neuromuscular dysfunction and irregular chest wall movements. Chronic respiratory diseases (CRDs) are long-term diseases of the airways and other structures of the lung. They are characterized by a high inflammatory cell recruitment ( neutrophil ) and/or destructive cycle of infection , (e.g. mediated by Pseudomonas aeruginosa ). Some of the most common are asthma , chronic obstructive pulmonary disease , and acute respiratory distress syndrome . CRDs are not curable; however, various forms of treatment that help dilate major air passages and improve shortness of breath can help control symptoms and increase the quality of life. Telerehabilitation for chronic respiratory disease The latest evidence suggests that primary pulmonary rehabilitation and maintenance rehabilitation delivered through telerehabilitation for people with chronic respiratory disease reaches outcomes similar to centre-based rehabilitation. While there are no safety issues identified, the findings are based on evidence limited by a small number of studies. Infections can affect any part of the respiratory system. They are traditionally divided into upper respiratory tract infections and lower respiratory tract infections. [ citation needed ] The upper airway is defined as all the structures connecting the glottis to the mouth and nose. The most common upper respiratory tract infection is the common cold . However, infections of specific organs of the upper respiratory tract such as sinusitis , tonsillitis , otitis media , pharyngitis and laryngitis are also considered upper respiratory tract infections. Epiglottitis is a bacterial infection of the larynx which causes life-threatening swelling of the epiglottis with a mortality rate of 7% in adults and 1% in children. Haemophilus influenzae is still the primary cause even with vaccinations. Also Streptococcus pyogenes can cause epiglottitis. Symptoms include drooling, stridor, difficulty breathing and swallowing, and a hoarse voice. Croup (Laryngotracheobronchitis) is a viral infection of the vocal cords typically lasting five to six days. The main symptom is a barking cough and low-grade fever . On an X-ray, croup can be recognized by the "steeple sign", which is a narrowing of the trachea . It most commonly occurs in winter months in children between the ages of 3 months and 5 years. A severe form caused by bacteria is called bacterial tracheitis. Tonsillitis is swelling of the tonsils by a bacterial or viral infection. This inflammation can lead to airway obstruction. From tonsillitis can come a peritonsillar abscess which is the most common upper airway infection and occurs primarily in young adults. It causes one swelling of one of tonsils pushing the uvula to the unaffected side. Diagnosis is usually made based on the presentation and examination. Symptoms generally include fever, sore throat, trouble swallowing, and sounding like they have a "hot potato" in their mouth. The most common lower respiratory tract infection is pneumonia , an infection of the lungs which is usually caused by bacteria, particularly Streptococcus pneumoniae in Western countries. Worldwide, tuberculosis is an important cause of pneumonia. Other pathogens such as viruses and fungi can cause pneumonia, for example severe acute respiratory syndrome , COVID-19 and pneumocystis pneumonia . Pneumonia may develop complications such as a lung abscess, a round cavity in the lung caused by the infection, or may spread to the pleural cavity . [ citation needed ] Poor oral care may be a contributing factor to lower respiratory disease, as bacteria from gum disease may travel through airways and into the lungs. Primary ciliary dyskinesia is a genetic disorder causing the cilia to not move in a coordinated manner. This causes chronic respiratory infections, cough, and nasal congestion. This can lead to bronchiectasis, which can cause life-threatening breathing issues. The upper airway is defined as all the structures connecting the glottis to the mouth and nose. The most common upper respiratory tract infection is the common cold . However, infections of specific organs of the upper respiratory tract such as sinusitis , tonsillitis , otitis media , pharyngitis and laryngitis are also considered upper respiratory tract infections. Epiglottitis is a bacterial infection of the larynx which causes life-threatening swelling of the epiglottis with a mortality rate of 7% in adults and 1% in children. Haemophilus influenzae is still the primary cause even with vaccinations. Also Streptococcus pyogenes can cause epiglottitis. Symptoms include drooling, stridor, difficulty breathing and swallowing, and a hoarse voice. Croup (Laryngotracheobronchitis) is a viral infection of the vocal cords typically lasting five to six days. The main symptom is a barking cough and low-grade fever . On an X-ray, croup can be recognized by the "steeple sign", which is a narrowing of the trachea . It most commonly occurs in winter months in children between the ages of 3 months and 5 years. A severe form caused by bacteria is called bacterial tracheitis. Tonsillitis is swelling of the tonsils by a bacterial or viral infection. This inflammation can lead to airway obstruction. From tonsillitis can come a peritonsillar abscess which is the most common upper airway infection and occurs primarily in young adults. It causes one swelling of one of tonsils pushing the uvula to the unaffected side. Diagnosis is usually made based on the presentation and examination. Symptoms generally include fever, sore throat, trouble swallowing, and sounding like they have a "hot potato" in their mouth. The most common lower respiratory tract infection is pneumonia , an infection of the lungs which is usually caused by bacteria, particularly Streptococcus pneumoniae in Western countries. Worldwide, tuberculosis is an important cause of pneumonia. Other pathogens such as viruses and fungi can cause pneumonia, for example severe acute respiratory syndrome , COVID-19 and pneumocystis pneumonia . Pneumonia may develop complications such as a lung abscess, a round cavity in the lung caused by the infection, or may spread to the pleural cavity . [ citation needed ] Poor oral care may be a contributing factor to lower respiratory disease, as bacteria from gum disease may travel through airways and into the lungs. Primary ciliary dyskinesia is a genetic disorder causing the cilia to not move in a coordinated manner. This causes chronic respiratory infections, cough, and nasal congestion. This can lead to bronchiectasis, which can cause life-threatening breathing issues. Malignant tumors of the respiratory system, particularly primary carcinomas of the lung , are a major health problem responsible for 15% of all cancer diagnoses and 30% of all cancer deaths. The majority of respiratory system cancers are attributable to smoking tobacco . [ citation needed ] The major histological types of respiratory system cancer are: Adenocarcinoma of the lung Squamous cell carcinoma of the lung Large cell lung carcinoma In addition, since many cancers spread via the bloodstream and the entire cardiac output passes through the lungs, it is common for cancer metastases to occur within the lung. Breast cancer may invade directly through local spread, and through lymph node metastases. After metastasis to the liver , colon cancer frequently metastasizes to the lung. Prostate cancer , germ cell cancer and renal cell carcinoma may also metastasize to the lung. Treatment of respiratory system cancer depends on the type of cancer. Surgical removal of part of a lung ( lobectomy , segmentectomy , or wedge resection ) or of an entire lung pneumonectomy ), along with chemotherapy and radiotherapy , are all used. The chance of surviving lung cancer depends on the cancer stage at the time the cancer is diagnosed, and to some extent on the histology , and is only about 14–17% overall. In the case of metastases to the lung, treatment can occasionally be curative but only in certain, rare circumstances. Benign tumors are relatively rare causes of respiratory disease. Examples of benign tumors are:Malignant tumors of the respiratory system, particularly primary carcinomas of the lung , are a major health problem responsible for 15% of all cancer diagnoses and 30% of all cancer deaths. The majority of respiratory system cancers are attributable to smoking tobacco . [ citation needed ] The major histological types of respiratory system cancer are: Adenocarcinoma of the lung Squamous cell carcinoma of the lung Large cell lung carcinoma In addition, since many cancers spread via the bloodstream and the entire cardiac output passes through the lungs, it is common for cancer metastases to occur within the lung. Breast cancer may invade directly through local spread, and through lymph node metastases. After metastasis to the liver , colon cancer frequently metastasizes to the lung. Prostate cancer , germ cell cancer and renal cell carcinoma may also metastasize to the lung. Treatment of respiratory system cancer depends on the type of cancer. Surgical removal of part of a lung ( lobectomy , segmentectomy , or wedge resection ) or of an entire lung pneumonectomy ), along with chemotherapy and radiotherapy , are all used. The chance of surviving lung cancer depends on the cancer stage at the time the cancer is diagnosed, and to some extent on the histology , and is only about 14–17% overall. In the case of metastases to the lung, treatment can occasionally be curative but only in certain, rare circumstances.Benign tumors are relatively rare causes of respiratory disease. Examples of benign tumors are:Pleural cavity diseases include pleural mesothelioma which are mentioned above. A collection of fluid in the pleural cavity is known as a pleural effusion . This may be due to fluid shifting from the bloodstream into the pleural cavity due to conditions such as congestive heart failure and cirrhosis. It may also be due to inflammation of the pleura itself as can occur with infection, pulmonary embolus , tuberculosis, mesothelioma and other conditions. A pneumothorax is a hole in the pleura covering the lung allowing air in the lung to escape into the pleural cavity. The affected lung "collapses" like a deflated balloon. A tension pneumothorax is a particularly severe form of this condition where the air in the pleural cavity cannot escape, so the pneumothorax keeps getting bigger until it compresses the heart and blood vessels, leading to a life-threatening situation.Pulmonary vascular diseases are conditions that affect the pulmonary circulation . Examples are: [ citation needed ]Pulmonary diseases also impact newborns and the disorders are often unique from those that affect adults. Infant respiratory distress syndrome most commonly occurs in less than six hours after birth in about 1% of all births in the United States. The main risk factor is prematurity with the likelihood of it occurring going up to 71% in infants under 750g. Other risk factors include infant of a diabetic mother (IDM), method of delivery, fetal asphyxia, genetics, prolonged rupture of membranes (PROM), maternal toxemia, chorioamnionitis , and male sex. The widely accepted pathophysiology of respiratory distress syndrome is it caused by insufficient surfactant production and immature lung and vascular development. The lack of surfactant makes the lungs atelectatic causing a ventilation to perfusion mismatch, lowered compliance, and increased air resistance. This causes hypoxia and respiratory acidosis which can lead to pulmonary hypertension . It has a ground glass appearance on an x-ray. Symptoms can include tachypnea, nasal flaring, paradoxical chest movement, grunting, and subcostal retractions. Bronchopulmonary Dysplasia is a condition that occurs after birth usually from mechanical ventilation and oxygen use. It happens almost exclusively in pre-mature infants and is characterized by the alveoli, and lung vasculature becoming inflamed and damaged. Complications from BPD can follow a patient into adulthood. As a child they may experience learning disabilities, pulmonary hypertension, and hearing problems. As an adult, there is an increased likelihood for asthma and exercise intolerance. Meconium Aspiration Syndrome occurs in full term or post-term infants who aspirate meconium . Risk factors include a diabetic mother, fetal hypoxia, precipitous delivery, and maternal high blood pressure. Its diagnosis is based on meconium stained amniotic fluid at delivery and staining on the skin, nails, and umbilical cord. Aspiration can cause airway obstruction, air-trapping, pneumonia, lung inflammation, and inactivated surfactant. It presents as patchy atelectasis and hyperinflation on an x-ray with a pneumothorax of pneumomediastinum also possible. Persistent Pulmonary Hypertension of the Newborn (PPHN) is a syndrome that occurs from an abnormal transition to extra-uterine life. It is marked by an elevated pulmonary vascular resistance and vasoconstriction causing a right-to-left shunt of the blood through the foramen ovale or ductus arteriosus . There are three main causes of PPHN are parenchymal diseases such as meconium aspiration syndrome, idiopathic, and hypoplastic vasculature like in a diaphragmatic hernia. It will eventually resolve in most infants. This is the only syndrome that inhaled nitric oxide is approved for by the FDA. Transient Tachypnea of the Newborn is caused by the retention of alveolar fluid in the lungs. It commonly occurs in infants who are delivered via caesarean section without the onset of labor because absorption of amniotic fluid in the lungs has not yet commenced. Other risk factors are male sex, macrosomia , multiple gestations, and maternal asthma. It usually presents with tachypnea and increased work of breathing. On an x-ray diffuse infiltrates, interlobar fissures, and sometimes pleural effusions can be seen. It is a diagnosis of exclusion because of its similarity to other diseases and frequently CPAP is used to help push the lung fluid into the pulmonary vasculature. Pulmonary interstitial emphysema is the condition of air escaping overdistended alveoli into the pulmonary interstitium. It is a rare disease that occurs most often in premature infants, even though it is possible to appear in adults. It often presents as a slow deterioration with the need for increased ventilatory support. Chest x-ray is the standard for diagnosis where it is seen as linear or cystic translucencies extending to the edges of the lungs. Bronchiolitis is the swelling and buildup of mucus in the bronchioles. It is usually caused by respiratory syncytial virus (RSV), which is spread when an infant touches the nose or throat fluids of someone infected. The virus infects the cells causing ciliary dysfunction and death. The debris, edema, and inflammation eventually leads to the symptoms. It is the most common reason for admission of children under the age of one year. It can present widely from a mild respiratory infection to respiratory failure. Since there is no medication to treat the disease, it is only managed supportively with fluids and oxygen. Respiratory diseases may be investigated by performing one or more of the following tests:Respiratory disease is a common and significant cause of illness and death around the world. In the US, approximately one billion common colds occur each year. A study found that in 2010, there were approximately 6.8 million emergency department visits for respiratory disorders in the U.S. for patients under the age of 18. In 2012, respiratory conditions were the most frequent reasons for hospital stays among children. In the UK, approximately 1 in 7 individuals are affected by some form of chronic lung disease, most commonly chronic obstructive pulmonary disease , which includes asthma , chronic bronchitis and emphysema . Respiratory diseases (including lung cancer) are responsible for over 10% of hospitalizations and over 16% of deaths in Canada. In 2011, respiratory disease with ventilator support accounted for 93.3% of ICU utilization in the United States.

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Acute hemorrhagic fever syndrome

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Upper gastrointestinal bleeding

Upper gastrointestinal bleeding is gastrointestinal bleeding ( hemorrhage ) in the upper gastrointestinal tract , commonly defined as bleeding arising from the esophagus , stomach , or duodenum . Blood may be observed in vomit or in altered form as black stool . Depending on the amount of the blood loss, symptoms may include shock . Upper gastrointestinal bleeding can be caused by peptic ulcers , gastric erosions , esophageal varices , and rarer causes such as gastric cancer . The initial assessment includes measurement of the blood pressure and heart rate , as well as blood tests to determine the hemoglobin . Significant upper gastrointestinal bleeding is considered a medical emergency . Fluid replacement , as well as blood transfusion , may be required. Endoscopy is recommended within 24 hours and bleeding can be stopped by various techniques. Proton pump inhibitors are often used. Tranexamic acid may also be useful. Procedures (such as TIPS for variceal bleeding) may be used. Recurrent or refractory bleeding may lead to need for surgery , although this has become uncommon as a result of improved endoscopic and medical treatment. Upper gastrointestinal bleeding affects around 50 to 150 people per 100,000 a year. It represents over 50% of cases of gastrointestinal bleeding. A 1995 UK study found an estimated mortality risk of 11% in those admitted to hospital for gastrointestinal bleeding. Persons with upper gastrointestinal bleeding often present with hematemesis , coffee ground vomiting , melena , or hematochezia (maroon-coloured stool) if the hemorrhage is severe. The presentation of bleeding depends on the amount and location of hemorrhage. A person with upper gastrointestinal bleeding may also present with complications of anemia , including chest pain , syncope , fatigue and shortness of breath . [ citation needed ] The physical examination performed by the physician concentrates on the following things: [ citation needed ] Laboratory findings include anemia , coagulopathy , and an elevated BUN-to-creatinine ratio .A number of medications increase the risk of bleeding including NSAIDs and SSRIs . SSRIs double the rate of upper gastrointestinal bleeding. There are many causes for upper gastrointestinal hemorrhage. Causes are usually anatomically divided into their location in the upper gastrointestinal tract. [ citation needed ] People are usually stratified into having either variceal or non-variceal sources of upper gastrointestinal hemorrhage, as the two have different treatment algorithms and prognosis. [ citation needed ] The causes for upper gastrointestinal hemorrhage include the following:The strongest predictors of an upper gastrointestinal bleed are black stool, age 12.9 g/dL (men) or >11.9 g/dL (women) Systolic blood pressure >109 mm Hg Pulse 12.9 g/dL (men) or >11.9 g/dL (women) Systolic blood pressure >109 mm Hg Pulse <100/minute Blood urea nitrogen level <18.2 mg/dL No melena or syncope No past or present liver disease or heart failureThe predictive values cited are based on the prevalences of upper gastrointestinal bleeding in the corresponding studies. A clinical calculator can be used to generate predictive values for other prevalences. [ citation needed ]The initial focus is on resuscitation beginning with airway management and fluid resuscitation using either intravenous fluids and or blood. A number of medications may improve outcomes depending on the source of the bleeding. Proton pump inhibitor medications are often given in the emergent setting before an endoscopy and may reduce the need for an endoscopic haemotstatic treatment. Proton pump inhibitors decrease gastric acid production. There is insufficient evidence to determine if proton pump inhibitors decrease death rates, re-bleeding events, or the need for surgical interventions. After the initial resuscitation has been completed, treatment is instigated to limit the likelihood of re-bleeds and correct any anemia that the bleeding may have caused. Those with a Glasgow Blatchford score less than 2 may not require admission to hospital. Based on evidence from people with other health problems crystalloid and colloids are believed to be equivalent for peptic ulcer bleeding. In people with a confirmed peptic ulcer, proton pump inhibitors do not reduce death rates, later bleeding events, or need for surgery. They may decrease signs of bleeding at endoscopy however. In those with less severe disease and where endoscopy is rapidly available, they are of less immediate clinical importance. Tranexamic acid might be effective to reduce mortality, but the evidence for this is weak. But the evidence is promising. Somatostatin and octreotide while recommended for variceal bleeding have not been found to be of general use for non-variceal bleeds. For initial fluid replacement colloids or albumin is preferred in people with cirrhosis. Medications typically includes octreotide or if not available vasopressin and nitroglycerin to reduce portal pressures. This is typically in addition to endoscopic banding or sclerotherapy for the varices. If this is sufficient then beta blockers and nitrates may be used for the prevention of re-bleeding. If bleeding continues then balloon tamponade with a Sengstaken-Blakemore tube or Minnesota tube may be used in an attempt to mechanically compress the varices. This may then be followed by a transjugular intrahepatic portosystemic shunt . If large amounts of pack red blood cells are used additional platelets and fresh frozen plasma should be administered to prevent coagulopathies . Some evidence supports holding off on blood transfusions in those who have a hemoglobin greater than 7 to 8 g/dL and only moderate bleeding. If the INR is greater than 1.5 to 1.8 correction with fresh frozen plasma, prothrombin complex may decrease mortality. Upper endoscopy within 24 hours is the recommended treatment. The benefits versus risks of placing a nasogastric tube in those with upper gastrointestinal bleeding are not well known. Prokinetic agents to empty thee stomach such as erythromycin before endoscopy can decrease the amount of blood in the stomach and thus improve the operators view. This erythromycin treatment may lead to a small decrease in the need for a blood transfusion, but the overall balance of how effective erythromycin is compared to potential risks is not clear. Proton pump inhibitors, if they have not been started earlier, are recommended in those in whom high risk signs for bleeding are found. It is also recommended that people with high risk signs are kept in hospital for at least 72 hours. Blood transfusions are not generally recommended to correct anemia, but blood transfusions are recommended if the person is not stable (cardiovascular system instability). Oral iron can be used, but this can lead to problems with compliance, tolerance, darkening stools which may mask evidence of rebleeding and tends to be slow, especially if used in conjunction with proton pump inhibitors. Parenteral Iron is increasingly used in these cases to improve patient outcomes and void blood usage. [ citation needed ]Based on evidence from people with other health problems crystalloid and colloids are believed to be equivalent for peptic ulcer bleeding. In people with a confirmed peptic ulcer, proton pump inhibitors do not reduce death rates, later bleeding events, or need for surgery. They may decrease signs of bleeding at endoscopy however. In those with less severe disease and where endoscopy is rapidly available, they are of less immediate clinical importance. Tranexamic acid might be effective to reduce mortality, but the evidence for this is weak. But the evidence is promising. Somatostatin and octreotide while recommended for variceal bleeding have not been found to be of general use for non-variceal bleeds. For initial fluid replacement colloids or albumin is preferred in people with cirrhosis. Medications typically includes octreotide or if not available vasopressin and nitroglycerin to reduce portal pressures. This is typically in addition to endoscopic banding or sclerotherapy for the varices. If this is sufficient then beta blockers and nitrates may be used for the prevention of re-bleeding. If bleeding continues then balloon tamponade with a Sengstaken-Blakemore tube or Minnesota tube may be used in an attempt to mechanically compress the varices. This may then be followed by a transjugular intrahepatic portosystemic shunt . If large amounts of pack red blood cells are used additional platelets and fresh frozen plasma should be administered to prevent coagulopathies . Some evidence supports holding off on blood transfusions in those who have a hemoglobin greater than 7 to 8 g/dL and only moderate bleeding. If the INR is greater than 1.5 to 1.8 correction with fresh frozen plasma, prothrombin complex may decrease mortality. Upper endoscopy within 24 hours is the recommended treatment. The benefits versus risks of placing a nasogastric tube in those with upper gastrointestinal bleeding are not well known. Prokinetic agents to empty thee stomach such as erythromycin before endoscopy can decrease the amount of blood in the stomach and thus improve the operators view. This erythromycin treatment may lead to a small decrease in the need for a blood transfusion, but the overall balance of how effective erythromycin is compared to potential risks is not clear. Proton pump inhibitors, if they have not been started earlier, are recommended in those in whom high risk signs for bleeding are found. It is also recommended that people with high risk signs are kept in hospital for at least 72 hours. Blood transfusions are not generally recommended to correct anemia, but blood transfusions are recommended if the person is not stable (cardiovascular system instability). Oral iron can be used, but this can lead to problems with compliance, tolerance, darkening stools which may mask evidence of rebleeding and tends to be slow, especially if used in conjunction with proton pump inhibitors. Parenteral Iron is increasingly used in these cases to improve patient outcomes and void blood usage. [ citation needed ]Depending on its severity, upper gastrointestinal bleeding may carry an estimated mortality risk of 11%. However, survival has improved to about 2 percent, likely as a result of improvements in medical therapy and endoscopic control of bleeding. About 75% of people presenting to the emergency department with gastrointestinal bleeding have an upper source. The diagnosis is easier when the people have hematemesis . In the absence of hematemesis, 40% to 50% of people in the emergency department with gastrointestinal bleeding have an upper source.

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Acute hemorrhagic fever syndrome

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Lupus

Lupus , technically known as systemic lupus erythematosus ( SLE ), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common symptoms include painful and swollen joints , fever , chest pain , hair loss , mouth ulcers , swollen lymph nodes , feeling tired , and a red rash which is most commonly on the face. Often there are periods of illness, called flares , and periods of remission during which there are few symptoms. The cause of SLE is not clear. It is thought to involve a combination of genetics and environmental factors . Among identical twins , if one is affected there is a 24% chance the other one will also develop the disease. Female sex hormones , sunlight, smoking, vitamin D deficiency , and certain infections are also believed to increase a person's risk. The mechanism involves an immune response by autoantibodies against a person's own tissues. These are most commonly anti-nuclear antibodies and they result in inflammation . Diagnosis can be difficult and is based on a combination of symptoms and laboratory tests. There are a number of other kinds of lupus erythematosus including discoid lupus erythematosus , neonatal lupus , and subacute cutaneous lupus erythematosus . There is no cure for SLE, but there are experimental and symptomatic treatments. Treatments may include NSAIDs , corticosteroids , immunosuppressants , hydroxychloroquine , and methotrexate . Although corticosteroids are rapidly effective, long-term use results in side effects. Alternative medicine has not been shown to affect the disease. Men have higher mortality. SLE significantly increases the risk of cardiovascular disease , with this being the most common cause of death. While women with lupus have higher risk pregnancies, most are successful. Rate of SLE varies between countries from 20 to 70 per 100,000. Women of childbearing age are affected about nine times more often than men. While it most commonly begins between the ages of 15 and 45, a wide range of ages can be affected. Those of African , Caribbean , and Chinese descent are at higher risk than those of European descent . Rates of disease in the developing world are unclear. Lupus is Latin for "wolf": the disease was so-named in the 13th century as the rash was thought to appear like a wolf's bite. SLE is one of several diseases known as " the great imitator " because it often mimics or is mistaken for other illnesses. SLE is a classical item in differential diagnosis , because SLE symptoms vary widely and come and go unpredictably. Diagnosis can thus be elusive, with some people having unexplained symptoms of SLE for years before a definitive diagnosis is reached. Common initial and chronic complaints include fever , malaise , joint pains , muscle pains , and fatigue . Because these symptoms are so often seen in association with other diseases, these signs and symptoms are not part of the diagnostic criteria for SLE. When occurring in conjunction with other signs and symptoms, however, they are considered suggestive. While SLE can occur in both males and females, it is found far more often in women, and the symptoms associated with each sex are different. Females tend to have a greater number of relapses , a low white blood cell count , more arthritis , Raynaud syndrome , and psychiatric symptoms . Males tend to have more seizures , kidney disease , serositis (inflammation of tissues lining the lungs and heart), skin problems , and peripheral neuropathy . As many as 70% of people with lupus have some skin symptoms. The three main categories of lesions are chronic cutaneous (discoid) lupus, subacute cutaneous lupus, and acute cutaneous lupus. People with discoid lupus may exhibit thick, red scaly patches on the skin. Similarly, subacute cutaneous lupus manifests as red, scaly patches of skin but with distinct edges. Acute cutaneous lupus manifests as a rash. Some have the classic malar rash (commonly known as the butterfly rash ) associated with the disease. This rash occurs in 30–60% of people with SLE. Hair loss , mouth and nasal ulcers, and lesions on the skin are other possible manifestations. The most commonly sought medical attention is for joint pain , with the small joints of the hand and wrist usually affected, although all joints are at risk. More than 90 percent of those affected will experience joint or muscle pain at some time during the course of their illness. Unlike rheumatoid arthritis , lupus arthritis is less disabling and usually does not cause severe destruction of the joints. Fewer than ten percent of people with lupus arthritis will develop deformities of the hands and feet. People with SLE are at particular risk of developing osteoarticular tuberculosis . A possible association between rheumatoid arthritis and SLE has been suggested, and SLE may be associated with an increased risk of bone fractures in relatively young women. Anemia is common in children with SLE and develops in about 50% of cases. Low platelet count ( thrombocytopenia ) and low white blood cell count ( leukopenia ) may be due to the disease or a side effect of pharmacological treatment. People with SLE may have an association with antiphospholipid antibody syndrome (a thrombotic disorder), wherein autoantibodies to phospholipids are present in their serum. Abnormalities associated with antiphospholipid antibody syndrome include a paradoxical prolonged partial thromboplastin time (which usually occurs in hemorrhagic disorders) and a positive test for antiphospholipid antibodies; the combination of such findings have earned the term " lupus anticoagulant -positive". Another autoantibody finding in SLE is the anti-cardiolipin antibody , which can cause a false positive test for syphilis . [ citation needed ] SLE may cause pericarditis (inflammation of the outer lining surrounding the heart), myocarditis (inflammation of the heart muscle), or endocarditis (inflammation of the inner lining of the heart). The endocarditis of SLE is non-infectious, and is also called Libman–Sacks endocarditis . It involves either the mitral valve or the tricuspid valve . Atherosclerosis also occurs more often and advances more rapidly than in the general population. Steroids are sometimes prescribed as an anti-inflammatory treatment for lupus; however, they can increase one's risk for heart disease, high cholesterol, and atherosclerosis. SLE can cause pleuritic pain as well as inflammation of the pleurae known as pleurisy , which can rarely give rise to shrinking lung syndrome involving a reduced lung volume. Other associated lung conditions include pneumonitis , chronic diffuse interstitial lung disease , pulmonary hypertension , pulmonary emboli , and pulmonary hemorrhage . [ citation needed ] Painless passage of blood or protein in the urine may often be the only presenting sign of kidney involvement. Acute or chronic renal impairment may develop with lupus nephritis , leading to acute or end-stage kidney failure . Because of early recognition and management of SLE with immunosuppressive drugs or corticosteroids, end-stage renal failure occurs in less than 5% of cases; except in the black population, where the risk is many times higher. The histological hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities. This finding is due to immune complex deposition along the glomerular basement membrane , leading to a typical granular appearance in immunofluorescence testing. Neuropsychiatric syndromes can result when SLE affects the central or peripheral nervous system . The American College of Rheumatology defines 19 neuropsychiatric syndromes in systemic lupus erythematosus. The diagnosis of neuropsychiatric syndromes concurrent with SLE (now termed as NPSLE), is one of the most difficult challenges in medicine, because it can involve so many different patterns of symptoms, some of which may be mistaken for signs of infectious disease or stroke. A common neurological disorder people with SLE have is headache , although the existence of a specific lupus headache and the optimal approach to headache in SLE cases remains controversial. Other common neuropsychiatric manifestations of SLE include cognitive disorder , mood disorder , cerebrovascular disease , seizures , polyneuropathy , anxiety disorder , psychosis , depression , and in some extreme cases, personality disorders. Steroid psychosis can also occur as a result of treating the disease. It can rarely present with intracranial hypertension syndrome , characterized by an elevated intracranial pressure , papilledema , and headache with occasional abducens nerve paresis , absence of a space-occupying lesion or ventricular enlargement, and normal cerebrospinal fluid chemical and hematological constituents. More rare manifestations are acute confusional state , Guillain–Barré syndrome , aseptic meningitis , autonomic disorder , demyelinating syndrome , mononeuropathy (which might manifest as mononeuritis multiplex ), movement disorder (more specifically, chorea ), myasthenia gravis , myelopathy , cranial neuropathy and plexopathy . [ citation needed ] Neurological disorders contribute to a significant percentage of morbidity and mortality in people with lupus. As a result, the neural side of lupus is being studied in hopes of reducing morbidity and mortality rates. One aspect of this disease is severe damage to the epithelial cells of the blood–brain barrier . In certain regions, depression affects up to 60% of women with SLE. Eye involvement is seen in up to one-third of people. The most common diseases are dry eye syndrome and secondary Sjögren's syndrome , but episcleritis , scleritis , retinopathy (more often affecting both eyes than one), ischemic optic neuropathy , retinal detachment , and secondary angle-closure glaucoma may occur. In addition, the medications used to treat SLE can cause eye disease: long-term glucocorticoid use can cause cataracts and secondary open-angle glaucoma, and long-term hydroxychloroquine treatment can cause vortex keratopathy and maculopathy . While most pregnancies have positive outcomes, there is a greater risk of adverse events occurring during pregnancy. SLE causes an increased rate of fetal death in utero and spontaneous abortion (miscarriage). The overall live-birth rate in people with SLE has been estimated to be 72%. Pregnancy outcome appears to be worse in people with SLE whose disease flares up during pregnancy. Neonatal lupus is the occurrence of SLE symptoms in an infant born from a mother with SLE, most commonly presenting with a rash resembling discoid lupus erythematosus , and sometimes with systemic abnormalities such as heart block or enlargement of the liver and spleen . Neonatal lupus is usually benign and self-limited. Medications for treatment of SLE can carry severe risks for female and male reproduction. Cyclophosphamide (also known as Cytoxan), can lead to infertility by causing premature ovarian insufficiency (POI), the loss of normal function of one's ovaries prior to age forty. Methotrexate can cause termination or deformity in fetuses and is a common abortifacient , and for men taking a high dose and planning to father, a discontinuation period of 6 months is recommended before insemination. Fatigue in SLE is probably multifactorial and has been related to not only disease activity or complications such as anemia or hypothyroidism , but also to pain , depression , poor sleep quality, poor physical fitness and lack of social support . As many as 70% of people with lupus have some skin symptoms. The three main categories of lesions are chronic cutaneous (discoid) lupus, subacute cutaneous lupus, and acute cutaneous lupus. People with discoid lupus may exhibit thick, red scaly patches on the skin. Similarly, subacute cutaneous lupus manifests as red, scaly patches of skin but with distinct edges. Acute cutaneous lupus manifests as a rash. Some have the classic malar rash (commonly known as the butterfly rash ) associated with the disease. This rash occurs in 30–60% of people with SLE. Hair loss , mouth and nasal ulcers, and lesions on the skin are other possible manifestations. The most commonly sought medical attention is for joint pain , with the small joints of the hand and wrist usually affected, although all joints are at risk. More than 90 percent of those affected will experience joint or muscle pain at some time during the course of their illness. Unlike rheumatoid arthritis , lupus arthritis is less disabling and usually does not cause severe destruction of the joints. Fewer than ten percent of people with lupus arthritis will develop deformities of the hands and feet. People with SLE are at particular risk of developing osteoarticular tuberculosis . A possible association between rheumatoid arthritis and SLE has been suggested, and SLE may be associated with an increased risk of bone fractures in relatively young women. Anemia is common in children with SLE and develops in about 50% of cases. Low platelet count ( thrombocytopenia ) and low white blood cell count ( leukopenia ) may be due to the disease or a side effect of pharmacological treatment. People with SLE may have an association with antiphospholipid antibody syndrome (a thrombotic disorder), wherein autoantibodies to phospholipids are present in their serum. Abnormalities associated with antiphospholipid antibody syndrome include a paradoxical prolonged partial thromboplastin time (which usually occurs in hemorrhagic disorders) and a positive test for antiphospholipid antibodies; the combination of such findings have earned the term " lupus anticoagulant -positive". Another autoantibody finding in SLE is the anti-cardiolipin antibody , which can cause a false positive test for syphilis . [ citation needed ]SLE may cause pericarditis (inflammation of the outer lining surrounding the heart), myocarditis (inflammation of the heart muscle), or endocarditis (inflammation of the inner lining of the heart). The endocarditis of SLE is non-infectious, and is also called Libman–Sacks endocarditis . It involves either the mitral valve or the tricuspid valve . Atherosclerosis also occurs more often and advances more rapidly than in the general population. Steroids are sometimes prescribed as an anti-inflammatory treatment for lupus; however, they can increase one's risk for heart disease, high cholesterol, and atherosclerosis. SLE can cause pleuritic pain as well as inflammation of the pleurae known as pleurisy , which can rarely give rise to shrinking lung syndrome involving a reduced lung volume. Other associated lung conditions include pneumonitis , chronic diffuse interstitial lung disease , pulmonary hypertension , pulmonary emboli , and pulmonary hemorrhage . [ citation needed ]Painless passage of blood or protein in the urine may often be the only presenting sign of kidney involvement. Acute or chronic renal impairment may develop with lupus nephritis , leading to acute or end-stage kidney failure . Because of early recognition and management of SLE with immunosuppressive drugs or corticosteroids, end-stage renal failure occurs in less than 5% of cases; except in the black population, where the risk is many times higher. The histological hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities. This finding is due to immune complex deposition along the glomerular basement membrane , leading to a typical granular appearance in immunofluorescence testing.Neuropsychiatric syndromes can result when SLE affects the central or peripheral nervous system . The American College of Rheumatology defines 19 neuropsychiatric syndromes in systemic lupus erythematosus. The diagnosis of neuropsychiatric syndromes concurrent with SLE (now termed as NPSLE), is one of the most difficult challenges in medicine, because it can involve so many different patterns of symptoms, some of which may be mistaken for signs of infectious disease or stroke. A common neurological disorder people with SLE have is headache , although the existence of a specific lupus headache and the optimal approach to headache in SLE cases remains controversial. Other common neuropsychiatric manifestations of SLE include cognitive disorder , mood disorder , cerebrovascular disease , seizures , polyneuropathy , anxiety disorder , psychosis , depression , and in some extreme cases, personality disorders. Steroid psychosis can also occur as a result of treating the disease. It can rarely present with intracranial hypertension syndrome , characterized by an elevated intracranial pressure , papilledema , and headache with occasional abducens nerve paresis , absence of a space-occupying lesion or ventricular enlargement, and normal cerebrospinal fluid chemical and hematological constituents. More rare manifestations are acute confusional state , Guillain–Barré syndrome , aseptic meningitis , autonomic disorder , demyelinating syndrome , mononeuropathy (which might manifest as mononeuritis multiplex ), movement disorder (more specifically, chorea ), myasthenia gravis , myelopathy , cranial neuropathy and plexopathy . [ citation needed ] Neurological disorders contribute to a significant percentage of morbidity and mortality in people with lupus. As a result, the neural side of lupus is being studied in hopes of reducing morbidity and mortality rates. One aspect of this disease is severe damage to the epithelial cells of the blood–brain barrier . In certain regions, depression affects up to 60% of women with SLE. Eye involvement is seen in up to one-third of people. The most common diseases are dry eye syndrome and secondary Sjögren's syndrome , but episcleritis , scleritis , retinopathy (more often affecting both eyes than one), ischemic optic neuropathy , retinal detachment , and secondary angle-closure glaucoma may occur. In addition, the medications used to treat SLE can cause eye disease: long-term glucocorticoid use can cause cataracts and secondary open-angle glaucoma, and long-term hydroxychloroquine treatment can cause vortex keratopathy and maculopathy . While most pregnancies have positive outcomes, there is a greater risk of adverse events occurring during pregnancy. SLE causes an increased rate of fetal death in utero and spontaneous abortion (miscarriage). The overall live-birth rate in people with SLE has been estimated to be 72%. Pregnancy outcome appears to be worse in people with SLE whose disease flares up during pregnancy. Neonatal lupus is the occurrence of SLE symptoms in an infant born from a mother with SLE, most commonly presenting with a rash resembling discoid lupus erythematosus , and sometimes with systemic abnormalities such as heart block or enlargement of the liver and spleen . Neonatal lupus is usually benign and self-limited. Medications for treatment of SLE can carry severe risks for female and male reproduction. Cyclophosphamide (also known as Cytoxan), can lead to infertility by causing premature ovarian insufficiency (POI), the loss of normal function of one's ovaries prior to age forty. Methotrexate can cause termination or deformity in fetuses and is a common abortifacient , and for men taking a high dose and planning to father, a discontinuation period of 6 months is recommended before insemination. Fatigue in SLE is probably multifactorial and has been related to not only disease activity or complications such as anemia or hypothyroidism , but also to pain , depression , poor sleep quality, poor physical fitness and lack of social support . SLE is presumably caused by a genetic susceptibility coupled with an environmental trigger which results in defects in the immune system. One of the factors associated with SLE is vitamin D deficiency . SLE does run in families, but no single causal gene has been identified. Instead, multiple genes appear to influence a person's chance of developing lupus when triggered by environmental factors. HLA class I, class II, and class III genes are associated with SLE, but only classes I and II contribute independently to increased risk of SLE. Other genes which contain risk variants for SLE are IRF5 , PTPN22 , STAT4 , CDKN1A , ITGAM , BLK , OX40L and BANK1 . Some of the susceptibility genes may be population specific. Genetic studies of the rates of disease in families supports the genetic basis of this disease with a heritability of >66%. Identical ( monozygotic ) twins were found to share susceptibility to the disease at >35% rate compared to fraternal ( dizygotic ) twins and other full siblings who only showed a 2–5% concordance in shared inheritance. Since SLE is associated with many genetic regions, it is likely an oligogenic trait, meaning that there are several genes that control susceptibility to the disease. SLE is regarded as a prototype disease due to the significant overlap in its symptoms with other autoimmune diseases. Drug-induced lupus erythematosus is a (generally) reversible condition that usually occurs in people being treated for a long-term illness. Drug-induced lupus mimics SLE. However, symptoms of drug-induced lupus generally disappear once the medication that triggered the episode is stopped. More than 38 medications can cause this condition, the most common of which are procainamide , isoniazid , hydralazine , quinidine , and phenytoin . Discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed by biopsy of rash on the face, neck, scalp or arms. Approximately 5% of people with DLE progress to SLE. SLE does run in families, but no single causal gene has been identified. Instead, multiple genes appear to influence a person's chance of developing lupus when triggered by environmental factors. HLA class I, class II, and class III genes are associated with SLE, but only classes I and II contribute independently to increased risk of SLE. Other genes which contain risk variants for SLE are IRF5 , PTPN22 , STAT4 , CDKN1A , ITGAM , BLK , OX40L and BANK1 . Some of the susceptibility genes may be population specific. Genetic studies of the rates of disease in families supports the genetic basis of this disease with a heritability of >66%. Identical ( monozygotic ) twins were found to share susceptibility to the disease at >35% rate compared to fraternal ( dizygotic ) twins and other full siblings who only showed a 2–5% concordance in shared inheritance. Since SLE is associated with many genetic regions, it is likely an oligogenic trait, meaning that there are several genes that control susceptibility to the disease. SLE is regarded as a prototype disease due to the significant overlap in its symptoms with other autoimmune diseases. Drug-induced lupus erythematosus is a (generally) reversible condition that usually occurs in people being treated for a long-term illness. Drug-induced lupus mimics SLE. However, symptoms of drug-induced lupus generally disappear once the medication that triggered the episode is stopped. More than 38 medications can cause this condition, the most common of which are procainamide , isoniazid , hydralazine , quinidine , and phenytoin . Discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed by biopsy of rash on the face, neck, scalp or arms. Approximately 5% of people with DLE progress to SLE. SLE is triggered by environmental factors that are unknown. In SLE, the body's immune system produces antibodies against self-protein , particularly against proteins in the cell nucleus . These antibody attacks are the immediate cause of SLE. SLE is a chronic inflammatory disease believed to be a type III hypersensitivity response with potential type II involvement. Reticulate and stellate acral pigmentation should be considered a possible manifestation of SLE and high titers of anti-cardiolipin antibodies , or a consequence of therapy. People with SLE have intense polyclonal B-cell activation, with a population shift towards immature B cells. Memory B cells with increased CD27 +/ IgD —are less susceptible to immunosuppression. CD27-/IgD- memory B cells are associated with increased disease activity and renal lupus. T cells, which regulate B-cell responses and infiltrate target tissues, have defects in signaling, adhesion, co-stimulation, gene transcription, and alternative splicing. The cytokines B-lymphocyte stimulator (BLyS), also known as B-cell activating factor (BAFF), interleukin 6, interleukin 17, interleukin 18, type I interferons, and tumor necrosis factor α (TNFα) are involved in the inflammatory process and are potential therapeutic targets. SLE is associated with low C3 levels in the complement system . Tingible body macrophages (TBMs) – large phagocytic cells in the germinal centers of secondary lymph nodes – express CD68 protein. These cells normally engulf B cells that have undergone apoptosis after somatic hypermutation . In some people with SLE, significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Also, uningested apoptotic nuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells. Dendritic cells in the germinal center may endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin and nuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating other B cells that may have randomly acquired self-protein specificity through somatic hypermutation. Necrosis, a pro-inflammatory form of cell death, is increased in T lymphocytes, due to mitochondrial dysfunction, oxidative stress, and depletion of ATP. Impaired clearance of dying cells is a potential pathway for the development of this systemic autoimmune disease . This includes deficient phagocytic activity, impaired lysosomal degradation, and scant serum components in addition to increased apoptosis . [ citation needed ] SLE is associated with defects in apoptotic clearance, and the damaging effects caused by apoptotic debris. Early apoptotic cells express "eat-me" signals, of cell-surface proteins such as phosphatidylserine, that prompt immune cells to engulf them. Apoptotic cells also express find-me signals to attract macrophages and dendritic cells. When apoptotic material is not removed correctly by phagocytes, they are captured instead by antigen-presenting cells, which leads to the development of antinuclear antibodies. Monocytes isolated from whole blood of people with SLE show reduced expression of CD44 surface molecules involved in the uptake of apoptotic cells. Most of the monocytes and tingible body macrophages (TBMs), which are found in the germinal centres of lymph nodes , even show a definitely different morphology; they are smaller or scarce and die earlier. Serum components like complement factors, CRP , and some glycoproteins are, furthermore, decisively important for an efficiently operating phagocytosis. With SLE, these components are often missing, diminished, or inefficient. [ citation needed ] Macrophages during SLE fail to mature their lysosomes and as a result have impaired degradation of internalized apoptotic debris, which results in chronic activation of Toll-like receptors and permeabilization of the phagolysosomal membrane, allowing activation of cytosolic sensors. In addition, intact apoptotic debris recycles back to the cell membrane and accumulate on the surface of the cell. Recent research has found an association between certain people with lupus (especially those with lupus nephritis ) and an impairment in degrading neutrophil extracellular traps (NETs). These were due to DNAse1 inhibiting factors, or NET protecting factors in people's serum, rather than abnormalities in the DNAse1 itself. DNAse1 mutations in lupus have so far only been found in some Japanese cohorts. The clearance of early apoptotic cells is an important function in multicellular organisms. It leads to a progression of the apoptosis process and finally to secondary necrosis of the cells if this ability is disturbed. Necrotic cells release nuclear fragments as potential autoantigens , as well as internal danger signals, inducing maturation of dendritic cells (DCs) since they have lost their membranes' integrity. Increased appearance of apoptotic cells also stimulates inefficient clearance. That leads to the maturation of DCs and also to the presentation of intracellular antigens of late apoptotic or secondary necrotic cells, via MHC molecules. Autoimmunity possibly results from the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells. B and T cell tolerance for apoptotic cells is abrogated, and the lymphocytes get activated by these autoantigens; inflammation and the production of autoantibodies by plasma cells is initiated. A clearance deficiency in the skin for apoptotic cells has also been observed in people with cutaneous lupus erythematosus (CLE). In healthy conditions, apoptotic lymphocytes are removed in germinal centers (GC) by specialized phagocytes, the tingible body macrophages (TBM), which is why no free apoptotic and potential autoantigenic material can be seen. In some people with SLE, a buildup of apoptotic debris can be observed in GC because of an ineffective clearance of apoptotic cells. Close to TBM, follicular dendritic cells (FDC) are localised in GC, which attach antigen material to their surface and, in contrast to bone marrow -derived DC, neither take it up nor present it via MHC molecules. Autoreactive B cells can accidentally emerge during somatic hypermutation and migrate into the germinal center light zone. Autoreactive B cells, maturated coincidentally, normally do not receive survival signals by antigen planted on follicular dendritic cells and perish by apoptosis. In the case of clearance deficiency, apoptotic nuclear debris accumulates in the light zone of GC and gets attached to FDC. This serves as a germinal centre survival signal for autoreactive B-cells. After migration into the mantle zone, autoreactive B cells require further survival signals from autoreactive helper T cells, which promote the maturation of autoantibody-producing plasma cells and B memory cells. In the presence of autoreactive T cells, a chronic autoimmune disease may be the consequence. Anti-nRNP autoantibodies to nRNP A and nRNP C initially targeted restricted, proline -rich motifs . Antibody binding subsequently spread to other epitopes . The similarity and cross-reactivity between the initial targets of nRNP and Sm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope spreading. Elevated expression of HMGB1 was found in the sera of people and mice with systemic lupus erythematosus, high mobility group box 1 ( HMGB1 ) is a nuclear protein participating in chromatin architecture and transcriptional regulation . Recently, there is increasing evidence HMGB1 contributes to the pathogenesis of chronic inflammatory and autoimmune diseases due to its inflammatory and immune stimulating properties. Tingible body macrophages (TBMs) – large phagocytic cells in the germinal centers of secondary lymph nodes – express CD68 protein. These cells normally engulf B cells that have undergone apoptosis after somatic hypermutation . In some people with SLE, significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Also, uningested apoptotic nuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells. Dendritic cells in the germinal center may endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin and nuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating other B cells that may have randomly acquired self-protein specificity through somatic hypermutation. Necrosis, a pro-inflammatory form of cell death, is increased in T lymphocytes, due to mitochondrial dysfunction, oxidative stress, and depletion of ATP. Impaired clearance of dying cells is a potential pathway for the development of this systemic autoimmune disease . This includes deficient phagocytic activity, impaired lysosomal degradation, and scant serum components in addition to increased apoptosis . [ citation needed ] SLE is associated with defects in apoptotic clearance, and the damaging effects caused by apoptotic debris. Early apoptotic cells express "eat-me" signals, of cell-surface proteins such as phosphatidylserine, that prompt immune cells to engulf them. Apoptotic cells also express find-me signals to attract macrophages and dendritic cells. When apoptotic material is not removed correctly by phagocytes, they are captured instead by antigen-presenting cells, which leads to the development of antinuclear antibodies. Monocytes isolated from whole blood of people with SLE show reduced expression of CD44 surface molecules involved in the uptake of apoptotic cells. Most of the monocytes and tingible body macrophages (TBMs), which are found in the germinal centres of lymph nodes , even show a definitely different morphology; they are smaller or scarce and die earlier. Serum components like complement factors, CRP , and some glycoproteins are, furthermore, decisively important for an efficiently operating phagocytosis. With SLE, these components are often missing, diminished, or inefficient. [ citation needed ] Macrophages during SLE fail to mature their lysosomes and as a result have impaired degradation of internalized apoptotic debris, which results in chronic activation of Toll-like receptors and permeabilization of the phagolysosomal membrane, allowing activation of cytosolic sensors. In addition, intact apoptotic debris recycles back to the cell membrane and accumulate on the surface of the cell. Recent research has found an association between certain people with lupus (especially those with lupus nephritis ) and an impairment in degrading neutrophil extracellular traps (NETs). These were due to DNAse1 inhibiting factors, or NET protecting factors in people's serum, rather than abnormalities in the DNAse1 itself. DNAse1 mutations in lupus have so far only been found in some Japanese cohorts. The clearance of early apoptotic cells is an important function in multicellular organisms. It leads to a progression of the apoptosis process and finally to secondary necrosis of the cells if this ability is disturbed. Necrotic cells release nuclear fragments as potential autoantigens , as well as internal danger signals, inducing maturation of dendritic cells (DCs) since they have lost their membranes' integrity. Increased appearance of apoptotic cells also stimulates inefficient clearance. That leads to the maturation of DCs and also to the presentation of intracellular antigens of late apoptotic or secondary necrotic cells, via MHC molecules. Autoimmunity possibly results from the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells. B and T cell tolerance for apoptotic cells is abrogated, and the lymphocytes get activated by these autoantigens; inflammation and the production of autoantibodies by plasma cells is initiated. A clearance deficiency in the skin for apoptotic cells has also been observed in people with cutaneous lupus erythematosus (CLE). In healthy conditions, apoptotic lymphocytes are removed in germinal centers (GC) by specialized phagocytes, the tingible body macrophages (TBM), which is why no free apoptotic and potential autoantigenic material can be seen. In some people with SLE, a buildup of apoptotic debris can be observed in GC because of an ineffective clearance of apoptotic cells. Close to TBM, follicular dendritic cells (FDC) are localised in GC, which attach antigen material to their surface and, in contrast to bone marrow -derived DC, neither take it up nor present it via MHC molecules. Autoreactive B cells can accidentally emerge during somatic hypermutation and migrate into the germinal center light zone. Autoreactive B cells, maturated coincidentally, normally do not receive survival signals by antigen planted on follicular dendritic cells and perish by apoptosis. In the case of clearance deficiency, apoptotic nuclear debris accumulates in the light zone of GC and gets attached to FDC. This serves as a germinal centre survival signal for autoreactive B-cells. After migration into the mantle zone, autoreactive B cells require further survival signals from autoreactive helper T cells, which promote the maturation of autoantibody-producing plasma cells and B memory cells. In the presence of autoreactive T cells, a chronic autoimmune disease may be the consequence.Anti-nRNP autoantibodies to nRNP A and nRNP C initially targeted restricted, proline -rich motifs . Antibody binding subsequently spread to other epitopes . The similarity and cross-reactivity between the initial targets of nRNP and Sm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope spreading. Elevated expression of HMGB1 was found in the sera of people and mice with systemic lupus erythematosus, high mobility group box 1 ( HMGB1 ) is a nuclear protein participating in chromatin architecture and transcriptional regulation . Recently, there is increasing evidence HMGB1 contributes to the pathogenesis of chronic inflammatory and autoimmune diseases due to its inflammatory and immune stimulating properties. Antinuclear antibody (ANA) testing and anti-extractable nuclear antigen ( anti-ENA ) form the mainstay of serologic testing for SLE. If ANA is negative the disease can be ruled out. Several techniques are used to detect ANAs. The most widely used is indirect immunofluorescence (IF). The pattern of fluorescence suggests the type of antibody present in the people's serum. Direct immunofluorescence can detect deposits of immunoglobulins and complement proteins in people's skin. When skin not exposed to the sun is tested, a positive direct IF (the so-called lupus band test ) is evidence of systemic lupus erythematosus. ANA screening yields positive results in many connective tissue disorders and other autoimmune diseases, and may occur in normal individuals. Subtypes of antinuclear antibodies include anti-Smith and anti-double stranded DNA (dsDNA) antibodies (which are linked to SLE) and anti-histone antibodies (which are linked to drug-induced lupus). Anti-dsDNA antibodies are highly specific for SLE; they are present in 70% of cases, whereas they appear in only 0.5% of people without SLE. Laboratory tests can also help distinguish between closely related connective tissue diseases. A multianalyte panel (MAP) of autoantibodies, including ANA, anti-dsDNA , and anti-Smith in combination with the measurement of cell-bound complement activation products (CB-CAPs) with an integrated algorithm has demonstrated 80% diagnostic sensitivity and 86% specificity in differentiating diagnosed SLE from other autoimmune connective tissue diseases. The MAP approach has been further studied in over 40,000 patients tested with either the MAP or traditional ANA testing strategy (tANA), demonstrating patients who test MAP positive are at up to 6-fold increased odds of receiving a new SLE diagnosis and up to 3-fold increased odds of starting a new SLE medication regimen as compared to patients testing positive with the tANA approach. The anti-dsDNA antibody titers also tend to reflect disease activity, although not in all cases. Other ANA that may occur in people with SLE are anti-U1 RNP (which also appears in systemic sclerosis and mixed connective tissue disease ), SS-A (or anti-Ro ) and SS-B (or anti-La ; both of which are more common in Sjögren's syndrome ). SS-A and SS-B confer a specific risk for heart conduction block in neonatal lupus. Other tests routinely performed in suspected SLE are complement system levels (low levels suggest consumption by the immune system), electrolytes and kidney function (disturbed if the kidney is involved), liver enzymes , and complete blood count . [ citation needed ] The lupus erythematosus (LE) cell test was commonly used for diagnosis, but it is no longer used because the LE cells are only found in 50–75% of SLE cases and they are also found in some people with rheumatoid arthritis, scleroderma, and drug sensitivities. Because of this, the LE cell test is now performed only rarely and is mostly of historical significance. Some physicians make a diagnosis based on the American College of Rheumatology (ACR) classification criteria. However, these criteria were primarily established for use in scientific research, including selection for randomized controlled trials , which require higher confidence levels. As a result, many people with SLE may not meet the full ACR criteria. [ citation needed ] The American College of Rheumatology (ACR) established eleven criteria in 1982, which were revised in 1997 as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individuals and do not do well in that capacity. For the purpose of identifying people for clinical studies, a person has SLE if any 4 out of 11 symptoms are present simultaneously or serially on two separate occasions. Other than the ACR criteria, people with lupus may also have: Fever (over 100 °F/ 37.7 °C) Extreme fatigue Hair loss Fingers turning white or blue when cold ( Raynaud syndrome ) Some people, especially those with antiphospholipid syndrome , may have SLE without four of the above criteria, and also SLE may present with features other than those listed in the criteria. Recursive partitioning has been used to identify more parsimonious criteria. This analysis presented two diagnostic classification trees: Simplest classification tree: SLE is diagnosed if a person has an immunologic disorder (anti-DNA antibody, anti-Smith antibody, false positive syphilis test, or LE cells) or malar rash . It has sensitivity = 92% and specificity = 92%. Full classification tree: Uses six criteria. It has sensitivity = 97% and specificity = 95%. Other alternative criteria have been suggested, e.g. the St. Thomas' Hospital "alternative" criteria in 1998. Antinuclear antibody (ANA) testing and anti-extractable nuclear antigen ( anti-ENA ) form the mainstay of serologic testing for SLE. If ANA is negative the disease can be ruled out. Several techniques are used to detect ANAs. The most widely used is indirect immunofluorescence (IF). The pattern of fluorescence suggests the type of antibody present in the people's serum. Direct immunofluorescence can detect deposits of immunoglobulins and complement proteins in people's skin. When skin not exposed to the sun is tested, a positive direct IF (the so-called lupus band test ) is evidence of systemic lupus erythematosus. ANA screening yields positive results in many connective tissue disorders and other autoimmune diseases, and may occur in normal individuals. Subtypes of antinuclear antibodies include anti-Smith and anti-double stranded DNA (dsDNA) antibodies (which are linked to SLE) and anti-histone antibodies (which are linked to drug-induced lupus). Anti-dsDNA antibodies are highly specific for SLE; they are present in 70% of cases, whereas they appear in only 0.5% of people without SLE. Laboratory tests can also help distinguish between closely related connective tissue diseases. A multianalyte panel (MAP) of autoantibodies, including ANA, anti-dsDNA , and anti-Smith in combination with the measurement of cell-bound complement activation products (CB-CAPs) with an integrated algorithm has demonstrated 80% diagnostic sensitivity and 86% specificity in differentiating diagnosed SLE from other autoimmune connective tissue diseases. The MAP approach has been further studied in over 40,000 patients tested with either the MAP or traditional ANA testing strategy (tANA), demonstrating patients who test MAP positive are at up to 6-fold increased odds of receiving a new SLE diagnosis and up to 3-fold increased odds of starting a new SLE medication regimen as compared to patients testing positive with the tANA approach. The anti-dsDNA antibody titers also tend to reflect disease activity, although not in all cases. Other ANA that may occur in people with SLE are anti-U1 RNP (which also appears in systemic sclerosis and mixed connective tissue disease ), SS-A (or anti-Ro ) and SS-B (or anti-La ; both of which are more common in Sjögren's syndrome ). SS-A and SS-B confer a specific risk for heart conduction block in neonatal lupus. Other tests routinely performed in suspected SLE are complement system levels (low levels suggest consumption by the immune system), electrolytes and kidney function (disturbed if the kidney is involved), liver enzymes , and complete blood count . [ citation needed ] The lupus erythematosus (LE) cell test was commonly used for diagnosis, but it is no longer used because the LE cells are only found in 50–75% of SLE cases and they are also found in some people with rheumatoid arthritis, scleroderma, and drug sensitivities. Because of this, the LE cell test is now performed only rarely and is mostly of historical significance. Some physicians make a diagnosis based on the American College of Rheumatology (ACR) classification criteria. However, these criteria were primarily established for use in scientific research, including selection for randomized controlled trials , which require higher confidence levels. As a result, many people with SLE may not meet the full ACR criteria. [ citation needed ] The American College of Rheumatology (ACR) established eleven criteria in 1982, which were revised in 1997 as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individuals and do not do well in that capacity. For the purpose of identifying people for clinical studies, a person has SLE if any 4 out of 11 symptoms are present simultaneously or serially on two separate occasions. Other than the ACR criteria, people with lupus may also have: Fever (over 100 °F/ 37.7 °C) Extreme fatigue Hair loss Fingers turning white or blue when cold ( Raynaud syndrome ) Some people, especially those with antiphospholipid syndrome , may have SLE without four of the above criteria, and also SLE may present with features other than those listed in the criteria. Recursive partitioning has been used to identify more parsimonious criteria. This analysis presented two diagnostic classification trees: Simplest classification tree: SLE is diagnosed if a person has an immunologic disorder (anti-DNA antibody, anti-Smith antibody, false positive syphilis test, or LE cells) or malar rash . It has sensitivity = 92% and specificity = 92%. Full classification tree: Uses six criteria. It has sensitivity = 97% and specificity = 95%. Other alternative criteria have been suggested, e.g. the St. Thomas' Hospital "alternative" criteria in 1998. The American College of Rheumatology (ACR) established eleven criteria in 1982, which were revised in 1997 as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individuals and do not do well in that capacity. For the purpose of identifying people for clinical studies, a person has SLE if any 4 out of 11 symptoms are present simultaneously or serially on two separate occasions. Other than the ACR criteria, people with lupus may also have: Fever (over 100 °F/ 37.7 °C) Extreme fatigue Hair loss Fingers turning white or blue when cold ( Raynaud syndrome )Some people, especially those with antiphospholipid syndrome , may have SLE without four of the above criteria, and also SLE may present with features other than those listed in the criteria. Recursive partitioning has been used to identify more parsimonious criteria. This analysis presented two diagnostic classification trees: Simplest classification tree: SLE is diagnosed if a person has an immunologic disorder (anti-DNA antibody, anti-Smith antibody, false positive syphilis test, or LE cells) or malar rash . It has sensitivity = 92% and specificity = 92%. Full classification tree: Uses six criteria. It has sensitivity = 97% and specificity = 95%. Other alternative criteria have been suggested, e.g. the St. Thomas' Hospital "alternative" criteria in 1998. There is no cure for Lupus. The treatment of SLE involves preventing flares and reducing their severity and duration when they occur. [ citation needed ] Treatment can include corticosteroids and anti-malarial drugs. Certain types of lupus nephritis such as diffuse proliferative glomerulonephritis require intermittent cytotoxic drugs. These drugs include cyclophosphamide and mycophenolate . Cyclophosphamide increases the risk of developing infections, pancreas problems, high blood sugar, and high blood pressure. Hydroxychloroquine was approved by the FDA for lupus in 1955. Some drugs approved for other diseases are used for SLE 'off-label'. In November 2010, an FDA advisory panel recommended approving belimumab (Benlysta) as a treatment for the pain and flare-ups common in lupus. The drug was approved by the FDA in March 2011. In terms of healthcare utilization and costs, one study found that "patients from the US with SLE, especially individuals with moderate or severe disease, utilize significant healthcare resources and incur high medical costs." Due to the variety of symptoms and organ system involvement with SLE, its severity in an individual must be assessed to successfully treat SLE. Mild or remittent disease may, sometimes, be safely left untreated. If required, nonsteroidal anti-inflammatory drugs and antimalarials may be used. Medications such as prednisone , mycophenolic acid and tacrolimus have been used in the past. [ citation needed ] Disease-modifying antirheumatic drugs (DMARDs) are used preventively to reduce the incidence of flares, the progress of the disease, and the need for steroid use; when flares occur, they are treated with corticosteroids . DMARDs commonly in use are antimalarials such as hydroxychloroquine and immunosuppressants (e.g. methotrexate and azathioprine ). Hydroxychloroquine is an FDA-approved antimalarial used for constitutional, cutaneous, and articular manifestations. Hydroxychloroquine has relatively few side effects, and there is evidence that it improves survival among people who have SLE. Cyclophosphamide is used for severe glomerulonephritis or other organ-damaging complications. Mycophenolic acid is also used for the treatment of lupus nephritis, but it is not FDA-approved for this indication, and FDA is investigating reports that it may be associated with birth defects when used by pregnant women. A study involving more than 1,000 people with lupus found that people have a similar risk of serious infection with azathioprine and mycophenolic acid as with newer biological therapies ( rituximab and belimumab ). In more severe cases, medications that modulate the immune system (primarily corticosteroids and immunosuppressants ) are used to control the disease and prevent recurrence of symptoms (known as flares). Depending on the dosage, people who require steroids may develop Cushing's syndrome , symptoms of which may include obesity , puffy round face, diabetes mellitus , increased appetite, difficulty sleeping, and osteoporosis . These may subside if and when the large initial dosage is reduced, but long-term use of even low doses can cause elevated blood pressure and cataracts . [ citation needed ] Numerous new immunosuppressive drugs are being actively tested for SLE. Rather than broadly suppressing the immune system, as corticosteroids do, they target the responses of specific types of immune cells. Some of these drugs are already FDA-approved for treatment of rheumatoid arthritis , however due to high-toxicity, their use remains limited. Since a large percentage of people with SLE have varying amounts of chronic pain , stronger prescription analgesics (painkillers) may be used if over-the-counter drugs (mainly nonsteroidal anti-inflammatory drugs ) do not provide effective relief. Potent NSAIDs such as indomethacin and diclofenac are relatively contraindicated for people with SLE because they increase the risk of kidney failure and heart failure. Pain is typically treated with opioids , varying in potency based on the severity of symptoms. When opioids are used for prolonged periods, drug tolerance, chemical dependency, and addiction may occur. Opiate addiction is not typically a concern since the condition is not likely to ever completely disappear. Thus, lifelong treatment with opioids is fairly common for chronic pain symptoms, accompanied by periodic titration that is typical of any long-term opioid regimen. [ citation needed ] Intravenous immunoglobulins may be used to control SLE with organ involvement, or vasculitis . It is believed that they reduce antibody production or promote the clearance of immune complexes from the body, even though their mechanism of action is not well understood. Unlike immunosuppressives and corticosteroids , IVIGs do not suppress the immune system , so there is less risk of serious infections with these drugs. Avoiding sunlight in SLE is critical since ultraviolet radiation is known to exacerbate skin manifestations of the disease. Avoiding activities that induce fatigue is also important since those with SLE fatigue easily and it can be debilitating. These two problems can lead to people becoming housebound for long periods of time. Physical exercise has been shown to help improve fatigue in adult with SLE. Drugs unrelated to SLE should be prescribed only when known not to exacerbate the disease. Occupational exposure to silica , pesticides , and mercury can also worsen the disease. Recommendations for evidence based non-pharmacological interventions in the management of SLE have been developed by an international task force of clinicians and patients with SLE. Kidney transplants are the treatment of choice for end-stage kidney disease , which is one of the complications of lupus nephritis , but the recurrence of the full disease is common in up to 30% of people. Approximately 20% of people with SLE have clinically significant levels of antiphospholipid antibodies, which are associated with antiphospholipid syndrome . Antiphospholipid syndrome is also related to the onset of neural lupus symptoms in the brain. In this form of the disease, the cause is very different from lupus: thromboses (blood clots or "sticky blood") form in blood vessels, which prove to be fatal if they move within the bloodstream. If the thromboses migrate to the brain, they can potentially cause a stroke by blocking the blood supply to the brain. If this disorder is suspected in people, brain scans are usually required for early detection. These scans can show localized areas of the brain where blood supply has not been adequate. The treatment plan for these people requires anticoagulation. Often, low-dose aspirin is prescribed for this purpose, although for cases involving thrombosis anticoagulants such as warfarin are used. While most infants born to mothers who have SLE are healthy, pregnant mothers with SLE should remain under medical care until delivery. Neonatal lupus is rare, but identification of mothers at the highest risk for complications allows for prompt treatment before or after birth. In addition, SLE can flare up during pregnancy, and proper treatment can maintain the health of the mother longer. Women pregnant and known to have anti-Ro (SSA) or anti-La antibodies (SSB) often have echocardiograms during the 16th and 30th weeks of pregnancy to monitor the health of the heart and surrounding vasculature. Contraception and other reliable forms of pregnancy prevention are routinely advised for women with SLE since getting pregnant during active disease was found to be harmful. Lupus nephritis was the most common manifestation. [ citation needed ]Due to the variety of symptoms and organ system involvement with SLE, its severity in an individual must be assessed to successfully treat SLE. Mild or remittent disease may, sometimes, be safely left untreated. If required, nonsteroidal anti-inflammatory drugs and antimalarials may be used. Medications such as prednisone , mycophenolic acid and tacrolimus have been used in the past. [ citation needed ] Disease-modifying antirheumatic drugs (DMARDs) are used preventively to reduce the incidence of flares, the progress of the disease, and the need for steroid use; when flares occur, they are treated with corticosteroids . DMARDs commonly in use are antimalarials such as hydroxychloroquine and immunosuppressants (e.g. methotrexate and azathioprine ). Hydroxychloroquine is an FDA-approved antimalarial used for constitutional, cutaneous, and articular manifestations. Hydroxychloroquine has relatively few side effects, and there is evidence that it improves survival among people who have SLE. Cyclophosphamide is used for severe glomerulonephritis or other organ-damaging complications. Mycophenolic acid is also used for the treatment of lupus nephritis, but it is not FDA-approved for this indication, and FDA is investigating reports that it may be associated with birth defects when used by pregnant women. A study involving more than 1,000 people with lupus found that people have a similar risk of serious infection with azathioprine and mycophenolic acid as with newer biological therapies ( rituximab and belimumab ). In more severe cases, medications that modulate the immune system (primarily corticosteroids and immunosuppressants ) are used to control the disease and prevent recurrence of symptoms (known as flares). Depending on the dosage, people who require steroids may develop Cushing's syndrome , symptoms of which may include obesity , puffy round face, diabetes mellitus , increased appetite, difficulty sleeping, and osteoporosis . These may subside if and when the large initial dosage is reduced, but long-term use of even low doses can cause elevated blood pressure and cataracts . [ citation needed ] Numerous new immunosuppressive drugs are being actively tested for SLE. Rather than broadly suppressing the immune system, as corticosteroids do, they target the responses of specific types of immune cells. Some of these drugs are already FDA-approved for treatment of rheumatoid arthritis , however due to high-toxicity, their use remains limited. Since a large percentage of people with SLE have varying amounts of chronic pain , stronger prescription analgesics (painkillers) may be used if over-the-counter drugs (mainly nonsteroidal anti-inflammatory drugs ) do not provide effective relief. Potent NSAIDs such as indomethacin and diclofenac are relatively contraindicated for people with SLE because they increase the risk of kidney failure and heart failure. Pain is typically treated with opioids , varying in potency based on the severity of symptoms. When opioids are used for prolonged periods, drug tolerance, chemical dependency, and addiction may occur. Opiate addiction is not typically a concern since the condition is not likely to ever completely disappear. Thus, lifelong treatment with opioids is fairly common for chronic pain symptoms, accompanied by periodic titration that is typical of any long-term opioid regimen. [ citation needed ] Intravenous immunoglobulins may be used to control SLE with organ involvement, or vasculitis . It is believed that they reduce antibody production or promote the clearance of immune complexes from the body, even though their mechanism of action is not well understood. Unlike immunosuppressives and corticosteroids , IVIGs do not suppress the immune system , so there is less risk of serious infections with these drugs. Disease-modifying antirheumatic drugs (DMARDs) are used preventively to reduce the incidence of flares, the progress of the disease, and the need for steroid use; when flares occur, they are treated with corticosteroids . DMARDs commonly in use are antimalarials such as hydroxychloroquine and immunosuppressants (e.g. methotrexate and azathioprine ). Hydroxychloroquine is an FDA-approved antimalarial used for constitutional, cutaneous, and articular manifestations. Hydroxychloroquine has relatively few side effects, and there is evidence that it improves survival among people who have SLE. Cyclophosphamide is used for severe glomerulonephritis or other organ-damaging complications. Mycophenolic acid is also used for the treatment of lupus nephritis, but it is not FDA-approved for this indication, and FDA is investigating reports that it may be associated with birth defects when used by pregnant women. A study involving more than 1,000 people with lupus found that people have a similar risk of serious infection with azathioprine and mycophenolic acid as with newer biological therapies ( rituximab and belimumab ). In more severe cases, medications that modulate the immune system (primarily corticosteroids and immunosuppressants ) are used to control the disease and prevent recurrence of symptoms (known as flares). Depending on the dosage, people who require steroids may develop Cushing's syndrome , symptoms of which may include obesity , puffy round face, diabetes mellitus , increased appetite, difficulty sleeping, and osteoporosis . These may subside if and when the large initial dosage is reduced, but long-term use of even low doses can cause elevated blood pressure and cataracts . [ citation needed ] Numerous new immunosuppressive drugs are being actively tested for SLE. Rather than broadly suppressing the immune system, as corticosteroids do, they target the responses of specific types of immune cells. Some of these drugs are already FDA-approved for treatment of rheumatoid arthritis , however due to high-toxicity, their use remains limited. Since a large percentage of people with SLE have varying amounts of chronic pain , stronger prescription analgesics (painkillers) may be used if over-the-counter drugs (mainly nonsteroidal anti-inflammatory drugs ) do not provide effective relief. Potent NSAIDs such as indomethacin and diclofenac are relatively contraindicated for people with SLE because they increase the risk of kidney failure and heart failure. Pain is typically treated with opioids , varying in potency based on the severity of symptoms. When opioids are used for prolonged periods, drug tolerance, chemical dependency, and addiction may occur. Opiate addiction is not typically a concern since the condition is not likely to ever completely disappear. Thus, lifelong treatment with opioids is fairly common for chronic pain symptoms, accompanied by periodic titration that is typical of any long-term opioid regimen. [ citation needed ]Intravenous immunoglobulins may be used to control SLE with organ involvement, or vasculitis . It is believed that they reduce antibody production or promote the clearance of immune complexes from the body, even though their mechanism of action is not well understood. Unlike immunosuppressives and corticosteroids , IVIGs do not suppress the immune system , so there is less risk of serious infections with these drugs. Avoiding sunlight in SLE is critical since ultraviolet radiation is known to exacerbate skin manifestations of the disease. Avoiding activities that induce fatigue is also important since those with SLE fatigue easily and it can be debilitating. These two problems can lead to people becoming housebound for long periods of time. Physical exercise has been shown to help improve fatigue in adult with SLE. Drugs unrelated to SLE should be prescribed only when known not to exacerbate the disease. Occupational exposure to silica , pesticides , and mercury can also worsen the disease. Recommendations for evidence based non-pharmacological interventions in the management of SLE have been developed by an international task force of clinicians and patients with SLE. Kidney transplants are the treatment of choice for end-stage kidney disease , which is one of the complications of lupus nephritis , but the recurrence of the full disease is common in up to 30% of people. Approximately 20% of people with SLE have clinically significant levels of antiphospholipid antibodies, which are associated with antiphospholipid syndrome . Antiphospholipid syndrome is also related to the onset of neural lupus symptoms in the brain. In this form of the disease, the cause is very different from lupus: thromboses (blood clots or "sticky blood") form in blood vessels, which prove to be fatal if they move within the bloodstream. If the thromboses migrate to the brain, they can potentially cause a stroke by blocking the blood supply to the brain. If this disorder is suspected in people, brain scans are usually required for early detection. These scans can show localized areas of the brain where blood supply has not been adequate. The treatment plan for these people requires anticoagulation. Often, low-dose aspirin is prescribed for this purpose, although for cases involving thrombosis anticoagulants such as warfarin are used. While most infants born to mothers who have SLE are healthy, pregnant mothers with SLE should remain under medical care until delivery. Neonatal lupus is rare, but identification of mothers at the highest risk for complications allows for prompt treatment before or after birth. In addition, SLE can flare up during pregnancy, and proper treatment can maintain the health of the mother longer. Women pregnant and known to have anti-Ro (SSA) or anti-La antibodies (SSB) often have echocardiograms during the 16th and 30th weeks of pregnancy to monitor the health of the heart and surrounding vasculature. Contraception and other reliable forms of pregnancy prevention are routinely advised for women with SLE since getting pregnant during active disease was found to be harmful. Lupus nephritis was the most common manifestation. [ citation needed ]No cure is available for SLE but there are many treatments for the disease. In the 1950s, most people diagnosed with SLE lived fewer than five years. Today, over 90% now survive for more than ten years, and many live relatively symptom-free. 80–90% can expect to live a normal lifespan. Mortality rates are however elevated compared to people without SLE. Prognosis is typically worse for men and children than for women; however, if symptoms are present after age 60, the disease tends to run a more benign course. Early mortality, within five years, is due to organ failure or overwhelming infections, both of which can be altered by early diagnosis and treatment. The mortality risk is fivefold when compared to the normal population in the late stages, which can be attributed to cardiovascular disease from accelerated atherosclerosis, the leading cause of death for people with SLE. To reduce the potential for cardiovascular issues, high blood pressure and high cholesterol should be prevented or treated aggressively. Steroids should be used at the lowest dose for the shortest possible period, and other drugs that can reduce symptoms should be used whenever possible. The global rates of SLE are approximately 20–70 per 100,000 people. In females, the rate is highest between 45 and 64 years of age. The lowest overall rate exists in Iceland and Japan. The highest rates exist in the US and France. However, there is not sufficient evidence to conclude why SLE is less common in some countries compared to others; it could be the environmental variability in these countries. For example, different countries receive different levels of sunlight, and exposure to UV rays affects dermatological symptoms of SLE. Certain studies hypothesize that a genetic connection exists between race and lupus which affects disease prevalence. If this is true, the racial composition of countries affects disease and will cause the incidence in a country to change as the racial makeup changes. To understand if this is true, countries with largely homogenous and racially stable populations should be studied to better understand incidence. Rates of disease in the developing world are unclear. The rate of SLE varies between countries, ethnicity, and sex, and changes over time. In the United States, one estimate of the rate of SLE is 53 per 100,000; another estimate places the total affected population at 322,000 to over 1 million (98 to over 305 per 100,000). In Northern Europe the rate is about 40 per 100,000 people. SLE occurs more frequently and with greater severity among those of non-European descent. That rate has been found to be as high as 159 per 100,000 among those of Afro-Caribbean descent. Childhood-onset systemic lupus erythematosus generally presents between the ages of 3 and 15 and is four times more common in girls. While the onset and persistence of SLE can show disparities between genders, socioeconomic status also plays a major role. Women with SLE and of lower socioeconomic status have been shown to have higher depression scores, higher body mass index, and more restricted access to medical care than women of higher socioeconomic statuses with the illness. People with SLE had more self-reported anxiety and depression scores if they were from a lower socioeconomic status. There are assertions that race affects the rate of SLE. However, a 2010 review of studies that correlate race and SLE identified several sources of systematic and methodological error, indicating that the connection between race and SLE may be spurious. For example, studies show that social support is a modulating factor which buffers against SLE-related damage and maintains physiological functionality. Studies have not been conducted to determine whether people of different racial backgrounds receive differing levels of social support. If there is a difference, this could act as a confounding variable in studies correlating race and SLE. Another caveat to note when examining studies about SLE is that symptoms are often self-reported. This process introduces additional sources of methodological error. Studies have shown that self-reported data is affected by more than just the patient's experience with the disease- social support, the level of helplessness, and abnormal illness-related behaviors also factor into a self-assessment. Additionally, other factors like the degree of social support that a person receives, socioeconomic status, health insurance, and access to care can contribute to an individual's disease progression. Racial differences in lupus progression have not been found in studies that control for the socioeconomic status [SES] of participants. Studies that control for the SES of its participants have found that non-white people have more abrupt disease onset compared to white people and that their disease progresses more quickly. Non-white patients often report more hematological, serosal, neurological, and renal symptoms. However, the severity of symptoms and mortality are both similar in white and non-white patients. Studies that report different rates of disease progression in late-stage SLE are most likely reflecting differences in socioeconomic status and the corresponding access to care. The people who receive medical care have often accrued less disease-related damage and are less likely to be below the poverty line. Additional studies have found that education, marital status, occupation, and income create a social context that affects disease progression. SLE, like many autoimmune diseases, affects females more frequently than males, at a rate of about 9 to 1. Hormonal mechanisms could explain the increased incidence of SLE in females. The onset of SLE could be attributed to the elevated hydroxylation of estrogen and the abnormally decreased levels of androgens in females. In addition, differences in GnRH signalling have also been shown to contribute to the onset of SLE. While females are more likely to relapse than males, the intensity of these relapses is the same for both sexes. In addition to hormonal mechanisms, specific genetic influences found on the X chromosome may also contribute to the development of SLE. The X chromosome carries immunologic genes like CD40L , which can mutate or simply escape silencing by X-chromosome inactivation and contribute to the onset of SLE. A study has shown an association between Klinefelter syndrome and SLE. XXY males with SLE have an abnormal X–Y translocation resulting in the partial triplication of the PAR1 gene region. Research has also implicated XIST , which encodes a long non-coding RNA that coats the inactive member of the pair of X chromosomes in females as part of a ribonucleoprotein complex, as a source of autoimmunity. The rate of SLE in the United States increased from 1.0 in 1955 to 7.6 in 1974. Whether the increase is due to better diagnosis or an increased frequency of the disease is unknown. There are assertions that race affects the rate of SLE. However, a 2010 review of studies that correlate race and SLE identified several sources of systematic and methodological error, indicating that the connection between race and SLE may be spurious. For example, studies show that social support is a modulating factor which buffers against SLE-related damage and maintains physiological functionality. Studies have not been conducted to determine whether people of different racial backgrounds receive differing levels of social support. If there is a difference, this could act as a confounding variable in studies correlating race and SLE. Another caveat to note when examining studies about SLE is that symptoms are often self-reported. This process introduces additional sources of methodological error. Studies have shown that self-reported data is affected by more than just the patient's experience with the disease- social support, the level of helplessness, and abnormal illness-related behaviors also factor into a self-assessment. Additionally, other factors like the degree of social support that a person receives, socioeconomic status, health insurance, and access to care can contribute to an individual's disease progression. Racial differences in lupus progression have not been found in studies that control for the socioeconomic status [SES] of participants. Studies that control for the SES of its participants have found that non-white people have more abrupt disease onset compared to white people and that their disease progresses more quickly. Non-white patients often report more hematological, serosal, neurological, and renal symptoms. However, the severity of symptoms and mortality are both similar in white and non-white patients. Studies that report different rates of disease progression in late-stage SLE are most likely reflecting differences in socioeconomic status and the corresponding access to care. The people who receive medical care have often accrued less disease-related damage and are less likely to be below the poverty line. Additional studies have found that education, marital status, occupation, and income create a social context that affects disease progression. SLE, like many autoimmune diseases, affects females more frequently than males, at a rate of about 9 to 1. Hormonal mechanisms could explain the increased incidence of SLE in females. The onset of SLE could be attributed to the elevated hydroxylation of estrogen and the abnormally decreased levels of androgens in females. In addition, differences in GnRH signalling have also been shown to contribute to the onset of SLE. While females are more likely to relapse than males, the intensity of these relapses is the same for both sexes. In addition to hormonal mechanisms, specific genetic influences found on the X chromosome may also contribute to the development of SLE. The X chromosome carries immunologic genes like CD40L , which can mutate or simply escape silencing by X-chromosome inactivation and contribute to the onset of SLE. A study has shown an association between Klinefelter syndrome and SLE. XXY males with SLE have an abnormal X–Y translocation resulting in the partial triplication of the PAR1 gene region. Research has also implicated XIST , which encodes a long non-coding RNA that coats the inactive member of the pair of X chromosomes in females as part of a ribonucleoprotein complex, as a source of autoimmunity. The rate of SLE in the United States increased from 1.0 in 1955 to 7.6 in 1974. Whether the increase is due to better diagnosis or an increased frequency of the disease is unknown. The history of SLE can be divided into three periods: classical, neoclassical, and modern. In each period, research and documentation advanced the understanding and diagnosis of SLE, leading to its classification as an autoimmune disease in 1851, and to the various diagnostic options and treatments now available to people with SLE. The advances made by medical science in the diagnosis and treatment of SLE have dramatically improved the life expectancy of a person diagnosed with SLE. There are several explanations ventured for the term lupus erythematosus. Lupus is Latin for "wolf", and in Medieval Latin was also used to refer to a disease of the skin, and "erythematosus" is derived from ἐρύθημα , Ancient Greek for "redness of the skin". All explanations originate with the reddish, butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks. The reason the term lupus was used to describe this disease comes from the mid-19th century. Many diseases that caused ulceration or necrosis were given the term "lupus" due to the wound being reminiscent of a wolf's bite. This is similar to the naming of lupus vulgaris or chronic facial tuberculosis, where the lesions are ragged and punched out and are said to resemble the bite of a wolf. The classical period began when the disease was first recognized in the Middle Ages. The term lupus is attributed to 12th-century Italian physician Rogerius Frugard , who used it to describe ulcerating sores on the legs of people. No formal treatment for the disease existed and the resources available to physicians to help people were limited. The neoclassical period began in 1851 when the skin disease which is now known as discoid lupus was documented by the French physician, Pierre Cazenave . Cazenave termed the illness lupus and added the word erythematosus to distinguish this disease from other illnesses that affected the skin except they were infectious. Cazenave observed the disease in several people and made very detailed notes to assist others in its diagnosis. He was one of the first to document that lupus affected adults from adolescence into the early thirties and that facial rash is its most distinguishing feature. Research and documentation of the disease continued in the neoclassical period with the work of Ferdinand von Hebra and his son-in-law, Moritz Kaposi . They documented the physical effects of lupus as well as some insights into the possibility that the disease caused internal trauma. Von Hebra observed that lupus symptoms could last many years and that the disease could go "dormant" after years of aggressive activity and then re-appear with symptoms following the same general pattern. These observations led Hebra to term lupus a chronic disease in 1872. Kaposi observed that lupus assumed two forms: the skin lesions (now known as discoid lupus) and a more aggravated form that affected not only the skin but also caused fever, arthritis, and other systemic disorders in people. The latter also presented a rash confined to the face, appearing on the cheeks and across the bridge of the nose; he called this the " butterfly rash ". Kaposi also observed those patients who developed the butterfly rash were often afflicted with another disease such as tuberculosis, anemia, or chlorisis which often caused death. Kaposi was one of the first people to recognize what is now termed systemic lupus erythematosus in his documentation of the remitting and relapsing nature of the disease and the relationship of skin and systemic manifestations during disease activity. The 19th century's research into lupus continued with the work of Sir William Osler who, in 1895, published the first of his three papers about the internal complications of erythema exudativum multiforme . Not all the patient cases in his paper had SLE but Osler's work expanded the knowledge of systemic diseases and documented extensive and critical visceral complications for several diseases including lupus. Noting that many people with lupus had a disease that not only affected the skin but many other organs in the body as well, Osler added the word "systemic" to the term lupus erythematosus to distinguish this type of disease from discoid lupus erythematosus. Osler's second paper noted that reoccurrence is a special feature of the disease and that attacks can be sustained for months or even years. Further study of the disease led to a third paper, published in 1903, documenting afflictions such as arthritis, pneumonia, the inability to form coherent ideas, delirium, and central nervous system damage as all affecting patients diagnosed with SLE. The modern period, beginning in 1920, saw major developments in research into the cause and treatment of discoid and systemic lupus. Research conducted in the 1920s and 1930s led to the first detailed pathologic descriptions of lupus and demonstrated how the disease affected the kidney, heart, and lung tissue. A breakthrough was made in 1948 with the discovery of the LE cell (the lupus erythematosus cell—a misnomer, as it occurs with other diseases as well). Discovered by a team of researchers at the Mayo Clinic , they discovered that the white blood cells contained the nucleus of another cell that was pushing against the white's cell proper nucleus. Noting that the invading nucleus was coated with antibody that allowed it to be ingested by a phagocytic or scavenger cell, they named the antibody that causes one cell to ingest another the LE factor and the two nuclei cell result in the LE cell. The LE cell, it was determined, was a part of an anti-nuclear antibody (ANA) reaction; the body produces antibodies against its own tissue. This discovery led to one of the first definitive tests for lupus since LE cells are found in approximately 60% of all people diagnosed with lupus. The LE cell test is rarely performed as a definitive lupus test today as LE cells do not always occur in people with SLE and can occur in individuals with other autoimmune diseases. Their presence can help establish a diagnosis but no longer indicates a definitive SLE diagnosis. The discovery of the LE cell led to further research and this resulted in more definitive tests for lupus. Building on the knowledge that those with SLE had auto-antibodies that would attach themselves to the nuclei of normal cells, causing the immune system to send white blood cells to fight off these "invaders", a test was developed to look for the anti-nuclear antibody (ANA) rather than the LE cell specifically. This ANA test was easier to perform and led not only to a definitive diagnosis of lupus but also many other related diseases. This discovery led to the understanding of what is now known as autoimmune diseases. To ensure that the person has lupus and not another autoimmune disease, the American College of Rheumatology (ACR) established a list of clinical and immunologic criteria that, in any combination, point to SLE. The criteria include symptoms that the person can identify (e.g. pain) and things that a physician can detect in a physical examination and through laboratory test results. The list was originally compiled in 1971, initially revised in 1982, and further revised and improved in 2009. Medical historians have theorized that people with porphyria (a disease that shares many symptoms with SLE) generated folklore stories of vampires and werewolves, due to the photosensitivity, scarring, hair growth, and porphyrin brownish-red stained teeth in severe recessive forms of porphyria (or combinations of the disorder, known as dual, homozygous, or compound heterozygous porphyrias). Useful medication for the disease was first found in 1894 when quinine was first reported as an effective therapy. Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit. This was the best available treatment until the middle of the twentieth century when Hench discovered the efficacy of corticosteroids in the treatment of SLE. There are several explanations ventured for the term lupus erythematosus. Lupus is Latin for "wolf", and in Medieval Latin was also used to refer to a disease of the skin, and "erythematosus" is derived from ἐρύθημα , Ancient Greek for "redness of the skin". All explanations originate with the reddish, butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks. The reason the term lupus was used to describe this disease comes from the mid-19th century. Many diseases that caused ulceration or necrosis were given the term "lupus" due to the wound being reminiscent of a wolf's bite. This is similar to the naming of lupus vulgaris or chronic facial tuberculosis, where the lesions are ragged and punched out and are said to resemble the bite of a wolf. The classical period began when the disease was first recognized in the Middle Ages. The term lupus is attributed to 12th-century Italian physician Rogerius Frugard , who used it to describe ulcerating sores on the legs of people. No formal treatment for the disease existed and the resources available to physicians to help people were limited. The neoclassical period began in 1851 when the skin disease which is now known as discoid lupus was documented by the French physician, Pierre Cazenave . Cazenave termed the illness lupus and added the word erythematosus to distinguish this disease from other illnesses that affected the skin except they were infectious. Cazenave observed the disease in several people and made very detailed notes to assist others in its diagnosis. He was one of the first to document that lupus affected adults from adolescence into the early thirties and that facial rash is its most distinguishing feature. Research and documentation of the disease continued in the neoclassical period with the work of Ferdinand von Hebra and his son-in-law, Moritz Kaposi . They documented the physical effects of lupus as well as some insights into the possibility that the disease caused internal trauma. Von Hebra observed that lupus symptoms could last many years and that the disease could go "dormant" after years of aggressive activity and then re-appear with symptoms following the same general pattern. These observations led Hebra to term lupus a chronic disease in 1872. Kaposi observed that lupus assumed two forms: the skin lesions (now known as discoid lupus) and a more aggravated form that affected not only the skin but also caused fever, arthritis, and other systemic disorders in people. The latter also presented a rash confined to the face, appearing on the cheeks and across the bridge of the nose; he called this the " butterfly rash ". Kaposi also observed those patients who developed the butterfly rash were often afflicted with another disease such as tuberculosis, anemia, or chlorisis which often caused death. Kaposi was one of the first people to recognize what is now termed systemic lupus erythematosus in his documentation of the remitting and relapsing nature of the disease and the relationship of skin and systemic manifestations during disease activity. The 19th century's research into lupus continued with the work of Sir William Osler who, in 1895, published the first of his three papers about the internal complications of erythema exudativum multiforme . Not all the patient cases in his paper had SLE but Osler's work expanded the knowledge of systemic diseases and documented extensive and critical visceral complications for several diseases including lupus. Noting that many people with lupus had a disease that not only affected the skin but many other organs in the body as well, Osler added the word "systemic" to the term lupus erythematosus to distinguish this type of disease from discoid lupus erythematosus. Osler's second paper noted that reoccurrence is a special feature of the disease and that attacks can be sustained for months or even years. Further study of the disease led to a third paper, published in 1903, documenting afflictions such as arthritis, pneumonia, the inability to form coherent ideas, delirium, and central nervous system damage as all affecting patients diagnosed with SLE. The modern period, beginning in 1920, saw major developments in research into the cause and treatment of discoid and systemic lupus. Research conducted in the 1920s and 1930s led to the first detailed pathologic descriptions of lupus and demonstrated how the disease affected the kidney, heart, and lung tissue. A breakthrough was made in 1948 with the discovery of the LE cell (the lupus erythematosus cell—a misnomer, as it occurs with other diseases as well). Discovered by a team of researchers at the Mayo Clinic , they discovered that the white blood cells contained the nucleus of another cell that was pushing against the white's cell proper nucleus. Noting that the invading nucleus was coated with antibody that allowed it to be ingested by a phagocytic or scavenger cell, they named the antibody that causes one cell to ingest another the LE factor and the two nuclei cell result in the LE cell. The LE cell, it was determined, was a part of an anti-nuclear antibody (ANA) reaction; the body produces antibodies against its own tissue. This discovery led to one of the first definitive tests for lupus since LE cells are found in approximately 60% of all people diagnosed with lupus. The LE cell test is rarely performed as a definitive lupus test today as LE cells do not always occur in people with SLE and can occur in individuals with other autoimmune diseases. Their presence can help establish a diagnosis but no longer indicates a definitive SLE diagnosis. The discovery of the LE cell led to further research and this resulted in more definitive tests for lupus. Building on the knowledge that those with SLE had auto-antibodies that would attach themselves to the nuclei of normal cells, causing the immune system to send white blood cells to fight off these "invaders", a test was developed to look for the anti-nuclear antibody (ANA) rather than the LE cell specifically. This ANA test was easier to perform and led not only to a definitive diagnosis of lupus but also many other related diseases. This discovery led to the understanding of what is now known as autoimmune diseases. To ensure that the person has lupus and not another autoimmune disease, the American College of Rheumatology (ACR) established a list of clinical and immunologic criteria that, in any combination, point to SLE. The criteria include symptoms that the person can identify (e.g. pain) and things that a physician can detect in a physical examination and through laboratory test results. The list was originally compiled in 1971, initially revised in 1982, and further revised and improved in 2009. Medical historians have theorized that people with porphyria (a disease that shares many symptoms with SLE) generated folklore stories of vampires and werewolves, due to the photosensitivity, scarring, hair growth, and porphyrin brownish-red stained teeth in severe recessive forms of porphyria (or combinations of the disorder, known as dual, homozygous, or compound heterozygous porphyrias). Useful medication for the disease was first found in 1894 when quinine was first reported as an effective therapy. Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit. This was the best available treatment until the middle of the twentieth century when Hench discovered the efficacy of corticosteroids in the treatment of SLE. A study called BLISS-76 tested the drug belimumab , a fully human monoclonal anti- BAFF (or anti-BLyS) antibody. BAFF stimulates and extends the life of B lymphocytes , which produce antibodies against foreign and self-protein . It was approved by the FDA in March 2011. Genetically engineered immune cells are also being studied in animal models of the disease as of 2019. In September 2022, researchers at the University of Erlangen-Nuremberg published promising results using genetically altered immune cells to treat severely ill patients. Four women and one man received transfusions of CAR T cells modified to attack their B cells , eliminating the aberrant ones. The therapy drove the disease into remission in all five patients, who have been off lupus medication for several months after the treatment ended.

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Acute hemorrhagic fever syndrome

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Pulmonary embolism

Pulmonary embolism ( PE ) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream ( embolism ). Symptoms of a PE may include shortness of breath , chest pain particularly upon breathing in, and coughing up blood . Symptoms of a blood clot in the leg may also be present, such as a red , warm, swollen, and painful leg. Signs of a PE include low blood oxygen levels , rapid breathing , rapid heart rate , and sometimes a mild fever . Severe cases can lead to passing out , abnormally low blood pressure , obstructive shock , and sudden death . PE usually results from a blood clot in the leg that travels to the lung. The risk of blood clots is increased by advanced age , cancer , prolonged bed rest and immobilization, smoking , stroke , long-haul travel over 4 hours, certain genetic conditions, estrogen-based medication , pregnancy , obesity , trauma or bone fracture , and after some types of surgery. A small proportion of cases are due to the embolization of air , fat , or amniotic fluid . Diagnosis is based on signs and symptoms in combination with test results. If the risk is low, a blood test known as a D-dimer may rule out the condition. Otherwise, a CT pulmonary angiography , lung ventilation/perfusion scan , or ultrasound of the legs may confirm the diagnosis. Together, deep vein thrombosis and PE are known as venous thromboembolism (VTE). Efforts to prevent PE include beginning to move as soon as possible after surgery, lower leg exercises during periods of sitting, and the use of blood thinners after some types of surgery. Treatment is with anticoagulants such as heparin , warfarin or one of the direct-acting oral anticoagulants (DOACs). These are recommended for at least three months. However, treatment using anticoagulants is not recommended for those at high risk of bleeding, as well as those with renal failure. Severe cases may require thrombolysis using medication such as tissue plasminogen activator (tPA) given intravenously or through a catheter, and some may require surgery (a pulmonary thrombectomy ). If blood thinners are not appropriate, a temporary vena cava filter may be used. Pulmonary emboli affect about 430,000 people each year in Europe. In the United States, between 300,000 and 600,000 cases occur each year, which contribute to at least 40,000 deaths. Rates are similar in males and females. They become more common as people get older. Symptoms of pulmonary embolism are typically sudden in onset and may include one or many of the following: dyspnea (shortness of breath), tachypnea (rapid breathing), chest pain of a "pleuritic" nature (worsened by breathing), cough and hemoptysis (coughing up blood). More severe cases can include signs such as cyanosis (blue discoloration, usually of the lips and fingers), collapse, and circulatory instability because of decreased blood flow through the lungs and into the left side of the heart. About 15% of all cases of sudden death are attributable to PE. While PE may present with syncope , less than 1% of syncope cases are due to PE. On physical examination, the lungs are usually normal. Occasionally, a pleural friction rub may be audible over the affected area of the lung (mostly in PE with infarct ). A pleural effusion is sometimes present that is exudative, detectable by decreased percussion note, audible breath sounds, and vocal resonance. Strain on the right ventricle may be detected as a left parasternal heave, a loud pulmonary component of the second heart sound , and/or raised jugular venous pressure . A low-grade fever may be present, particularly if there is associated pulmonary hemorrhage or infarction. As smaller pulmonary emboli tend to lodge in more peripheral areas without collateral circulation, they are more likely to cause lung infarction and small effusions (both of which are painful), but not hypoxia, dyspnea, or hemodynamic instability such as tachycardia. Larger PEs, which tend to lodge centrally, typically cause dyspnea, hypoxia, low blood pressure , fast heart rate and fainting , but are often painless because there is no lung infarction due to collateral circulation. The classic presentation for PE with pleuritic pain, dyspnea, and tachycardia is likely caused by a large fragmented embolism causing both large and small PEs. Thus, small PEs are often missed because they cause pleuritic pain alone without any other findings and large PEs are often missed because they are painless and mimic other conditions often causing ECG changes and small rises in troponin and brain natriuretic peptide levels. PEs are sometimes described as massive, submassive, and nonmassive depending on the clinical signs and symptoms. Although the exact definitions of these are unclear, an accepted definition of massive PE is one in which there is hemodynamic instability. This is a cause of obstructive shock, which presents as sustained low blood pressure, slowed heart rate , or pulselessness. About 90% of emboli are from a deep vein thrombosis located above the knee termed a proximal DVT , which includes an iliofemoral DVT . The rare venous thoracic outlet syndrome can also be a cause of DVTs, especially in young men without significant risk factors. DVTs are at risk for dislodging and migrating to the lung circulation. The conditions are generally regarded as a continuum known as a venous thromboembolism (VTE). [ citation needed ] VTE is much more common in immunocompromised individuals as well as individuals with comorbidities including: The development of thrombosis is classically due to a group of causes named Virchow's triad (alterations in blood flow, factors in the vessel wall, and factors affecting the properties of the blood). Often, more than one risk factor is present. [ citation needed ] Although most pulmonary embolisms are the result of proximal DVTs , there are still many other risk factors that can also result in a pulmonary embolism. After a first PE, the search for secondary causes is usually brief. Only when a second PE occurs, and especially when this happens while still under anticoagulant therapy, a further search for underlying conditions is undertaken. This will include testing ("thrombophilia screen") for Factor V Leiden mutation , antiphospholipid antibodies, protein C and S and antithrombin levels, and later prothrombin mutation, MTHFR mutation, Factor VIII concentration and rarer inherited coagulation abnormalities. After a first PE, the search for secondary causes is usually brief. Only when a second PE occurs, and especially when this happens while still under anticoagulant therapy, a further search for underlying conditions is undertaken. This will include testing ("thrombophilia screen") for Factor V Leiden mutation , antiphospholipid antibodies, protein C and S and antithrombin levels, and later prothrombin mutation, MTHFR mutation, Factor VIII concentration and rarer inherited coagulation abnormalities. To diagnose a pulmonary embolism, a review of clinical criteria to determine the need for testing is recommended. In those who have low risk, age less than 50, heart rate less than 100 beats per minute, oxygen level more than 94% on room air, and no leg swelling, coughing up of blood, surgery or trauma in the last four weeks, previous blood clots, or estrogen use, further testing is not typically needed. In situations with more high risk individuals, further testing is needed. A CT pulmonary angiogram (CTPA) is the preferred method for diagnosis of a pulmonary embolism due to its easy administration and accuracy. Although a CTPA is preferred, there are also other tests that can be done. For example, a proximal lower limb compression ultrasound (CUS) can be used. This is a test which is primarily used as a confirmatory test, meaning it confirms a previous analysis showing the presence or suspected presence of a pulmonary embolism. According to a cross-sectional study, CUS tests have a sensitivity of 41% and specificity of 96%. If there are concerns this is followed by testing to determine a likelihood of being able to confirm a diagnosis by imaging, followed by imaging if other tests have shown that there is a likelihood of a PE diagnosis. The diagnosis of PE is based primarily on validated clinical criteria combined with selective testing because the typical clinical presentation ( shortness of breath , chest pain ) cannot be definitively differentiated from other causes of chest pain and shortness of breath. The decision to perform medical imaging is based on clinical reasoning, that is, the medical history , symptoms, and findings on physical examination , followed by an assessment of clinical probability. The most commonly used method to predict clinical probability, the Wells score , is a clinical prediction rule , whose use is complicated by multiple versions being available. In 1995, Philip Steven Wells , initially developed a prediction rule (based on a literature search) to predict the likelihood of DVT, based on clinical criteria. A new prediction score for PE was created in 1998 This prediction rule was revised by Wells et al. in 2000. In the 2000 publication, Wells proposed two different scoring systems using cutoffs of 2 or 4 with the same prediction rule, and also included D-dimer testing in the rule-out of PE in low probability patients. In 2001, Wells published results using the more conservative cutoff of 2 to create three categories. An additional version, the "modified extended version", using the more recent cutoff of 2 but including findings from Wells's initial studies were proposed. Most recently, a further study reverted to Wells's earlier use of a cutoff of 4 points to create only two categories. There are additional prediction rules for PE, such as the Geneva rule . More importantly, the use of any rule is associated with reduction in recurrent thromboembolism . The Wells score : Traditional interpretation Alternative interpretation Score > 4 – PE likely. Consider diagnostic imaging. Score 4 or less – PE unlikely. Consider D-dimer to rule out PE. Recommendations for a diagnostic algorithm were published by the PIOPED investigators; however, these recommendations do not reflect research using 64 slice MDCT. These investigators recommended: Low clinical probability. If negative D-dimer, PE is excluded. If positive D-dimer, obtain MDCT and base treatment on results. Moderate clinical probability. If negative D-dimer, PE is excluded. However , the authors were not concerned that a negative MDCT with negative D-dimer in this setting has a 5% probability of being false. Presumably, the 5% error rate will fall as 64 slice MDCT is more commonly used. If positive D-dimer, obtain MDCT and base treatment on results. High clinical probability. Proceed to MDCT. If positive, treat, if negative, more tests are needed to exclude PE. A D-dimer of less than 750 ug/L does not rule out PE in those who are at high risk. The pulmonary embolism rule-out criteria (PERC) helps assess people in whom pulmonary embolism is suspected, but unlikely. Unlike the Wells score and Geneva score , which are clinical prediction rules intended to risk stratify people with suspected PE, the PERC rule is designed to rule out the risk of PE in people when the physician has already stratified them into a low-risk category. People in this low risk category without any of these criteria may undergo no further testing for PE: low oxygen saturations – Sa O 2 50, hormone use, fast heart rate. The rationale behind this decision is that further testing (specifically CT angiogram of the chest) may cause more harm (from radiation exposure and contrast dye) than the risk of PE. The PERC rule has a sensitivity of 97.4% and specificity of 21.9% with a false negative rate of 1.0% (16/1666). In people with a low or moderate suspicion of PE, a normal D-dimer level (shown in a blood test ) is enough to exclude the possibility of thrombotic PE, with a three-month risk of thromboembolic events being 0.14%. D-dimer is highly sensitive but not specific (specificity around 50%). In other words, a positive D-dimer is not synonymous with PE, but a negative D-dimer is, with a good degree of certainty, an indication of absence of a PE. A low pretest probability is also valuable in ruling out PE. The typical cut off is 500 μg/L, although this varies based on the assay. However, in those over the age of 50, changing the cut-off value to the person's age multiplied by 10 μg/L (accounting for assay which has been used) is recommended as it decreases the number of falsely positive tests without missing any additional cases of PE. When a PE is being suspected, several blood tests are done in order to exclude important secondary causes of PE. This includes a full blood count , clotting status ( PT , aPTT , TT ), and some screening tests ( erythrocyte sedimentation rate , kidney function , liver enzymes , electrolytes ). If one of these is abnormal, further investigations might be warranted to the issue. Troponin levels are increased in between 16 and 47% with pulmonary embolism. In typical people who are not known to be at high risk of PE, imaging is helpful to confirm or exclude a diagnosis of PE after simpler first-line tests are used. Medical societies recommend tests such as the D-dimer to first provide supporting evidence for the need for imaging, and imaging would be done if other tests confirmed a moderate or high probability of finding evidence to support a diagnosis of PE. CT pulmonary angiography is the recommended first line diagnostic imaging test in most people. Ultrasound of the legs can confirm the presence of a PE but cannot rule it out. CT pulmonary angiography (CTPA) is a pulmonary angiogram obtained using computed tomography (CT) with radiocontrast rather than right heart catheterization. Its advantages are that it is accurate, it is non-invasive, it is more often available, and it may identifying other lung disorders in case there is no pulmonary embolism. The accuracy and non-invasive nature of CTPA also make it advantageous for people who are pregnant. Assessing the accuracy of CT pulmonary angiography is hindered by the rapid changes in the number of rows of detectors available in multidetector CT (MDCT) machines. According to a cohort study , single-slice spiral CT may help diagnose detection among people with suspected pulmonary embolism. In this study, the sensitivity was 69% and specificity was 84%. In this study which had a prevalence of detection was 32%, the positive predictive value of 67.0% and negative predictive value of 85.2%. However, this study's results may be biased due to possible incorporation bias, since the CT scan was the final diagnostic tool in people with pulmonary embolism. The authors noted that a negative single slice CT scan is insufficient to rule out pulmonary embolism on its own. A separate study with a mixture of 4 slice and 16 slice scanners reported a sensitivity of 83% and a specificity of 96%, which means that it is a good test for ruling out a pulmonary embolism if it is not seen on imaging and that it is very good at confirming a pulmonary embolism is present if it is seen. This study noted that additional testing is necessary when the clinical probability is inconsistent with the imaging results. CTPA is non-inferior to VQ scanning, and identifies more emboli (without necessarily improving the outcome) compared to VQ scanning. A ventilation/perfusion scan (or V/Q scan or lung scintigraphy ) shows that some areas of the lung are being ventilated but not perfused with blood (due to obstruction by a clot). This type of examination is as accurate as multislice CT, but is less used, due to the greater availability of CT technology. It is particularly useful in people who have an allergy to iodinated contrast , impaired kidney function, or are pregnant (due to its lower radiation exposure as compared to CT). The test can be performed with planar two-dimensional imaging, or single photon emission computed tomography ( SPECT ) which enables three-dimensional imaging. Hybrid devices combining SPECT and CT (SPECT/CT) further enable anatomic characterization of any abnormality. Tests that are frequently done that are not sensitive for PE, but can be diagnostic. Historically, the gold standard for diagnosis was pulmonary angiography by fluoroscopy , but this has fallen into disuse with the increased availability of non-invasive techniques that offer similar diagnostic accuracy. The primary use of the ECG is to rule out other causes of chest pain. An electrocardiogram (ECG) is routinely done on people with chest pain to quickly diagnose myocardial infarctions (heart attacks), an important differential diagnosis in an individual with chest pain. While certain ECG changes may occur with PE, none are specific enough to confirm or sensitive enough to rule out the diagnosis. An ECG may show signs of right heart strain or acute cor pulmonale in cases of large PEs – the classic signs are a large S wave in lead I, a large Q wave in lead III, and an inverted T wave in lead III (S1Q3T3), which occurs in 12–50% of people with the diagnosis, yet also occurs in 12% without the diagnosis. This is occasionally present (occurring in up to 20% of people), but may also occur in other acute lung conditions, and, therefore, has limited diagnostic value. The most commonly seen signs in the ECG are sinus tachycardia , right axis deviation, and right bundle branch block . Sinus tachycardia, however, is still only found in 8–69% of people with PE. ECG findings associated with pulmonary emboli may suggest worse prognosis since the six findings identified with RV strain on ECG (heart rate > 100 beats per minute, S1Q3T3, inverted T waves in leads V1-V4, ST elevation in aVR, complete right bundle branch block, and atrial fibrillation) are associated with increased risk of circulatory shock and death. Cases with inverted T in leads V 1-3 are suspected with PE or inferior myocardial infarction. PE cases show inverted T waves in leads II and aV F , but inferior myocardial infarction cases do not show inverted T waves in II and aV F . In massive and submassive PE, dysfunction of the right side of the heart may be seen on echocardiography , an indication that the pulmonary artery is severely obstructed and the right ventricle , a low-pressure pump, is unable to match the pressure. Some studies (see below) suggest that this finding may be an indication for thrombolysis . Not every person with a (suspected) pulmonary embolism requires an echocardiogram, but elevations in cardiac troponins or brain natriuretic peptide may indicate heart strain and warrant an echocardiogram, and be important in prognosis. The specific appearance of the right ventricle on echocardiography is referred to as the McConnell's sign . This is the finding of akinesia of the mid-free wall but a normal motion of the apex. This phenomenon has a 77% sensitivity and a 94% specificity for the diagnosis of acute pulmonary embolism in the setting of right ventricular dysfunction. The most commonly used method to predict clinical probability, the Wells score , is a clinical prediction rule , whose use is complicated by multiple versions being available. In 1995, Philip Steven Wells , initially developed a prediction rule (based on a literature search) to predict the likelihood of DVT, based on clinical criteria. A new prediction score for PE was created in 1998 This prediction rule was revised by Wells et al. in 2000. In the 2000 publication, Wells proposed two different scoring systems using cutoffs of 2 or 4 with the same prediction rule, and also included D-dimer testing in the rule-out of PE in low probability patients. In 2001, Wells published results using the more conservative cutoff of 2 to create three categories. An additional version, the "modified extended version", using the more recent cutoff of 2 but including findings from Wells's initial studies were proposed. Most recently, a further study reverted to Wells's earlier use of a cutoff of 4 points to create only two categories. There are additional prediction rules for PE, such as the Geneva rule . More importantly, the use of any rule is associated with reduction in recurrent thromboembolism . The Wells score : Traditional interpretation Alternative interpretation Score > 4 – PE likely. Consider diagnostic imaging. Score 4 or less – PE unlikely. Consider D-dimer to rule out PE. Recommendations for a diagnostic algorithm were published by the PIOPED investigators; however, these recommendations do not reflect research using 64 slice MDCT. These investigators recommended: Low clinical probability. If negative D-dimer, PE is excluded. If positive D-dimer, obtain MDCT and base treatment on results. Moderate clinical probability. If negative D-dimer, PE is excluded. However , the authors were not concerned that a negative MDCT with negative D-dimer in this setting has a 5% probability of being false. Presumably, the 5% error rate will fall as 64 slice MDCT is more commonly used. If positive D-dimer, obtain MDCT and base treatment on results. High clinical probability. Proceed to MDCT. If positive, treat, if negative, more tests are needed to exclude PE. A D-dimer of less than 750 ug/L does not rule out PE in those who are at high risk. The pulmonary embolism rule-out criteria (PERC) helps assess people in whom pulmonary embolism is suspected, but unlikely. Unlike the Wells score and Geneva score , which are clinical prediction rules intended to risk stratify people with suspected PE, the PERC rule is designed to rule out the risk of PE in people when the physician has already stratified them into a low-risk category. People in this low risk category without any of these criteria may undergo no further testing for PE: low oxygen saturations – Sa O 2 50, hormone use, fast heart rate. The rationale behind this decision is that further testing (specifically CT angiogram of the chest) may cause more harm (from radiation exposure and contrast dye) than the risk of PE. The PERC rule has a sensitivity of 97.4% and specificity of 21.9% with a false negative rate of 1.0% (16/1666). The pulmonary embolism rule-out criteria (PERC) helps assess people in whom pulmonary embolism is suspected, but unlikely. Unlike the Wells score and Geneva score , which are clinical prediction rules intended to risk stratify people with suspected PE, the PERC rule is designed to rule out the risk of PE in people when the physician has already stratified them into a low-risk category. People in this low risk category without any of these criteria may undergo no further testing for PE: low oxygen saturations – Sa O 2 50, hormone use, fast heart rate. The rationale behind this decision is that further testing (specifically CT angiogram of the chest) may cause more harm (from radiation exposure and contrast dye) than the risk of PE. The PERC rule has a sensitivity of 97.4% and specificity of 21.9% with a false negative rate of 1.0% (16/1666). In people with a low or moderate suspicion of PE, a normal D-dimer level (shown in a blood test ) is enough to exclude the possibility of thrombotic PE, with a three-month risk of thromboembolic events being 0.14%. D-dimer is highly sensitive but not specific (specificity around 50%). In other words, a positive D-dimer is not synonymous with PE, but a negative D-dimer is, with a good degree of certainty, an indication of absence of a PE. A low pretest probability is also valuable in ruling out PE. The typical cut off is 500 μg/L, although this varies based on the assay. However, in those over the age of 50, changing the cut-off value to the person's age multiplied by 10 μg/L (accounting for assay which has been used) is recommended as it decreases the number of falsely positive tests without missing any additional cases of PE. When a PE is being suspected, several blood tests are done in order to exclude important secondary causes of PE. This includes a full blood count , clotting status ( PT , aPTT , TT ), and some screening tests ( erythrocyte sedimentation rate , kidney function , liver enzymes , electrolytes ). If one of these is abnormal, further investigations might be warranted to the issue. Troponin levels are increased in between 16 and 47% with pulmonary embolism. In typical people who are not known to be at high risk of PE, imaging is helpful to confirm or exclude a diagnosis of PE after simpler first-line tests are used. Medical societies recommend tests such as the D-dimer to first provide supporting evidence for the need for imaging, and imaging would be done if other tests confirmed a moderate or high probability of finding evidence to support a diagnosis of PE. CT pulmonary angiography is the recommended first line diagnostic imaging test in most people. Ultrasound of the legs can confirm the presence of a PE but cannot rule it out. CT pulmonary angiography (CTPA) is a pulmonary angiogram obtained using computed tomography (CT) with radiocontrast rather than right heart catheterization. Its advantages are that it is accurate, it is non-invasive, it is more often available, and it may identifying other lung disorders in case there is no pulmonary embolism. The accuracy and non-invasive nature of CTPA also make it advantageous for people who are pregnant. Assessing the accuracy of CT pulmonary angiography is hindered by the rapid changes in the number of rows of detectors available in multidetector CT (MDCT) machines. According to a cohort study , single-slice spiral CT may help diagnose detection among people with suspected pulmonary embolism. In this study, the sensitivity was 69% and specificity was 84%. In this study which had a prevalence of detection was 32%, the positive predictive value of 67.0% and negative predictive value of 85.2%. However, this study's results may be biased due to possible incorporation bias, since the CT scan was the final diagnostic tool in people with pulmonary embolism. The authors noted that a negative single slice CT scan is insufficient to rule out pulmonary embolism on its own. A separate study with a mixture of 4 slice and 16 slice scanners reported a sensitivity of 83% and a specificity of 96%, which means that it is a good test for ruling out a pulmonary embolism if it is not seen on imaging and that it is very good at confirming a pulmonary embolism is present if it is seen. This study noted that additional testing is necessary when the clinical probability is inconsistent with the imaging results. CTPA is non-inferior to VQ scanning, and identifies more emboli (without necessarily improving the outcome) compared to VQ scanning. A ventilation/perfusion scan (or V/Q scan or lung scintigraphy ) shows that some areas of the lung are being ventilated but not perfused with blood (due to obstruction by a clot). This type of examination is as accurate as multislice CT, but is less used, due to the greater availability of CT technology. It is particularly useful in people who have an allergy to iodinated contrast , impaired kidney function, or are pregnant (due to its lower radiation exposure as compared to CT). The test can be performed with planar two-dimensional imaging, or single photon emission computed tomography ( SPECT ) which enables three-dimensional imaging. Hybrid devices combining SPECT and CT (SPECT/CT) further enable anatomic characterization of any abnormality. Tests that are frequently done that are not sensitive for PE, but can be diagnostic. Historically, the gold standard for diagnosis was pulmonary angiography by fluoroscopy , but this has fallen into disuse with the increased availability of non-invasive techniques that offer similar diagnostic accuracy. CT pulmonary angiography (CTPA) is a pulmonary angiogram obtained using computed tomography (CT) with radiocontrast rather than right heart catheterization. Its advantages are that it is accurate, it is non-invasive, it is more often available, and it may identifying other lung disorders in case there is no pulmonary embolism. The accuracy and non-invasive nature of CTPA also make it advantageous for people who are pregnant. Assessing the accuracy of CT pulmonary angiography is hindered by the rapid changes in the number of rows of detectors available in multidetector CT (MDCT) machines. According to a cohort study , single-slice spiral CT may help diagnose detection among people with suspected pulmonary embolism. In this study, the sensitivity was 69% and specificity was 84%. In this study which had a prevalence of detection was 32%, the positive predictive value of 67.0% and negative predictive value of 85.2%. However, this study's results may be biased due to possible incorporation bias, since the CT scan was the final diagnostic tool in people with pulmonary embolism. The authors noted that a negative single slice CT scan is insufficient to rule out pulmonary embolism on its own. A separate study with a mixture of 4 slice and 16 slice scanners reported a sensitivity of 83% and a specificity of 96%, which means that it is a good test for ruling out a pulmonary embolism if it is not seen on imaging and that it is very good at confirming a pulmonary embolism is present if it is seen. This study noted that additional testing is necessary when the clinical probability is inconsistent with the imaging results. CTPA is non-inferior to VQ scanning, and identifies more emboli (without necessarily improving the outcome) compared to VQ scanning. A ventilation/perfusion scan (or V/Q scan or lung scintigraphy ) shows that some areas of the lung are being ventilated but not perfused with blood (due to obstruction by a clot). This type of examination is as accurate as multislice CT, but is less used, due to the greater availability of CT technology. It is particularly useful in people who have an allergy to iodinated contrast , impaired kidney function, or are pregnant (due to its lower radiation exposure as compared to CT). The test can be performed with planar two-dimensional imaging, or single photon emission computed tomography ( SPECT ) which enables three-dimensional imaging. Hybrid devices combining SPECT and CT (SPECT/CT) further enable anatomic characterization of any abnormality. Tests that are frequently done that are not sensitive for PE, but can be diagnostic.Historically, the gold standard for diagnosis was pulmonary angiography by fluoroscopy , but this has fallen into disuse with the increased availability of non-invasive techniques that offer similar diagnostic accuracy. The primary use of the ECG is to rule out other causes of chest pain. An electrocardiogram (ECG) is routinely done on people with chest pain to quickly diagnose myocardial infarctions (heart attacks), an important differential diagnosis in an individual with chest pain. While certain ECG changes may occur with PE, none are specific enough to confirm or sensitive enough to rule out the diagnosis. An ECG may show signs of right heart strain or acute cor pulmonale in cases of large PEs – the classic signs are a large S wave in lead I, a large Q wave in lead III, and an inverted T wave in lead III (S1Q3T3), which occurs in 12–50% of people with the diagnosis, yet also occurs in 12% without the diagnosis. This is occasionally present (occurring in up to 20% of people), but may also occur in other acute lung conditions, and, therefore, has limited diagnostic value. The most commonly seen signs in the ECG are sinus tachycardia , right axis deviation, and right bundle branch block . Sinus tachycardia, however, is still only found in 8–69% of people with PE. ECG findings associated with pulmonary emboli may suggest worse prognosis since the six findings identified with RV strain on ECG (heart rate > 100 beats per minute, S1Q3T3, inverted T waves in leads V1-V4, ST elevation in aVR, complete right bundle branch block, and atrial fibrillation) are associated with increased risk of circulatory shock and death. Cases with inverted T in leads V 1-3 are suspected with PE or inferior myocardial infarction. PE cases show inverted T waves in leads II and aV F , but inferior myocardial infarction cases do not show inverted T waves in II and aV F . In massive and submassive PE, dysfunction of the right side of the heart may be seen on echocardiography , an indication that the pulmonary artery is severely obstructed and the right ventricle , a low-pressure pump, is unable to match the pressure. Some studies (see below) suggest that this finding may be an indication for thrombolysis . Not every person with a (suspected) pulmonary embolism requires an echocardiogram, but elevations in cardiac troponins or brain natriuretic peptide may indicate heart strain and warrant an echocardiogram, and be important in prognosis. The specific appearance of the right ventricle on echocardiography is referred to as the McConnell's sign . This is the finding of akinesia of the mid-free wall but a normal motion of the apex. This phenomenon has a 77% sensitivity and a 94% specificity for the diagnosis of acute pulmonary embolism in the setting of right ventricular dysfunction. Pulmonary embolism may be preventable in those with risk factors. People admitted to hospital may receive preventative medication, including unfractionated heparin , low molecular weight heparin (LMWH), or fondaparinux , and anti-thrombosis stockings to reduce the risk of a DVT in the leg that could dislodge and migrate to the lungs. Following the completion of anticoagulation in those with prior PE, long-term aspirin is useful to prevent recurrence. Anticoagulant therapy is the mainstay of treatment. Acutely, supportive treatments, such as oxygen or analgesia , may be required. People are often admitted to hospital in the early stages of treatment, and tend to remain under inpatient care until the INR has reached therapeutic levels (if warfarin is used). Increasingly, however, low-risk cases are managed at home in a fashion already common in the treatment of DVT. Evidence to support one approach versus the other is weak. [ needs update ] Anticoagulant therapy is the mainstay of treatment. For many years, vitamin K antagonists (warfarin or less commonly acenocoumarol or phenprocoumon ) have been the cornerstone. As vitamin K antagonists do not act immediately, initial treatment is with rapidly acting injectable anticoagulants: unfractionated heparin (UFH), low molecular weight heparin (LMWH), or fondaparinux , while oral vitamin K antagonists are initiated and titrated (usually as part of inpatient hospital care) to the international normalized ratio , a test that determines the dose. In terms of injectable treatments, LMWH may reduce bleeding among people with pulmonary embolism as compared to UFH. According to the same review, LMWH reduced the incidence of recurrent thrombotic complications and reduced thrombus size when compared to heparin. There was no difference in overall mortality between participants treated with LMWH and those treated with unfractionated heparin. Vitamin K antagonists require frequent dose adjustment and monitoring of the international normalized ratio (INR). In PE, INRs between 2.0 and 3.0 are generally considered ideal. If another episode of PE occurs under warfarin treatment, the INR window may be increased to e.g. 2.5–3.5 (unless there are contraindications) [ citation needed ] or anticoagulation may be changed to a different anticoagulant e.g. LMWH. In recent years, many anticoagulants have been introduced that offer similar to warfarin but without a need for titration to the INR. Known as the directly acting oral anticoagulants , these treatments are now preferred over vitamin K antagonists by American professional guidelines. Two of these ( rivaroxaban and apixaban ) do not require initial heparin or fondaparinux treatment, whereas dabigatran and edoxaban do. A Cochrane review found that there is no evidence of a difference between oral DTIs (dabigatran, rivaroxaban, edoxaban, apixaban) and standard anticoagulation in the prevention of recurrent pulmonary embolism. In people with cancer who develop pulmonary embolism, therapy with a course of LMWH is favored over warfarin or other oral anticoagulants. Similarly, pregnant women are treated with low molecular weight heparin until after delivery to avoid the known teratogenic effects of warfarin, especially in the early stages of pregnancy, but it can be used while breastfeeding. Anticoagulation therapy is usually continued for 3–6 months, or "lifelong" if there have been previous DVTs or PEs, or none of the usual transient risk factors is present. In those without a known cause that can be reversed 2 years of treatment may be better than 6 months. For those with small PEs (known as subsegmental PEs) the effects of anticoagulation is unknown as it has not been properly studied as of 2020. Massive PE causing hemodynamic instability (shock and/or low blood pressure, defined as a systolic blood pressure 15 min if not caused by new-onset arrhythmia, hypovolemia or sepsis) is an indication for thrombolysis , the enzymatic destruction of the clot with medication. In this situation, it is the best available treatment in those without contraindications and is supported by clinical guidelines. It is also recommended in those in cardiac arrest with a known PE. Catheter-directed thrombolysis (CDT) is a new technique found to be relatively safe and effective for massive PEs. This involves accessing the venous system by placing a catheter into a vein in the groin and guiding it through the veins by using fluoroscopic imaging until it is located next to the PE in the lung circulation. Medication that breaks up blood clots is released through the catheter so that its highest concentration is directly next to the pulmonary embolus. CDT is performed by interventional radiologists or vascular surgeons , and in medical centers that offer CDT, it may be offered as a first-line treatment. Catheter-based ultrasound-assisted thrombolysis is being investigated. The use of thrombolysis in non-massive PEs is still debated. Some have found that the treatment decreases the risk of death and increases the risk of bleeding including intracranial hemorrhage . Others have found no decrease in the risk of death. There are two situations when an inferior vena cava filter is considered advantageous, and those are if anticoagulant therapy is contraindicated (e.g. shortly after a major operation), or a person has a pulmonary embolus in spite of being anticoagulated. In these instances, it may be implanted to prevent new or existing DVTs from entering the pulmonary artery and combining with an existing blockage. In spite of the device's theoretical advantage of preventing pulmonary emboli, there is a lack of evidence supporting its effectiveness. Inferior vena cava filters should be removed as soon as it becomes safe to start using anticoagulation. Although modern filters are meant to be retrievable, complications may prevent some from being removed. The long-term safety profile of permanently leaving a filter inside the body is not known. Surgical management of acute pulmonary embolism ( pulmonary thrombectomy ) is uncommon and has largely been abandoned because of poor long-term outcomes. However, recently, it has gone through a resurgence with the revision of the surgical technique and is thought to benefit certain people. Chronic pulmonary embolism leading to pulmonary hypertension (known as chronic thromboembolic hypertension ) is treated with a surgical procedure known as a pulmonary thromboendarterectomy . Anticoagulant therapy is the mainstay of treatment. For many years, vitamin K antagonists (warfarin or less commonly acenocoumarol or phenprocoumon ) have been the cornerstone. As vitamin K antagonists do not act immediately, initial treatment is with rapidly acting injectable anticoagulants: unfractionated heparin (UFH), low molecular weight heparin (LMWH), or fondaparinux , while oral vitamin K antagonists are initiated and titrated (usually as part of inpatient hospital care) to the international normalized ratio , a test that determines the dose. In terms of injectable treatments, LMWH may reduce bleeding among people with pulmonary embolism as compared to UFH. According to the same review, LMWH reduced the incidence of recurrent thrombotic complications and reduced thrombus size when compared to heparin. There was no difference in overall mortality between participants treated with LMWH and those treated with unfractionated heparin. Vitamin K antagonists require frequent dose adjustment and monitoring of the international normalized ratio (INR). In PE, INRs between 2.0 and 3.0 are generally considered ideal. If another episode of PE occurs under warfarin treatment, the INR window may be increased to e.g. 2.5–3.5 (unless there are contraindications) [ citation needed ] or anticoagulation may be changed to a different anticoagulant e.g. LMWH. In recent years, many anticoagulants have been introduced that offer similar to warfarin but without a need for titration to the INR. Known as the directly acting oral anticoagulants , these treatments are now preferred over vitamin K antagonists by American professional guidelines. Two of these ( rivaroxaban and apixaban ) do not require initial heparin or fondaparinux treatment, whereas dabigatran and edoxaban do. A Cochrane review found that there is no evidence of a difference between oral DTIs (dabigatran, rivaroxaban, edoxaban, apixaban) and standard anticoagulation in the prevention of recurrent pulmonary embolism. In people with cancer who develop pulmonary embolism, therapy with a course of LMWH is favored over warfarin or other oral anticoagulants. Similarly, pregnant women are treated with low molecular weight heparin until after delivery to avoid the known teratogenic effects of warfarin, especially in the early stages of pregnancy, but it can be used while breastfeeding. Anticoagulation therapy is usually continued for 3–6 months, or "lifelong" if there have been previous DVTs or PEs, or none of the usual transient risk factors is present. In those without a known cause that can be reversed 2 years of treatment may be better than 6 months. For those with small PEs (known as subsegmental PEs) the effects of anticoagulation is unknown as it has not been properly studied as of 2020. Massive PE causing hemodynamic instability (shock and/or low blood pressure, defined as a systolic blood pressure 15 min if not caused by new-onset arrhythmia, hypovolemia or sepsis) is an indication for thrombolysis , the enzymatic destruction of the clot with medication. In this situation, it is the best available treatment in those without contraindications and is supported by clinical guidelines. It is also recommended in those in cardiac arrest with a known PE. Catheter-directed thrombolysis (CDT) is a new technique found to be relatively safe and effective for massive PEs. This involves accessing the venous system by placing a catheter into a vein in the groin and guiding it through the veins by using fluoroscopic imaging until it is located next to the PE in the lung circulation. Medication that breaks up blood clots is released through the catheter so that its highest concentration is directly next to the pulmonary embolus. CDT is performed by interventional radiologists or vascular surgeons , and in medical centers that offer CDT, it may be offered as a first-line treatment. Catheter-based ultrasound-assisted thrombolysis is being investigated. The use of thrombolysis in non-massive PEs is still debated. Some have found that the treatment decreases the risk of death and increases the risk of bleeding including intracranial hemorrhage . Others have found no decrease in the risk of death. There are two situations when an inferior vena cava filter is considered advantageous, and those are if anticoagulant therapy is contraindicated (e.g. shortly after a major operation), or a person has a pulmonary embolus in spite of being anticoagulated. In these instances, it may be implanted to prevent new or existing DVTs from entering the pulmonary artery and combining with an existing blockage. In spite of the device's theoretical advantage of preventing pulmonary emboli, there is a lack of evidence supporting its effectiveness. Inferior vena cava filters should be removed as soon as it becomes safe to start using anticoagulation. Although modern filters are meant to be retrievable, complications may prevent some from being removed. The long-term safety profile of permanently leaving a filter inside the body is not known. Surgical management of acute pulmonary embolism ( pulmonary thrombectomy ) is uncommon and has largely been abandoned because of poor long-term outcomes. However, recently, it has gone through a resurgence with the revision of the surgical technique and is thought to benefit certain people. Chronic pulmonary embolism leading to pulmonary hypertension (known as chronic thromboembolic hypertension ) is treated with a surgical procedure known as a pulmonary thromboendarterectomy . Fewer than 5 to 10% of symptomatic PEs are fatal within the first hour of symptoms. There are several markers used for risk stratification and these are also independent predictors of adverse outcomes. These include hypotension, cardiogenic shock, syncope, evidence of right heart dysfunction, and elevated cardiac enzymes. Some ECG changes including S1Q3T3 also correlate with a worse short-term prognosis. There have been other patient-related factors such as COPD and chronic heart failure thought to also play a role in prognosis. Prognosis depends on the amount of lung that is affected and on the co-existence of other medical conditions; chronic embolisation to the lung can lead to pulmonary hypertension . After a massive PE, the embolus must be resolved somehow if the patient is to survive. In thrombotic PE, the blood clot may be broken down by fibrinolysis , or it may be organized and recanalized so that a new channel forms through the clot. Blood flow is restored most rapidly in the first day or two after a PE. Improvement slows thereafter and some deficits may be permanent. There is controversy over whether small subsegmental PEs need treatment at all and some evidence exists that patients with subsegmental PEs may do well without treatment. Once anticoagulation is stopped, the risk of a fatal pulmonary embolism is 0.5% per year. Mortality from untreated PEs was said to be 26%. This figure comes from a trial published in 1960 by Barrit and Jordan, which compared anticoagulation against placebo for the management of PE. Barritt and Jordan performed their study in the Bristol Royal Infirmary in 1957. This study is the only placebo-controlled trial ever to examine the place of anticoagulants in the treatment of PE, the results of which were so convincing that the trial has never been repeated as to do so would be considered unethical. [ citation needed ] That said, the reported mortality rate of 26% in the placebo group is probably an overstatement, given that the technology of the day may have detected only severe PEs. The PESI and sPESI (= simplified Pulmonary Embolism Severity Index) scoring tools can estimate mortality of patients. The Geneva prediction rules and Wells criteria are used to calculate a pre-test probability of patients to predict who has a pulmonary embolism. These scores are tools to be used with clinical judgment in deciding diagnostic testing and types of therapy. The PESI algorithm comprises 11 routinely available clinical variables. It puts the subjects into one of five classes (I–V), with 30-day mortality ranging from 1.1% to 24.5%. Those in classes I and II are low-risk and those in classes III–V are high-risk. The PESI and sPESI (= simplified Pulmonary Embolism Severity Index) scoring tools can estimate mortality of patients. The Geneva prediction rules and Wells criteria are used to calculate a pre-test probability of patients to predict who has a pulmonary embolism. These scores are tools to be used with clinical judgment in deciding diagnostic testing and types of therapy. The PESI algorithm comprises 11 routinely available clinical variables. It puts the subjects into one of five classes (I–V), with 30-day mortality ranging from 1.1% to 24.5%. Those in classes I and II are low-risk and those in classes III–V are high-risk. There are roughly 10 million cases of pulmonary embolisms per year. In the United States, pulmonary embolisms are the primary cause of at least 10,000 to 12,000 deaths per year and a contributing cause in at least 30,000 to 40,000 deaths per year. True incidence involving pulmonary embolisms is unknown because they often go undiagnosed or unnoticed until autopsy. From 1993 to 2012, there have been an increased number of admissions in hospitals due to pulmonary embolisms, jumping from 23 cases per 100,000 people to 65 cases per 100,000 people. Despite this increase, there has been a decrease in mortality during that same time period due to medical advances that have occurred. Venous thromboembolism (VTE), a common risk factor, is present at much higher rates in those over the age of 70 (three times higher compared to those aged 45 to 69). This is likely due to there being a generally lower level of activity among the elderly, resulting in higher rates of immobility and obesity. VTE has a large, and continuously rising, case fatality rate. This rate is roughly 10% after 30 days, 15% after three months and up to 20% after one year. Pulmonary embolisms alone (when resulting in hospitalizations) have a case fatality rate of about 5% to 10% so VTE can play a large factor in the severity of the embolisms. When looking at all cases, the rate of fatal pulmonary emboli has declined from 6% to 2% over the last 25 years in the United States. In Europe, an average of approximately 40,000 deaths per year with pulmonary embolism as the primary cause were reported between 2013 and 2015, a conservative estimate because of potential underdiagnosis.

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Acute hemorrhagic fever syndrome

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MERS-related coronavirus

2012-nCoV Middle East respiratory syndrome–related coronavirus ( MERS-CoV ), or EMC/2012 ( HCoV-EMC/2012 ), is the virus that causes Middle East respiratory syndrome (MERS). It is a species of coronavirus which infects humans, bats, and camels. The infecting virus is an enveloped , positive-sense , single-stranded RNA virus which enters its host cell by binding to the DPP4 receptor . The species is a member of the genus Betacoronavirus and subgenus Merbecovirus . Initially called simply novel coronavirus or nCoV, with the provisional names 2012 novel coronavirus ( 2012-nCoV ) and human coronavirus 2012 ( HCoV-12 or hCoV-12 ), it was first reported in June 2012 after genome sequencing of a virus isolated from sputum samples from a person who fell ill in a 2012 outbreak of a new flu-like respiratory illness. By July 2015, MERS-CoV cases had been reported in over 21 countries, in Europe , North America and Asia as well as the Middle East . MERS-CoV is one of several viruses identified by the World Health Organization (WHO) as a likely cause of a future epidemic. They list it for urgent research and development. The virus MERS-CoV is a member of the beta group of coronavirus, Betacoronavirus , lineage C. MERS-CoV genomes are phylogenetically classified into two clades , clade A and B. The earliest cases were of clade A clusters, while the majority of more recent cases are of the genetically distinct clade B. MERS-CoV is one of seven known coronaviruses to infect humans, including HCoV-229E , HCoV-NL63 , HCoV-OC43 , HCoV-HKU1 , the original SARS-CoV (or SARS-CoV-1), and SARS-CoV-2 . It has frequently been referred to as a SARS-like virus. By November, 2019, 2,494 cases of MERS had been reported with 858 deaths, implying a case fatality rate of greater than 30%. The first confirmed case was reported in Jeddah, Saudi Arabia in April 2012. Egyptian virologist Ali Mohamed Zaki isolated and identified a previously unknown coronavirus from the man's lungs . Zaki then posted his findings on 24 September 2012 on ProMED-mail . The isolated cells showed cytopathic effects (CPE), in the form of rounding and syncytia formation. A second case was found in September 2012, when a 49-year-old man living in Qatar presented with similar flu symptoms. A sequence of the virus was nearly identical to that of the first case. In November 2012, similar cases appeared in Qatar and Saudi Arabia. Additional cases were noted, with deaths associated, and rapid research and monitoring of the novel coronavirus began. It is not known whether the infections are the result of a single zoonotic event with subsequent human-to-human transmission, or if the multiple geographic sites of infection represent multiple zoonotic events from an unknown common source. [ citation needed ] A study by Ziad Memish of Riyadh University and colleagues suggests that the virus arose some time between July 2007 and June 2012, with perhaps as many as seven separate zoonotic transmissions. [ citation needed ] Among animal reservoirs, CoV has a large genetic diversity yet the samples from patients suggested a similar genome, and therefore common source, though the data were limited. It was determined through molecular clock analysis that viruses from the EMC/2012 and England/Qatar/2012 date to early 2011, suggesting that these cases were descended from a single zoonotic event. It appeared the MERS-CoV had been circulating in the human population for more than a year without detection, and suggested independent transmission from an unknown source. In humans, the virus has a strong tropism for nonciliated bronchial epithelial cells, and it has been shown to effectively evade the innate immune responses and antagonize interferon (IFN) production in these cells. This tropism is unique in that most respiratory viruses target ciliated cells. Due to the clinical similarity between MERS-CoV and SARS-CoV , it was proposed that they may use the same cellular receptor; the exopeptidase, angiotensin converting enzyme 2 ( ACE2 ). However, it was later discovered that neutralization of ACE2 by recombinant antibodies does not prevent MERS-CoV infection. Further research identified dipeptidyl peptidase 4 ( DPP4 ; also known as CD26 ) as a functional cellular receptor for MERS-CoV. Unlike other known coronavirus receptors, the enzymatic activity of DPP4 is not required for infection. As would be expected, the amino acid sequence of DPP4 is highly conserved across species and is expressed in the human bronchial epithelium and kidneys. Bat DPP4 genes appear to have been subject to a high degree of adaptive evolution as a response to coronavirus infections, so the lineage leading to MERS-CoV may have circulated in bat populations for a long period of time before being transmitted to people. On 13 February 2013, the World Health Organization stated that "the risk of sustained person-to-person transmission appears to be very low." The cells MERS-CoV infects in the lungs only account for 20% of respiratory epithelial cells, so a large number of virions are likely needed to be inhaled to cause infection. Anthony Fauci of the National Institutes of Health in Bethesda, Maryland, stated that MERS-CoV "does not spread in a sustained person to person way at all," while noting the possibility that the virus could mutate into a strain that does transmit from person to person. However, the infection of healthcare workers has led to concerns of human to human transmission. The Centers for Disease Control and Prevention (CDC) list MERS as transmissible from human to human. They state that "MERS-CoV has been shown to spread between people who are in close contact. Transmission from infected patients to healthcare personnel has also been observed. Clusters of cases in several countries are being investigated." However, on the 28th of May, the CDC revealed that the Illinois man who was originally thought to have been the first incidence of person-to-person spread (from the Indiana man at a business meeting), had in fact tested negative for MERS-CoV. After completing additional and more definitive tests using a neutralising antibody assay, experts at the CDC concluded that the Indiana patient did not spread the virus to the Illinois patient. Tests concluded that the Illinois man had not been previously infected. It is possible for MERS to be symptomless, and early research has shown that up to 20% of cases show no signs of active infection but have MERS-CoV antibodies in their blood. The virus appears to have originated in bats. The virus itself has been isolated from a bat. This virus is closely related to the Tylonycteris bat coronavirus HKU4 and Pipistrellus bat coronavirus HKU5 . Serological evidence shows that these viruses have infected camels for at least 20 years. The most recent common ancestor of several human strains has been dated to March 2012 (95% confidence interval December 2011 to June 2012). It is thought that the viruses have been present in bats for some time and had spread to camels by the mid-1990s. The viruses appear to have spread from camels to humans in the early 2010s. The original bat host species and the time of initial infection in this species has yet to be determined. [ citation needed ] Examination of the sequences of 238 isolates suggested that this virus has evolved into three clades differing in codon usage, host, and geographic distribution. It is believed that the virus originated in bats, one candidate being the Egyptian tomb bat . Work by epidemiologist Ian Lipkin of Columbia University in New York showed that the virus isolated from a bat looked to be a match to the virus found in humans. 2c betacoronaviruses were detected in Nycteris bats in Ghana and Pipistrellus bats in Europe that are phylogenetically related to the MERS-CoV virus. However the major natural reservoir where humans get the virus infection remained unknown until on 9 August 2013, a report in the journal The Lancet Infectious Diseases showed that 50 out of 50 (100%) blood serum from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against the MERS-CoV spike protein. Blood serum from European sheep, goats, cattle, and other camelids had no such antibodies. Soon after on 5 September 2013 a seroepidemiological study published in the journal of Eurosurveillance by R.A Perera et al. where they investigated 1343 human and 625 animal sera indicated, the abundant presence of MERS-CoV specific antibody in 108 out of 110 Egyptian dromedary camels but not in other animals such as goats, cows or sheep in this region. These are the first and significant scientific reports that indicated the role of "dromedary camels" as a reservoir of MERS-CoV. [ citation needed ] Research has linked camels , showing that the coronavirus infection in dromedary camel calves and adults is a 99.9% match to the genomes of human clade B MERS-CoV. At least one person who has fallen sick with MERS was known to have come into contact with camels or recently drank camel milk . Countries like Saudi Arabia and the United Arab Emirates produce and consume large amounts of camel meat . The possibility exists that African or Australian bats harbor the virus and transmit it to camels. Imported camels from these regions might have carried the virus to the Middle East. In 2013 MERS-CoV was identified in three members of a dromedary camel herd held in a Qatar barn, which was linked to two confirmed human cases who have since recovered. The presence of MERS-CoV in the camels was confirmed by the National Institute of Public Health and Environment (RIVM) of the Ministry of Health and the Erasmus Medical Center (WHO Collaborating Center), the Netherlands. None of the camels showed any sign of disease when the samples were collected. The Qatar Supreme Council of Health advised in November 2013 that people with underlying health conditions, such as heart disease, diabetes, kidney disease, respiratory disease, the immunosuppressed, and the elderly, avoid any close animal contacts when visiting farms and markets, and to practice good hygiene, such as washing hands. A further study on dromedary camels from Saudi Arabia published in December 2013 revealed the presence of MERS-CoV in 90% of the evaluated dromedary camels (310), suggesting that dromedary camels not only could be the main reservoir of MERS-CoV, but also the animal source of MERS. According to the 27 March 2014 MERS-CoV summary update, recent studies support that camels serve as the primary source of the MERS-CoV infecting humans, while bats may be the ultimate reservoir of the virus. Evidence includes the frequency with which the virus has been found in camels to which human cases have been exposed, seriological data which shows widespread transmission in camels, and the similarity of the camel CoV to the human CoV. On 6 June 2014, the Arab News newspaper highlighted the latest research findings in the New England Journal of Medicine in which a 44-year-old Saudi man who kept a herd of nine camels died of MERS in November 2013. His friends said they witnessed him applying a topical medicine to the nose of one of his ill camels—four of them reportedly sick with nasal discharge—seven days before he himself became stricken with MERS. Researchers sequenced the virus found in one of the sick camels and the virus that killed the man, and found that their genomes were identical. In that same article, the Arab News reported that as of 6 June 2014, there have been 689 cases of MERS reported within the Kingdom of Saudi Arabia with 283 deaths. MERS-CoV is more closely related to the bat coronaviruses HKU4 and HKU5 (lineage 2C) than it is to SARS-CoV (lineage 2B) (2, 9), sharing more than 90% sequence identity with their closest relationships, bat coronaviruses HKU4 and HKU5 and therefore considered to belong to the same species by the International Committee on Taxonomy of Viruses (ICTV). [ citation needed ] Mnemonic: Taxon identifier: Scientific name: Middle East respiratory syndrome coronavirus Common name: MERS-CoV Synonym: Severe acute respiratory syndrome coronavirus Other names: novel coronavirus (nCoV) London1 novel CoV/2012 Human Coronavirus Erasmus Medical Center/2012 ( HCoV-EMC/2012 ) Rank: Lineage: Strains: Isolate: Isolate: NCBIThe first confirmed case was reported in Jeddah, Saudi Arabia in April 2012. Egyptian virologist Ali Mohamed Zaki isolated and identified a previously unknown coronavirus from the man's lungs . Zaki then posted his findings on 24 September 2012 on ProMED-mail . The isolated cells showed cytopathic effects (CPE), in the form of rounding and syncytia formation. A second case was found in September 2012, when a 49-year-old man living in Qatar presented with similar flu symptoms. A sequence of the virus was nearly identical to that of the first case. In November 2012, similar cases appeared in Qatar and Saudi Arabia. Additional cases were noted, with deaths associated, and rapid research and monitoring of the novel coronavirus began. It is not known whether the infections are the result of a single zoonotic event with subsequent human-to-human transmission, or if the multiple geographic sites of infection represent multiple zoonotic events from an unknown common source. [ citation needed ] A study by Ziad Memish of Riyadh University and colleagues suggests that the virus arose some time between July 2007 and June 2012, with perhaps as many as seven separate zoonotic transmissions. [ citation needed ] Among animal reservoirs, CoV has a large genetic diversity yet the samples from patients suggested a similar genome, and therefore common source, though the data were limited. It was determined through molecular clock analysis that viruses from the EMC/2012 and England/Qatar/2012 date to early 2011, suggesting that these cases were descended from a single zoonotic event. It appeared the MERS-CoV had been circulating in the human population for more than a year without detection, and suggested independent transmission from an unknown source. In humans, the virus has a strong tropism for nonciliated bronchial epithelial cells, and it has been shown to effectively evade the innate immune responses and antagonize interferon (IFN) production in these cells. This tropism is unique in that most respiratory viruses target ciliated cells. Due to the clinical similarity between MERS-CoV and SARS-CoV , it was proposed that they may use the same cellular receptor; the exopeptidase, angiotensin converting enzyme 2 ( ACE2 ). However, it was later discovered that neutralization of ACE2 by recombinant antibodies does not prevent MERS-CoV infection. Further research identified dipeptidyl peptidase 4 ( DPP4 ; also known as CD26 ) as a functional cellular receptor for MERS-CoV. Unlike other known coronavirus receptors, the enzymatic activity of DPP4 is not required for infection. As would be expected, the amino acid sequence of DPP4 is highly conserved across species and is expressed in the human bronchial epithelium and kidneys. Bat DPP4 genes appear to have been subject to a high degree of adaptive evolution as a response to coronavirus infections, so the lineage leading to MERS-CoV may have circulated in bat populations for a long period of time before being transmitted to people. On 13 February 2013, the World Health Organization stated that "the risk of sustained person-to-person transmission appears to be very low." The cells MERS-CoV infects in the lungs only account for 20% of respiratory epithelial cells, so a large number of virions are likely needed to be inhaled to cause infection. Anthony Fauci of the National Institutes of Health in Bethesda, Maryland, stated that MERS-CoV "does not spread in a sustained person to person way at all," while noting the possibility that the virus could mutate into a strain that does transmit from person to person. However, the infection of healthcare workers has led to concerns of human to human transmission. The Centers for Disease Control and Prevention (CDC) list MERS as transmissible from human to human. They state that "MERS-CoV has been shown to spread between people who are in close contact. Transmission from infected patients to healthcare personnel has also been observed. Clusters of cases in several countries are being investigated." However, on the 28th of May, the CDC revealed that the Illinois man who was originally thought to have been the first incidence of person-to-person spread (from the Indiana man at a business meeting), had in fact tested negative for MERS-CoV. After completing additional and more definitive tests using a neutralising antibody assay, experts at the CDC concluded that the Indiana patient did not spread the virus to the Illinois patient. Tests concluded that the Illinois man had not been previously infected. It is possible for MERS to be symptomless, and early research has shown that up to 20% of cases show no signs of active infection but have MERS-CoV antibodies in their blood. The virus appears to have originated in bats. The virus itself has been isolated from a bat. This virus is closely related to the Tylonycteris bat coronavirus HKU4 and Pipistrellus bat coronavirus HKU5 . Serological evidence shows that these viruses have infected camels for at least 20 years. The most recent common ancestor of several human strains has been dated to March 2012 (95% confidence interval December 2011 to June 2012). It is thought that the viruses have been present in bats for some time and had spread to camels by the mid-1990s. The viruses appear to have spread from camels to humans in the early 2010s. The original bat host species and the time of initial infection in this species has yet to be determined. [ citation needed ] Examination of the sequences of 238 isolates suggested that this virus has evolved into three clades differing in codon usage, host, and geographic distribution. It is believed that the virus originated in bats, one candidate being the Egyptian tomb bat . Work by epidemiologist Ian Lipkin of Columbia University in New York showed that the virus isolated from a bat looked to be a match to the virus found in humans. 2c betacoronaviruses were detected in Nycteris bats in Ghana and Pipistrellus bats in Europe that are phylogenetically related to the MERS-CoV virus. However the major natural reservoir where humans get the virus infection remained unknown until on 9 August 2013, a report in the journal The Lancet Infectious Diseases showed that 50 out of 50 (100%) blood serum from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against the MERS-CoV spike protein. Blood serum from European sheep, goats, cattle, and other camelids had no such antibodies. Soon after on 5 September 2013 a seroepidemiological study published in the journal of Eurosurveillance by R.A Perera et al. where they investigated 1343 human and 625 animal sera indicated, the abundant presence of MERS-CoV specific antibody in 108 out of 110 Egyptian dromedary camels but not in other animals such as goats, cows or sheep in this region. These are the first and significant scientific reports that indicated the role of "dromedary camels" as a reservoir of MERS-CoV. [ citation needed ] Research has linked camels , showing that the coronavirus infection in dromedary camel calves and adults is a 99.9% match to the genomes of human clade B MERS-CoV. At least one person who has fallen sick with MERS was known to have come into contact with camels or recently drank camel milk . Countries like Saudi Arabia and the United Arab Emirates produce and consume large amounts of camel meat . The possibility exists that African or Australian bats harbor the virus and transmit it to camels. Imported camels from these regions might have carried the virus to the Middle East. In 2013 MERS-CoV was identified in three members of a dromedary camel herd held in a Qatar barn, which was linked to two confirmed human cases who have since recovered. The presence of MERS-CoV in the camels was confirmed by the National Institute of Public Health and Environment (RIVM) of the Ministry of Health and the Erasmus Medical Center (WHO Collaborating Center), the Netherlands. None of the camels showed any sign of disease when the samples were collected. The Qatar Supreme Council of Health advised in November 2013 that people with underlying health conditions, such as heart disease, diabetes, kidney disease, respiratory disease, the immunosuppressed, and the elderly, avoid any close animal contacts when visiting farms and markets, and to practice good hygiene, such as washing hands. A further study on dromedary camels from Saudi Arabia published in December 2013 revealed the presence of MERS-CoV in 90% of the evaluated dromedary camels (310), suggesting that dromedary camels not only could be the main reservoir of MERS-CoV, but also the animal source of MERS. According to the 27 March 2014 MERS-CoV summary update, recent studies support that camels serve as the primary source of the MERS-CoV infecting humans, while bats may be the ultimate reservoir of the virus. Evidence includes the frequency with which the virus has been found in camels to which human cases have been exposed, seriological data which shows widespread transmission in camels, and the similarity of the camel CoV to the human CoV. On 6 June 2014, the Arab News newspaper highlighted the latest research findings in the New England Journal of Medicine in which a 44-year-old Saudi man who kept a herd of nine camels died of MERS in November 2013. His friends said they witnessed him applying a topical medicine to the nose of one of his ill camels—four of them reportedly sick with nasal discharge—seven days before he himself became stricken with MERS. Researchers sequenced the virus found in one of the sick camels and the virus that killed the man, and found that their genomes were identical. In that same article, the Arab News reported that as of 6 June 2014, there have been 689 cases of MERS reported within the Kingdom of Saudi Arabia with 283 deaths. MERS-CoV is more closely related to the bat coronaviruses HKU4 and HKU5 (lineage 2C) than it is to SARS-CoV (lineage 2B) (2, 9), sharing more than 90% sequence identity with their closest relationships, bat coronaviruses HKU4 and HKU5 and therefore considered to belong to the same species by the International Committee on Taxonomy of Viruses (ICTV). [ citation needed ] Mnemonic: Taxon identifier: Scientific name: Middle East respiratory syndrome coronavirus Common name: MERS-CoV Synonym: Severe acute respiratory syndrome coronavirus Other names: novel coronavirus (nCoV) London1 novel CoV/2012 Human Coronavirus Erasmus Medical Center/2012 ( HCoV-EMC/2012 ) Rank: Lineage: Strains: Isolate: Isolate: NCBISaudi officials had not given permission for Dr. Zaki, the first isolator of the human strain, to send a sample of the virus to Fouchier and were angered when Fouchier claimed the patent on the full genetic sequence of MERS-CoV. The editor of The Economist observed, "Concern over security must not slow urgent work. Studying a deadly virus is risky. Not studying it is riskier." Dr. Zaki was fired from his job at the hospital as a result of bypassing the Saudi Ministry of Health in his announcement and sharing his sample and findings. At their annual meeting of the World Health Assembly in May 2013, WHO chief Margaret Chan declared that intellectual property , or patents on strains of new virus, should not impede nations from protecting their citizens by limiting scientific investigations. Deputy Health Minister Ziad Memish raised concerns that scientists who held the patent for MERS-CoV would not allow other scientists to use patented material and were therefore delaying the development of diagnostic tests. Erasmus MC responded that the patent application did not restrict public health research into MERS and MERS-CoV, and that the virus and diagnostic tests were shipped—free of charge—to all that requested such reagents.There are a number of mapping efforts focused on tracking MERS coronavirus. On 2 May 2014, the Corona Map was launched to track the MERS coronavirus in realtime on the world map. The data is officially reported by WHO or the Ministry of Health of the respective country. HealthMap also tracks case reports with inclusion of news and social media as data sources as part of HealthMap MERS. South Korea was infected in mid-2015, with 38 deaths among 186 cases of infection. [ citation needed ]

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Acute hemorrhagic fever syndrome

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Zika fever

Zika fever , also known as Zika virus disease or simply Zika , is an infectious disease caused by the Zika virus . Most cases have no symptoms, but when present they are usually mild and can resemble dengue fever . Symptoms may include fever , red eyes , joint pain , headache, and a maculopapular rash . Symptoms generally last less than seven days. It has not caused any reported deaths during the initial infection. Mother-to-child transmission during pregnancy can cause microcephaly and other brain malformations in some babies. Infections in adults have been linked to Guillain–Barré syndrome (GBS). Zika fever is mainly spread via the bite of mosquitoes of the Aedes type. It can also be sexually transmitted and potentially spread by blood transfusions . Infections in pregnant women can spread to the baby. Diagnosis is by testing the blood, urine, or saliva for the presence of the virus's RNA when the person is sick, or the blood for antibodies after symptoms are present more than a week. Prevention involves decreasing mosquito bites in areas where the disease occurs and proper use of condoms. Efforts to prevent bites include the use of insect repellent , covering much of the body with clothing, mosquito nets , and getting rid of standing water where mosquitoes reproduce. There is no effective vaccine . Health officials recommended that women in areas affected by the 2015–16 Zika outbreak consider putting off pregnancy and that pregnant women not travel to these areas. While there is no specific treatment, paracetamol (acetaminophen) may help with the symptoms. Admission to hospital is rarely necessary. The virus that causes the disease was first isolated in Africa in 1947. The first documented outbreak among people occurred in 2007 in the Federated States of Micronesia . An outbreak started in Brazil in 2015, and spread to the Americas, Pacific, Asia, and Africa. This led the World Health Organization to declare it a Public Health Emergency of International Concern in February 2016. The emergency was lifted in November 2016, but 84 countries still reported cases as of March 2017. The last proven case of Zika spread in the Continental United States was in 2017. Most people who are infected have no or few symptoms. Otherwise the most common signs and symptoms of Zika fever are fever , rash , conjunctivitis (red eyes), muscle and joint pain , and headache, which are similar to signs and symptoms of dengue and chikungunya fever. The time from a mosquito bite to developing symptoms is not yet known, but is probably a few days to a week. The disease lasts for several days to a week and is usually mild enough that people do not have to go to a hospital. Due to being in the same family as dengue, there has been concern that it could cause similar bleeding disorders. However that has only been documented in one case, with blood seen in semen, also known as hematospermia . Zika virus infections have been strongly associated with Guillain–Barré syndrome (GBS), which is a rapid onset of muscle weakness caused by the immune system damaging the peripheral nervous system, and which can progress to paralysis. While both GBS and Zika infection can simultaneously occur in the same individual, it is difficult to definitively identify Zika virus as the cause of GBS. Though Zika virus has been shown to infect human Schwann cells . Several countries affected by Zika outbreaks have reported increases in the rate of new cases of GBS. During the 2013–2014 outbreak in French Polynesia there were 42 reported cases of GBS over a 3-month period, compared to between 3 and 10 annually prior to the outbreak. The disease spreads from mother to child in the womb and can cause multiple problems, most notably microcephaly , in the baby. The full range of birth defects caused by infection during pregnancy is not known, but they appear to be common, with large scale abnormalities seen in up to 42% of live births. The most common observed associations have been abnormalities with brain and eye development such as microcephaly and chorioretinal scarring. Less commonly there have been systemic abnormalities such as hydrops fetalis , where there is abnormal accumulation of fluid in the fetus. These abnormalities can lead to intellectual problems, seizures , vision problems , hearing problems , problems feeding and slow development. Whether the stage of pregnancy at which the mother becomes infected affects the risk to the fetus is not well understood, nor is whether other risk factors affect outcomes. One group has estimated the risk of a baby developing microcephaly at about 1% when the mother is infected during the first trimester, with the risk of developing microcephaly becoming uncertain beyond the first trimester. Affected babies might appear normal but actually have brain abnormalities; infection in newborns could also lead to brain damage. Zika virus infections have been strongly associated with Guillain–Barré syndrome (GBS), which is a rapid onset of muscle weakness caused by the immune system damaging the peripheral nervous system, and which can progress to paralysis. While both GBS and Zika infection can simultaneously occur in the same individual, it is difficult to definitively identify Zika virus as the cause of GBS. Though Zika virus has been shown to infect human Schwann cells . Several countries affected by Zika outbreaks have reported increases in the rate of new cases of GBS. During the 2013–2014 outbreak in French Polynesia there were 42 reported cases of GBS over a 3-month period, compared to between 3 and 10 annually prior to the outbreak. The disease spreads from mother to child in the womb and can cause multiple problems, most notably microcephaly , in the baby. The full range of birth defects caused by infection during pregnancy is not known, but they appear to be common, with large scale abnormalities seen in up to 42% of live births. The most common observed associations have been abnormalities with brain and eye development such as microcephaly and chorioretinal scarring. Less commonly there have been systemic abnormalities such as hydrops fetalis , where there is abnormal accumulation of fluid in the fetus. These abnormalities can lead to intellectual problems, seizures , vision problems , hearing problems , problems feeding and slow development. Whether the stage of pregnancy at which the mother becomes infected affects the risk to the fetus is not well understood, nor is whether other risk factors affect outcomes. One group has estimated the risk of a baby developing microcephaly at about 1% when the mother is infected during the first trimester, with the risk of developing microcephaly becoming uncertain beyond the first trimester. Affected babies might appear normal but actually have brain abnormalities; infection in newborns could also lead to brain damage. Zika virus is a mosquito - borne flavivirus closely related to the dengue and yellow fever viruses. While mosquitoes are the vector , the main reservoir species remains unknown, though serological evidence has been found in both West African monkeys and rodents. Transmission is via the bite of mosquitoes from the genus Aedes , primarily Aedes aegypti in tropical regions. It has also been isolated from Ae. africanus , Ae. apicoargenteus , Ae. luteocephalus , Ae. albopictus , Ae. vittatus and Ae. furcifer . During the 2007 outbreak on Yap Island in the South Pacific, Aedes hensilli was the vector, while Aedes polynesiensis spread the virus in French Polynesia in 2013. Zika virus can also spread by sexual transmission from infected men to their partners. Zika virus has been isolated from semen samples, with one person having 100,000 times more virus in semen than blood or urine, two weeks after being infected. It is unclear why levels in semen can be higher than other body fluids, and it is also unclear how long infectious virus can remain in semen. There have also been cases of men with no symptoms of Zika virus infection transmitting the disease. The CDC has recommended that all men who have travelled to affected areas should wait at least 6 months before trying to attempt conception , regardless of whether they were ill. To date there have been no reported sexual transmissions from women to their sexual partners. Oral, anal or vaginal sex can spread the disease. Cases of vertical perinatal transmission have been reported. The CDC recommends that women with Zika fever should wait at least 8 weeks after they start having symptoms of disease before attempting to conceive. There have been no reported cases of transmission from breastfeeding, but infectious virus has been found in breast milk. Like other flaviviruses it could potentially be transmitted by blood transfusion and several affected countries have developed strategies to screen blood donors. The U.S. FDA has recommended universal screening of blood products for Zika. The virus is detected in 3% of asymptomatic blood donors in French Polynesia. Zika virus is a mosquito - borne flavivirus closely related to the dengue and yellow fever viruses. While mosquitoes are the vector , the main reservoir species remains unknown, though serological evidence has been found in both West African monkeys and rodents. Transmission is via the bite of mosquitoes from the genus Aedes , primarily Aedes aegypti in tropical regions. It has also been isolated from Ae. africanus , Ae. apicoargenteus , Ae. luteocephalus , Ae. albopictus , Ae. vittatus and Ae. furcifer . During the 2007 outbreak on Yap Island in the South Pacific, Aedes hensilli was the vector, while Aedes polynesiensis spread the virus in French Polynesia in 2013. Zika virus can also spread by sexual transmission from infected men to their partners. Zika virus has been isolated from semen samples, with one person having 100,000 times more virus in semen than blood or urine, two weeks after being infected. It is unclear why levels in semen can be higher than other body fluids, and it is also unclear how long infectious virus can remain in semen. There have also been cases of men with no symptoms of Zika virus infection transmitting the disease. The CDC has recommended that all men who have travelled to affected areas should wait at least 6 months before trying to attempt conception , regardless of whether they were ill. To date there have been no reported sexual transmissions from women to their sexual partners. Oral, anal or vaginal sex can spread the disease. Cases of vertical perinatal transmission have been reported. The CDC recommends that women with Zika fever should wait at least 8 weeks after they start having symptoms of disease before attempting to conceive. There have been no reported cases of transmission from breastfeeding, but infectious virus has been found in breast milk. Like other flaviviruses it could potentially be transmitted by blood transfusion and several affected countries have developed strategies to screen blood donors. The U.S. FDA has recommended universal screening of blood products for Zika. The virus is detected in 3% of asymptomatic blood donors in French Polynesia. In fruit flies microcephaly appears to be caused by the flavivirid virus protein NS4A , which can disrupt brain growth by hijacking a pathway which regulates growth of new neurons. It is difficult to diagnose Zika virus infection based on clinical signs and symptoms alone due to overlaps with other arboviruses that are endemic to similar areas. The US Centers for Disease Control and Prevention (CDC) advises that "based on the typical clinical features, the differential diagnosis for Zika virus infection is broad. In addition to dengue, other considerations include leptospirosis , malaria , rickettsia , group A streptococcus , rubella , measles , and parvovirus , enterovirus , adenovirus , and alphavirus infections (e.g., chikungunya, Mayaro , Ross River , Barmah Forest , O'nyong'nyong , and Sindbis viruses)." In small case series, routine chemistry and complete blood counts have been normal in most patients. A few have been reported to have mild leukopenia , thrombocytopenia , and elevated liver transaminases . Zika virus can be identified by reverse transcriptase PCR (RT-PCR) in acutely ill patients. However, the period of viremia can be short and the World Health Organization (WHO) recommends RT-PCR testing be done on serum collected within 1 to 3 days of symptom onset or on saliva samples collected during the first 3 to 5 days. When evaluating paired samples, Zika virus was detected more frequently in saliva than serum. Urine samples can be collected and tested up to 14 days after the onset of symptoms, as the virus has been seen to survive longer in the urine than either saliva or serum. The longest period of detectable virus has been 11 days and Zika virus does not appear to establish latency. Later on, serology for the detection of specific IgM and IgG antibodies to Zika virus can be used. IgM antibodies can be detectable within 3 days of the onset of illness. Serological cross-reactions with closely related flaviviruses such as dengue and West Nile virus as well as vaccines to flaviviruses are possible. As of 2019, the FDA has authorized two tests to detect Zika virus antibodies. The CDC recommends screening some pregnant women even if they do not have symptoms of infection. Pregnant women who have traveled to affected areas should be tested between two and twelve weeks after their return from travel. Due to the difficulties with ordering and interpreting tests for Zika virus, the CDC also recommends that healthcare providers contact their local health department for assistance. For women living in affected areas, the CDC has recommended testing at the first prenatal visit with a doctor as well as in the mid-second trimester , though this may be adjusted based on local resources and the local burden of Zika virus. Additional testing should be done if there are any signs of Zika virus disease. Women with positive test results for Zika virus infection should have their fetus monitored by ultrasound every three to four weeks to monitor fetal anatomy and growth. For infants with suspected congenital Zika virus disease, the CDC recommends testing with both serologic and molecular assays such as RT-PCR, IgM ELISA and plaque reduction neutralization test (PRNT). RT-PCR of the infants serum and urine should be performed in the first two days of life. Newborns with a mother who was potentially exposed and who have positive blood tests, microcephaly or intracranial calcifications should have further testing including a thorough physical investigation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly, and rash or other skin lesions. Other recommended tests are cranial ultrasound, hearing evaluation, and eye examination. Testing should be done for any abnormalities encountered as well as for other congenital infections such as syphilis , toxoplasmosis , rubella, cytomegalovirus infection, lymphocytic choriomeningitis virus infection, and herpes simplex virus . Some tests should be repeated up to 6 months later as there can be delayed effects, particularly with hearing. In response to the widespread transmission of Zika virus during the 2016 outbreak and concerns of viral genetic material detected in breast milk the World Health Organization (WHO) released a Guideline of infant feeding in areas of Zika virus transmission, first in 2016 and updated in 2021, where the evidence showed that despite the detection of Zika virus in breast milk, there is unclear evidence of transmission to the infant, and considering that Zika virus infection among infants is mild, the balance between desirable and undesirable effects favours breastfeeding versus not breastfeeding. According to the 2021WHO guidelines: The CDC recommends screening some pregnant women even if they do not have symptoms of infection. Pregnant women who have traveled to affected areas should be tested between two and twelve weeks after their return from travel. Due to the difficulties with ordering and interpreting tests for Zika virus, the CDC also recommends that healthcare providers contact their local health department for assistance. For women living in affected areas, the CDC has recommended testing at the first prenatal visit with a doctor as well as in the mid-second trimester , though this may be adjusted based on local resources and the local burden of Zika virus. Additional testing should be done if there are any signs of Zika virus disease. Women with positive test results for Zika virus infection should have their fetus monitored by ultrasound every three to four weeks to monitor fetal anatomy and growth. For infants with suspected congenital Zika virus disease, the CDC recommends testing with both serologic and molecular assays such as RT-PCR, IgM ELISA and plaque reduction neutralization test (PRNT). RT-PCR of the infants serum and urine should be performed in the first two days of life. Newborns with a mother who was potentially exposed and who have positive blood tests, microcephaly or intracranial calcifications should have further testing including a thorough physical investigation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly, and rash or other skin lesions. Other recommended tests are cranial ultrasound, hearing evaluation, and eye examination. Testing should be done for any abnormalities encountered as well as for other congenital infections such as syphilis , toxoplasmosis , rubella, cytomegalovirus infection, lymphocytic choriomeningitis virus infection, and herpes simplex virus . Some tests should be repeated up to 6 months later as there can be delayed effects, particularly with hearing. In response to the widespread transmission of Zika virus during the 2016 outbreak and concerns of viral genetic material detected in breast milk the World Health Organization (WHO) released a Guideline of infant feeding in areas of Zika virus transmission, first in 2016 and updated in 2021, where the evidence showed that despite the detection of Zika virus in breast milk, there is unclear evidence of transmission to the infant, and considering that Zika virus infection among infants is mild, the balance between desirable and undesirable effects favours breastfeeding versus not breastfeeding. According to the 2021WHO guidelines: The virus is spread by mosquitoes, making mosquito avoidance an important element to disease control. The CDC recommends that individuals: The CDC also recommends strategies for controlling mosquitoes such as eliminating standing water, repairing septic tanks and using screens on doors and windows. Spraying insecticide is used to kill flying mosquitoes and larvicide can be used in water containers. Because Zika virus can be sexually transmitted, men who have gone to an area where Zika fever is occurring should be counseled to either abstain from sex or use condoms for 6 months after travel if their partner is pregnant or could potentially become pregnant. Breastfeeding is still recommended by the WHO, even by women who have had Zika fever. There have been no recorded cases of Zika transmission to infants through breastfeeding, though the replicative virus has been detected in breast milk. When returning from travel, with or without symptoms, it is suggested that prevention of mosquito bites continue for 3 weeks in order reduce the risk of virus transmission to uninfected mosquitos. Because of the "growing evidence of a link between Zika and microcephaly", in January 2016, the CDC issued a travel alert advising pregnant women to consider postponing travel to countries and territories with ongoing local transmission of Zika virus. Later, the advice was updated to caution pregnant women to avoid these areas entirely if possible and, if travel is unavoidable, to protect themselves from mosquito bites. Male partners of pregnant women and couples contemplating pregnancy who must travel to areas where Zika is active are advised to use condoms or abstain from sex. The agency also suggested that women thinking about becoming pregnant should consult with their physicians before traveling. In September 2016, the CDC travel advisories included: Cape Verde Many parts of the Caribbean: Anguilla, Antigua and Barbuda, Aruba, The Bahamas, Barbados, Bonaire, British Virgin Islands, Cayman Islands, Cuba, Curaçao, Dominica, Dominican Republic, Grenada, Guadeloupe, Haiti, Jamaica, Martinique, Puerto Rico, Saba, Saint Saint Barthélemy, Saint Lucia, Saint Martin, Saint Vincent and the Grenadines, Sint Eustatius, Sint Maarten, Trinidad and Tobago, and the U.S. Virgin Islands Central America: Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama Mexico Most of South America: Argentina, Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Paraguay, Peru, Suriname, and Venezuela Several Pacific Islands: American Samoa, Fiji, Marshall Islands, Micronesia, New Caledonia, Papua New Guinea, Samoa, and Tonga In Asia: Singapore, Malaysia, Brunei In December 2020, no active Zika outbreaks were reported by the CDC. Both the regional Pan American Health Organization (PAHO) as well as the WHO have issued statements of concern about the widespread public health impact of the Zika virus and its links to GBS and microcephaly. The WHO Director-General, Margaret Chan , issued a statement in February 2016 "declaring that the recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a Public Health Emergency of International Concern." The declaration allowed the WHO to coordinate international response to the virus as well as gave its guidance the force of international law under the International Health Regulations . The declaration was ended in November 2016. As of 2016 there was no available vaccine. Development was a priority of the US National Institutes of Health (NIH), but officials stated that development of a vaccine could take years. To speed new drug development regulatory strategies were proposed by the WHO and NIH. Animal and early human studies were underway as of September 2016. As of December 2019, there were several vaccine candidates in various stages of development. Disease control in the affected countries currently centres around mosquito control. Several approaches are available for the management of Aedes aegypti mosquito populations, including the destruction of larval breeding sites (the aquatic pools in which eggs are laid and larvae hatch prior to mosquito development into flying adults); and, insecticides targeting either the larval stages, adult mosquitoes or both. Additionally, a whole host of novel technologies are under current development for mosquito control and the World Health Organization has recently lent its support for the accelerated development of modern methods for mosquito control such as the use of Wolbachia bacteria to render mosquitoes resistant to the virus, and, the release of sterilized male mosquitoes that breed with wild female mosquitoes to give rise to non-viable offspring (offspring that do not survive to the biting, adult stage). Oxitec 's genetically modified OX513A mosquito was approved by Brazil's National Biosecurity Technical Commission (CTNBio) in April 2014 and it was being used to try to combat mosquitoes carrying the Zika virus in the town of Piracicaba , São Paulo in 2016. In the 1940s and 1950s, the Aedes aegypti mosquito was eradicated on some Caribbean islands and in at least eighteen Latin American countries. Decreasing political will and presumably available money, mosquito resistance to insecticide, and a pace of urbanization which exceeded eradication efforts led to this mosquito's comeback. Because of the "growing evidence of a link between Zika and microcephaly", in January 2016, the CDC issued a travel alert advising pregnant women to consider postponing travel to countries and territories with ongoing local transmission of Zika virus. Later, the advice was updated to caution pregnant women to avoid these areas entirely if possible and, if travel is unavoidable, to protect themselves from mosquito bites. Male partners of pregnant women and couples contemplating pregnancy who must travel to areas where Zika is active are advised to use condoms or abstain from sex. The agency also suggested that women thinking about becoming pregnant should consult with their physicians before traveling. In September 2016, the CDC travel advisories included: Cape Verde Many parts of the Caribbean: Anguilla, Antigua and Barbuda, Aruba, The Bahamas, Barbados, Bonaire, British Virgin Islands, Cayman Islands, Cuba, Curaçao, Dominica, Dominican Republic, Grenada, Guadeloupe, Haiti, Jamaica, Martinique, Puerto Rico, Saba, Saint Saint Barthélemy, Saint Lucia, Saint Martin, Saint Vincent and the Grenadines, Sint Eustatius, Sint Maarten, Trinidad and Tobago, and the U.S. Virgin Islands Central America: Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama Mexico Most of South America: Argentina, Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Paraguay, Peru, Suriname, and Venezuela Several Pacific Islands: American Samoa, Fiji, Marshall Islands, Micronesia, New Caledonia, Papua New Guinea, Samoa, and Tonga In Asia: Singapore, Malaysia, Brunei In December 2020, no active Zika outbreaks were reported by the CDC. Both the regional Pan American Health Organization (PAHO) as well as the WHO have issued statements of concern about the widespread public health impact of the Zika virus and its links to GBS and microcephaly. The WHO Director-General, Margaret Chan , issued a statement in February 2016 "declaring that the recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a Public Health Emergency of International Concern." The declaration allowed the WHO to coordinate international response to the virus as well as gave its guidance the force of international law under the International Health Regulations . The declaration was ended in November 2016. As of 2016 there was no available vaccine. Development was a priority of the US National Institutes of Health (NIH), but officials stated that development of a vaccine could take years. To speed new drug development regulatory strategies were proposed by the WHO and NIH. Animal and early human studies were underway as of September 2016. As of December 2019, there were several vaccine candidates in various stages of development. Disease control in the affected countries currently centres around mosquito control. Several approaches are available for the management of Aedes aegypti mosquito populations, including the destruction of larval breeding sites (the aquatic pools in which eggs are laid and larvae hatch prior to mosquito development into flying adults); and, insecticides targeting either the larval stages, adult mosquitoes or both. Additionally, a whole host of novel technologies are under current development for mosquito control and the World Health Organization has recently lent its support for the accelerated development of modern methods for mosquito control such as the use of Wolbachia bacteria to render mosquitoes resistant to the virus, and, the release of sterilized male mosquitoes that breed with wild female mosquitoes to give rise to non-viable offspring (offspring that do not survive to the biting, adult stage). Oxitec 's genetically modified OX513A mosquito was approved by Brazil's National Biosecurity Technical Commission (CTNBio) in April 2014 and it was being used to try to combat mosquitoes carrying the Zika virus in the town of Piracicaba , São Paulo in 2016. In the 1940s and 1950s, the Aedes aegypti mosquito was eradicated on some Caribbean islands and in at least eighteen Latin American countries. Decreasing political will and presumably available money, mosquito resistance to insecticide, and a pace of urbanization which exceeded eradication efforts led to this mosquito's comeback. There is currently no specific treatment for Zika virus infection. Care is supportive with treatment of pain, fever, and itching. Some authorities have recommended against using aspirin and other NSAIDs as these have been associated with hemorrhagic syndrome when used for other flaviviruses. Additionally, aspirin use is generally avoided in children when possible due to the risk of Reye syndrome . Zika virus had been relatively little studied until the major outbreak in 2015, and no specific antiviral treatments are available as yet. Advice to pregnant women is to avoid any risk of infection so far as possible, as once infected there is little that can be done beyond supportive treatment. Most of the time, Zika fever resolves on its own in two to seven days, but rarely, some people develop Guillain–Barré syndrome . The fetus of a pregnant woman who has Zika fever may die or be born with congenital central nervous system malformations, like microcephaly . In April 1947, as part of studies sponsored by the Rockefeller Foundation into yellow fever , 6 caged rhesus monkeys were placed in the canopy of the Zika Forest of Uganda. On April 18 one of the monkeys (no. 776) developed a fever and blood samples revealed the first known case of Zika fever. Population surveys at the time in Uganda found 6.1% of individuals to be seropositive for Zika. The first human cases were reported in Nigeria in 1954. A few outbreaks have been reported in tropical Africa and in some areas in Southeast Asia. Until recently there were no documented cases of Zika virus in the Indian subcontinent , however, the first cases were reported in 2017 from Gujarat state and Tamil Nadu, more cases were reported in Rajasthan state involving an outbreak of 153 reported cases and in a pregnant women living in Kerala state. A 1954 study assessing blood samples from several people from different states found antibodies to Zika in healthy people in India which could indicate past exposure, though it could also be due to cross-reaction with other flaviviruses. By using phylogenetic analysis of Asian strains, it was estimated that Zika virus had moved to Southeast Asia by 1945. In 1977–1978, Zika virus infection was described as a cause of fever in Indonesia. Before 2007, there were only 13 reported natural infections with Zika virus, all with a mild, self-limited febrile illness. As of July 2019, evidence of local transmission from mosquitoes to humans has been reported in a total of 87 countries from four of six WHO Regions ; African, Americas, South-East Asia and Western Pacific. The first major outbreak, with 185 confirmed cases, was reported in 2007 in the Yap Islands of the Federated States of Micronesia. A total of 108 cases were confirmed by PCR or serology and 72 additional cases were suspected. The most common symptoms were rash, fever, arthralgia, and conjunctivitis, and no deaths were reported. The mosquito Aedes hensilli , which was the predominant species identified in Yap during the outbreak, was probably the main vector of transmission. While the way of introduction of the virus on Yap Island remains uncertain, it is likely to have happened through introduction of infected mosquitoes or a human infected with a strain related to those in Southeast Asia. This was also the first time Zika fever had been reported outside Africa and Asia. Before the Yap Island outbreak, only 14 human cases had ever been reported. In 2013–2014, several outbreaks of Zika were reported in French Polynesia , New Caledonia , Easter Island and the Cook Islands . The source of the virus was thought to be an independent introduction of the virus from Southeast Asia , unrelated to the Yap Islands outbreak. Genetic analyses of Zika virus strains suggest that Zika first entered the Americas between May and December 2013. It was first detected in the Western Hemisphere in February 2014, and rapidly spread throughout South and Central America, reaching Mexico in November 2015. In 2016 it established local transmission in Florida and Texas. The first death in the United States due to Zika occurred in February 2016. In May 2015, Brazil officially reported its first 16 cases of the illness. Although, a case of illness was reported in March 2015 in a returning traveller. According to the Brazilian Health Ministry, as of November 2015 there was no official count of the number of people infected with the virus in Brazil, since the disease is not subject to compulsory notification. Even so, cases were reported in 14 states of the country. Mosquito-borne Zika virus is suspected to be the cause of 2,400 possible cases of microcephaly and 29 infant deaths in Brazil in 2015 (of the 2400 or so notified cases in 2015, 2165 were under investigation in December 2015, 134 were confirmed and 102 were ruled out for microcephaly). The Brazilian Health Ministry has reported at least 2,400 suspected cases of microcephaly in the country in 2015 as of 12 December, and 29 fatalities. Before the Zika outbreak, only an average of 150 to 200 cases per year were reported in Brazil. In the state of Pernambuco the reported rates of microcephaly in 2015 are 77 times higher than in the previous 5 years. A model using data from a Zika outbreak in French Polynesia estimated the risk of microcephaly in children born to mothers who acquired Zika virus in the first trimester to be 1%. On 24 January 2016, the WHO warned that the virus is likely to spread to nearly all countries of the Americas, since its vector, the mosquito Aedes aegypti , is found in all countries in the region, except for Canada and continental Chile . The mosquito and dengue fever have been detected in Chile's Easter Island, some 3,500 km (2,200 mi) away from its closest point in mainland Chile, since 2002. In February 2016, WHO declared the outbreak a Public Health Emergency of International Concern as evidence grew that Zika is a cause of birth defects and neurological problems. In April 2016, WHO stated there is a scientific consensus, based on preliminary evidence, that Zika is a cause of microcephaly in infants and Guillain–Barré syndrome in adults. Studies of this and prior outbreaks have found Zika infection during pregnancy to be associated with early pregnancy loss and other pregnancy problems. In the Americas the number of cases peaked during the first half of 2016 and declined through 2017–2018, with a total of 31,587 suspected, probable, and confirmed cases of ZIKV disease were reported in the Region of the Americas. Of these, 3,473 (11%) were laboratory confirmed. In general, transmission persists at low levels in some areas and is not uniformly distributed within countries. In 2016 imported or locally transmitted Zika was reported in all the countries of Asia except Brunei, Hong Kong, Myanmar and Nepal. Serological surveys have indicated that Zika virus is endemic in most areas of Asia, though at a low level. While there was a sharp rise in the number of cases of Zika detected in Singapore after the 2016 Summer Olympics in Brazil, genetic analysis revealed that the strains were more closely related to strains from Thailand than from those causing the epidemic in the Americas. The first major outbreak, with 185 confirmed cases, was reported in 2007 in the Yap Islands of the Federated States of Micronesia. A total of 108 cases were confirmed by PCR or serology and 72 additional cases were suspected. The most common symptoms were rash, fever, arthralgia, and conjunctivitis, and no deaths were reported. The mosquito Aedes hensilli , which was the predominant species identified in Yap during the outbreak, was probably the main vector of transmission. While the way of introduction of the virus on Yap Island remains uncertain, it is likely to have happened through introduction of infected mosquitoes or a human infected with a strain related to those in Southeast Asia. This was also the first time Zika fever had been reported outside Africa and Asia. Before the Yap Island outbreak, only 14 human cases had ever been reported. In 2013–2014, several outbreaks of Zika were reported in French Polynesia , New Caledonia , Easter Island and the Cook Islands . The source of the virus was thought to be an independent introduction of the virus from Southeast Asia , unrelated to the Yap Islands outbreak. Genetic analyses of Zika virus strains suggest that Zika first entered the Americas between May and December 2013. It was first detected in the Western Hemisphere in February 2014, and rapidly spread throughout South and Central America, reaching Mexico in November 2015. In 2016 it established local transmission in Florida and Texas. The first death in the United States due to Zika occurred in February 2016. In May 2015, Brazil officially reported its first 16 cases of the illness. Although, a case of illness was reported in March 2015 in a returning traveller. According to the Brazilian Health Ministry, as of November 2015 there was no official count of the number of people infected with the virus in Brazil, since the disease is not subject to compulsory notification. Even so, cases were reported in 14 states of the country. Mosquito-borne Zika virus is suspected to be the cause of 2,400 possible cases of microcephaly and 29 infant deaths in Brazil in 2015 (of the 2400 or so notified cases in 2015, 2165 were under investigation in December 2015, 134 were confirmed and 102 were ruled out for microcephaly). The Brazilian Health Ministry has reported at least 2,400 suspected cases of microcephaly in the country in 2015 as of 12 December, and 29 fatalities. Before the Zika outbreak, only an average of 150 to 200 cases per year were reported in Brazil. In the state of Pernambuco the reported rates of microcephaly in 2015 are 77 times higher than in the previous 5 years. A model using data from a Zika outbreak in French Polynesia estimated the risk of microcephaly in children born to mothers who acquired Zika virus in the first trimester to be 1%. On 24 January 2016, the WHO warned that the virus is likely to spread to nearly all countries of the Americas, since its vector, the mosquito Aedes aegypti , is found in all countries in the region, except for Canada and continental Chile . The mosquito and dengue fever have been detected in Chile's Easter Island, some 3,500 km (2,200 mi) away from its closest point in mainland Chile, since 2002. In February 2016, WHO declared the outbreak a Public Health Emergency of International Concern as evidence grew that Zika is a cause of birth defects and neurological problems. In April 2016, WHO stated there is a scientific consensus, based on preliminary evidence, that Zika is a cause of microcephaly in infants and Guillain–Barré syndrome in adults. Studies of this and prior outbreaks have found Zika infection during pregnancy to be associated with early pregnancy loss and other pregnancy problems. In the Americas the number of cases peaked during the first half of 2016 and declined through 2017–2018, with a total of 31,587 suspected, probable, and confirmed cases of ZIKV disease were reported in the Region of the Americas. Of these, 3,473 (11%) were laboratory confirmed. In general, transmission persists at low levels in some areas and is not uniformly distributed within countries. In 2016 imported or locally transmitted Zika was reported in all the countries of Asia except Brunei, Hong Kong, Myanmar and Nepal. Serological surveys have indicated that Zika virus is endemic in most areas of Asia, though at a low level. While there was a sharp rise in the number of cases of Zika detected in Singapore after the 2016 Summer Olympics in Brazil, genetic analysis revealed that the strains were more closely related to strains from Thailand than from those causing the epidemic in the Americas. It is named after the Zika Forest near Entebbe , Uganda , where the Zika virus was first identified. Zika virus was first identified in the late 1940s in Kampala, Uganda, Africa but was first confirmed in Brazil. Since it was first identified, Zika has been found in more than 27 countries and territories. Following the initial Zika outbreak in Northeastern Brazil in May 2015, physicians observed a very large surge of reports of infants born with microcephaly , with 20 times the number of expected cases. Many of these cases have since been confirmed, leading WHO officials to project that approximately 2,500 infants will be found to have born in Brazil with Zika-related microcephaly. Proving that Zika causes these effects was difficult and complex for several reasons. For example, the effects on an infant might not be seen until months after the mother's initial infection, long after the time when Zika is easily detected in the body. In addition, research was needed to determine the mechanism by which Zika produced these effects. Since the initial outbreak, studies that use several different methods found evidence of a link, leading public health officials to conclude that it appears increasingly likely the virus is linked to microcephaly and miscarriage. On 1 February 2016, the World Health Organization declared recently reported clusters of microcephaly and other neurological disorders a Public Health Emergency of International Concern (PHEIC). On 8 March 2016, the WHO Committee reconfirmed that the association between Zika and neurological disorders is of global concern. The Zika virus was first linked with newborn microcephaly during the Brazil Zika virus outbreak. In 2015, there were 2,782 suspected cases of microcephaly compared with 147 in 2014 and 167 in 2013. Confirmation of many of the recent cases is pending, and it is difficult to estimate how many cases went unreported before the recent awareness of the risk of virus infections. In November 2015, the Zika virus was isolated in a newborn baby from the northeastern state of Ceará , Brazil, with microcephaly and other congenital disorders . The Lancet medical journal reported in January 2016 that the Brazilian Ministry of Health had confirmed 134 cases of microcephaly "believed to be associated with Zika virus infection" with an additional 2,165 cases in 549 counties in 20 states remaining under investigation. An analysis of 574 cases of microcephaly in Brazil during 2015 and the first week of 2016, reported in March 2016, found an association with maternal illness involving rash and fever during the first trimester of pregnancy. During this period, 12 Brazilian states reported increases of at least 3 standard deviations (SDs) in cases of microcephaly compared with 2000–14, with the northeastern states of Bahia, Paraíba and Pernambuco reporting increases of more than 20 SDs. In January 2016, a baby in Oahu , Hawaii, was born with microcephaly, the first case in the United States of brain damage linked to the virus. The baby and mother tested positive for a past Zika virus infection. The mother, who had probably acquired the virus while traveling in Brazil in May 2015 during the early stages of her pregnancy, had reported her bout of Zika. She recovered before relocating to Hawaii. Her pregnancy had progressed normally, and the baby's condition was not known until birth. In February 2016, ocular disorders in newborns have been linked to Zika virus infection. In one study in Pernambuco state in Brazil, about 40 percent of babies with Zika-related microcephaly also had scarring of the retina with spots, or pigment alteration . On 20 February 2016, Brazilian scientists announced that they had successfully sequenced the Zika virus genome and expressed hope that this would help in both developing a vaccine and in determining the nature of any link to birth defects. Also in February 2016, rumors that microcephaly is caused by the use of the larvicide pyriproxyfen in drinking water were refuted by scientists. "It's important to state that some localities that do not use pyriproxyfen also had reported cases of microcephaly", read a Brazilian government statement. The Brazilian government also refuted conspiracy theories that chickenpox and rubella vaccinations or genetically modified mosquitoes were causing increases in microcephaly. Researchers also suspected that Zika virus could be transmitted by a pregnant woman to her baby (" vertical transmission "). This remained unproven until February 2016, when a paper by Calvet et al. was published, showing not only was the Zika virus genome found in the amniotic fluid but also IgM antibodies against the virus. This means that not only can the virus cross the placental barrier, but also the antibodies produced by the mother can reach the fetus, which suggests that vertical transmission is plausible in these cases. One other study published in March 2016 by Mlakar and colleagues analyzed autopsy tissues from a fetus with microcephaly that was probably related to Zika virus; researchers found ZIKV in the brain tissue and suggested that the brain injuries were probably associated with the virus, which also shed a light on the vertical transmission theory. Also in March 2016, first solid evidence was reported on how the virus affects the development of the brain, indicating that it appears to preferentially kill developing brain cells. The first cases of birth defects linked to Zika in Colombia and in Panama were reported in March 2016. In the same month, researchers published a prospective cohort study that found profound impacts in 29 percent of infants of mothers infected with Zika, some of whom were infected late in pregnancy. This study did not suffer from some of the difficulties of studying Zika: the study followed women who presented to a Rio de Janeiro clinic with fever and rash within the last five days. The women were then tested for Zika using PCR, then the progress of the pregnancies were followed using ultrasound. A high rate of the autoimmune disease Guillain–Barré syndrome (GBS), noted in the French Polynesia outbreak, has also been found in the outbreak that began in Brazil. Laboratory analysis found Zika infections in some patients with GBS in Brazil, El Salvador, Suriname and Venezuela, and the WHO declared on 22 March 2016 that Zika appeared to be "implicated" in GBS infection and that if the pattern was confirmed it would represent a global public health crisis. It is named after the Zika Forest near Entebbe , Uganda , where the Zika virus was first identified. Zika virus was first identified in the late 1940s in Kampala, Uganda, Africa but was first confirmed in Brazil. Since it was first identified, Zika has been found in more than 27 countries and territories. Following the initial Zika outbreak in Northeastern Brazil in May 2015, physicians observed a very large surge of reports of infants born with microcephaly , with 20 times the number of expected cases. Many of these cases have since been confirmed, leading WHO officials to project that approximately 2,500 infants will be found to have born in Brazil with Zika-related microcephaly. Proving that Zika causes these effects was difficult and complex for several reasons. For example, the effects on an infant might not be seen until months after the mother's initial infection, long after the time when Zika is easily detected in the body. In addition, research was needed to determine the mechanism by which Zika produced these effects. Since the initial outbreak, studies that use several different methods found evidence of a link, leading public health officials to conclude that it appears increasingly likely the virus is linked to microcephaly and miscarriage. On 1 February 2016, the World Health Organization declared recently reported clusters of microcephaly and other neurological disorders a Public Health Emergency of International Concern (PHEIC). On 8 March 2016, the WHO Committee reconfirmed that the association between Zika and neurological disorders is of global concern. The Zika virus was first linked with newborn microcephaly during the Brazil Zika virus outbreak. In 2015, there were 2,782 suspected cases of microcephaly compared with 147 in 2014 and 167 in 2013. Confirmation of many of the recent cases is pending, and it is difficult to estimate how many cases went unreported before the recent awareness of the risk of virus infections. In November 2015, the Zika virus was isolated in a newborn baby from the northeastern state of Ceará , Brazil, with microcephaly and other congenital disorders . The Lancet medical journal reported in January 2016 that the Brazilian Ministry of Health had confirmed 134 cases of microcephaly "believed to be associated with Zika virus infection" with an additional 2,165 cases in 549 counties in 20 states remaining under investigation. An analysis of 574 cases of microcephaly in Brazil during 2015 and the first week of 2016, reported in March 2016, found an association with maternal illness involving rash and fever during the first trimester of pregnancy. During this period, 12 Brazilian states reported increases of at least 3 standard deviations (SDs) in cases of microcephaly compared with 2000–14, with the northeastern states of Bahia, Paraíba and Pernambuco reporting increases of more than 20 SDs. In January 2016, a baby in Oahu , Hawaii, was born with microcephaly, the first case in the United States of brain damage linked to the virus. The baby and mother tested positive for a past Zika virus infection. The mother, who had probably acquired the virus while traveling in Brazil in May 2015 during the early stages of her pregnancy, had reported her bout of Zika. She recovered before relocating to Hawaii. Her pregnancy had progressed normally, and the baby's condition was not known until birth. In February 2016, ocular disorders in newborns have been linked to Zika virus infection. In one study in Pernambuco state in Brazil, about 40 percent of babies with Zika-related microcephaly also had scarring of the retina with spots, or pigment alteration . On 20 February 2016, Brazilian scientists announced that they had successfully sequenced the Zika virus genome and expressed hope that this would help in both developing a vaccine and in determining the nature of any link to birth defects. Also in February 2016, rumors that microcephaly is caused by the use of the larvicide pyriproxyfen in drinking water were refuted by scientists. "It's important to state that some localities that do not use pyriproxyfen also had reported cases of microcephaly", read a Brazilian government statement. The Brazilian government also refuted conspiracy theories that chickenpox and rubella vaccinations or genetically modified mosquitoes were causing increases in microcephaly. Researchers also suspected that Zika virus could be transmitted by a pregnant woman to her baby (" vertical transmission "). This remained unproven until February 2016, when a paper by Calvet et al. was published, showing not only was the Zika virus genome found in the amniotic fluid but also IgM antibodies against the virus. This means that not only can the virus cross the placental barrier, but also the antibodies produced by the mother can reach the fetus, which suggests that vertical transmission is plausible in these cases. One other study published in March 2016 by Mlakar and colleagues analyzed autopsy tissues from a fetus with microcephaly that was probably related to Zika virus; researchers found ZIKV in the brain tissue and suggested that the brain injuries were probably associated with the virus, which also shed a light on the vertical transmission theory. Also in March 2016, first solid evidence was reported on how the virus affects the development of the brain, indicating that it appears to preferentially kill developing brain cells. The first cases of birth defects linked to Zika in Colombia and in Panama were reported in March 2016. In the same month, researchers published a prospective cohort study that found profound impacts in 29 percent of infants of mothers infected with Zika, some of whom were infected late in pregnancy. This study did not suffer from some of the difficulties of studying Zika: the study followed women who presented to a Rio de Janeiro clinic with fever and rash within the last five days. The women were then tested for Zika using PCR, then the progress of the pregnancies were followed using ultrasound. A high rate of the autoimmune disease Guillain–Barré syndrome (GBS), noted in the French Polynesia outbreak, has also been found in the outbreak that began in Brazil. Laboratory analysis found Zika infections in some patients with GBS in Brazil, El Salvador, Suriname and Venezuela, and the WHO declared on 22 March 2016 that Zika appeared to be "implicated" in GBS infection and that if the pattern was confirmed it would represent a global public health crisis. Early in the 2015–16 Zika virus epidemic , research was begun to better understand how Zika virus causes microcephaly and other neurological disorders. However, with the 2019 election of Jair Bolsonaro in Brazil, who cut funding for research, and the emergence of the COVID-19 pandemic in early 2020, most Zika-related research projects were abandoned or reduced. It may involve infection of the primary neural stem cells of the fetal brain, known as neural progenitor cells. The main roles of brain stem cells are to proliferate until the correct number is achieved, and then to produce neurons through the process of neurogenesis . Zika proteins NS4A and NS4B have also been shown to directly suppress neurogenesis. Infection of brain stem cells can cause cell death, which reduces the production of future neurons and leads to a smaller brain. Zika also appears to have an equal tropism for cells of the developing eye, leading to high rates of eye abnormalities as well. In addition to inducing cell death, infection of neural progenitor cells may alter the process of cell proliferation, causing a depletion in the pool of progenitor cells. A large number of cases of microcephaly have been associated with inherited gene mutations, and specifically with mutations that lead to dysfunction of the mitotic spindle . There is some evidence that Zika virus may directly or indirectly interfere with mitotic function, this may play a role in altering cell proliferation. Another line of research considers that Zika, unlike other flaviviruses, may target developing brain cells after it crosses the placenta, and considers the resulting damage likely to be the result of inflammation as a byproduct of the immune response to the infection of those cells. Some experimental methods of prevention include breeding and releasing mosquitoes that have been genetically modified to prevent them from transmitting pathogens, or have been infected with the Wolbachia bacterium, believed to inhibit the spread of viruses. A strain of Wolbachia helped to reduce the vector competence of the Zika virus in infected Aedes aegypti released in Medellin, Colombia. Gene drive is a technique for changing wild populations, for instance to combat insects so they cannot transmit diseases (in particular mosquitoes in the cases of malaria and Zika). Another method which been researched aims to render male mosquitoes infertile by nuclear radiation in the hope to reduce populations; this is done with a cobalt-60 gamma cell irradiator. In 2016 the World Health Organization encouraged field trials of transgenic male Aedes aegypti mosquitoes developed by Oxitec to try to halt the spread of the Zika virus. Early in the 2015–16 Zika virus epidemic , research was begun to better understand how Zika virus causes microcephaly and other neurological disorders. However, with the 2019 election of Jair Bolsonaro in Brazil, who cut funding for research, and the emergence of the COVID-19 pandemic in early 2020, most Zika-related research projects were abandoned or reduced. It may involve infection of the primary neural stem cells of the fetal brain, known as neural progenitor cells. The main roles of brain stem cells are to proliferate until the correct number is achieved, and then to produce neurons through the process of neurogenesis . Zika proteins NS4A and NS4B have also been shown to directly suppress neurogenesis. Infection of brain stem cells can cause cell death, which reduces the production of future neurons and leads to a smaller brain. Zika also appears to have an equal tropism for cells of the developing eye, leading to high rates of eye abnormalities as well. In addition to inducing cell death, infection of neural progenitor cells may alter the process of cell proliferation, causing a depletion in the pool of progenitor cells. A large number of cases of microcephaly have been associated with inherited gene mutations, and specifically with mutations that lead to dysfunction of the mitotic spindle . There is some evidence that Zika virus may directly or indirectly interfere with mitotic function, this may play a role in altering cell proliferation. Another line of research considers that Zika, unlike other flaviviruses, may target developing brain cells after it crosses the placenta, and considers the resulting damage likely to be the result of inflammation as a byproduct of the immune response to the infection of those cells. Some experimental methods of prevention include breeding and releasing mosquitoes that have been genetically modified to prevent them from transmitting pathogens, or have been infected with the Wolbachia bacterium, believed to inhibit the spread of viruses. A strain of Wolbachia helped to reduce the vector competence of the Zika virus in infected Aedes aegypti released in Medellin, Colombia. Gene drive is a technique for changing wild populations, for instance to combat insects so they cannot transmit diseases (in particular mosquitoes in the cases of malaria and Zika). Another method which been researched aims to render male mosquitoes infertile by nuclear radiation in the hope to reduce populations; this is done with a cobalt-60 gamma cell irradiator. In 2016 the World Health Organization encouraged field trials of transgenic male Aedes aegypti mosquitoes developed by Oxitec to try to halt the spread of the Zika virus.

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Acute hemorrhagic fever syndrome

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

Hepatitis D

Hepatitis D is a type of viral hepatitis caused by the hepatitis delta virus ( HDV ). HDV is one of five known hepatitis viruses: A , B , C , D, and E . HDV is considered to be a satellite (a type of subviral agent ) because it can propagate only in the presence of the hepatitis B virus (HBV). Transmission of HDV can occur either via simultaneous infection with HBV ( coinfection ) or superimposed on chronic hepatitis B or hepatitis B carrier state ( superinfection ). HDV infecting a person with chronic hepatitis B (superinfection) is considered the most serious type of viral hepatitis due to its severity of complications. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis , with an increased risk of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%. A recent estimate from 2020 suggests that currently 48 million people are infected with this virus. Passive immunization Active immunization Vaccine (hepatitis B)Deltavirus cameroonense [HDV-7] Deltavirus carense [HDV-6] Deltavirus italiense [HDV-1] Deltavirus japanense [HDV-2] Deltavirus peruense [HDV-3] Deltavirus senegalense [HDV-8] Deltavirus taiwanense [HDV-4] Deltavirus togense [HDV-5] The hepatitis delta viruses, or HDV, are eight species of negative-sense single-stranded RNA viruses (or virus-like particles) classified together as the genus Deltavirus , within the realm Ribozyviria . The HDV virion is a small, spherical, enveloped particle with a 36 nm diameter; its viral envelope contains host phospholipids, as well as three proteins taken from the hepatitis B virus—the large, medium, and small hepatitis B surface antigens. This assembly surrounds an inner ribonucleoprotein (RNP) particle, which contains the genome surrounded by about 200 molecules of hepatitis D antigen (HDAg) for each genome. The central region of HDAg has been shown to bind RNA. Several interactions are also mediated by a coiled-coil region at the N terminus of HDAg. The HDV genome is negative sense , single-stranded, closed circular RNA ; with a genome of approximately 1700 nucleotides, HDV is the smallest "virus" known to infect animals. It has been proposed that HDV may have originated from a class of plant pathogens called viroids , which are much smaller than viruses. Its genome is unique among animal viruses because of its high GC nucleotide content. Its nucleotide sequence is about 70% self-complementary, allowing the genome to form a partially double-stranded, rod-like RNA structure. HDV strains are highly divergent; fusions of different strains exist and sequences had been deposited in public databases employing different start sites for the circular viral RNA involved. This had resulted in something of chaos with respect to molecular classification of this virus, a situation which has been resolved recently with the adoption of a proposed reference genome and a uniform classification system. Like hepatitis B, HDV gains entry into liver cells via the sodium taurocholate cotransporting polypeptide (NTCP) bile transporter. HDV recognizes its receptor via the N-terminal domain of the large hepatitis B surface antigen, HBsAg . Mapping by mutagenesis of this domain has shown that amino acid residues 9–15 make up the receptor-binding site. After entering the hepatocyte, the virus is uncoated and the nucleocapsid translocated to the nucleus due to a signal in HDAg Since the HDV genome does not code for an RNA polymerase to replicate the virus' genome, the virus makes use of the host cellular RNA polymerases . Initially thought to use just RNA polymerase II, now RNA polymerases I and III have also been shown to be involved in HDV replication. Normally RNA polymerase II utilizes DNA as a template and produces mRNA. Consequently, if HDV indeed utilizes RNA polymerase II during replication, it would be the only known animal pathogen capable of using a DNA-dependent polymerase as an RNA-dependent polymerase. [ citation needed ] The RNA polymerases treat the RNA genome as double-stranded DNA due to the folded rod-like structure it is in. Three forms of RNA are made; circular genomic RNA, circular complementary antigenomic RNA, and a linear polyadenylated antigenomic RNA, which is the mRNA containing the open reading frame for the HDAg. Synthesis of antigenomic RNA occurs in the nucleolus, mediated by RNA polymerase I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA polymerase II. HDV RNA is synthesized first as linear RNA that contains many copies of the genome. The genomic and antigenomic RNA contain a sequence of 85 nucleotides, the hepatitis delta virus ribozyme , that acts as a ribozyme , which self-cleaves the linear RNA into monomers. These monomers are then ligated to form circular RNA. A significant difference between viroids and HDV is that, while viroids produce no proteins, HDV is known to produce one protein, namely HDAg. It comes in two forms; a 27kDa large-HDAg, and a small-HDAg of 24kDa. The N-terminals of the two forms are identical, they differ by 19 more amino acids in the C-terminal of the large HDAg. Both isoforms are produced from the same reading frame which contains an UAG stop codon at codon 196, which normally produces only the small-HDAg. However, editing by cellular enzyme adenosine deaminase acting on RNA (ADAR) changes the stop codon to UGG, allowing the large-HDAg to be produced. Despite having 90% identical sequences, these two proteins play diverging roles during the course of an infection. HDAg-S is produced in the early stages of an infection and enters the nucleus and supports viral replication. HDAg-L, in contrast, is produced during the later stages of an infection, acts as an inhibitor of viral replication, and is required for assembly of viral particles. Thus RNA editing by the cellular enzymes is critical to the virus' life cycle because it regulates the balance between viral replication and virion assembly. [ citation needed ] The HDV envelope protein has three of the HBV surface proteins anchored to it. The S region of the genome is most commonly expressed and its main function is to assemble subviral particles. HDV antigen proteins combine with the viral genome to form a ribonucleoprotein (RNP) which when enveloped with the subviral particles can form viral-like particles that are almost identical to mature HDV, but they are not infectious. Researchers had concluded that the determinant of infectivity of HDV was within the N-terminal pre-S1 domain of the large protein (L). It was found to be a mediator in binding to the cellular receptor. Researchers Georges Abou Jaoudé and Camille Sureau published an article in 2005 that studied the role of the antigenic loop, found in HDV envelope proteins, in the infectivity of the virus. The antigenic loop, like the N-terminal pre-S1 domain of the large protein, is exposed at the virion surface. Jaoudé and Sureau's study provided evidence that the antigenic loop may be an important factor in HDV entry into the host cell and by mutating parts of the antigenic loop, the infectivity of HDV may be minimized. The hepatitis delta viruses, or HDV, are eight species of negative-sense single-stranded RNA viruses (or virus-like particles) classified together as the genus Deltavirus , within the realm Ribozyviria . The HDV virion is a small, spherical, enveloped particle with a 36 nm diameter; its viral envelope contains host phospholipids, as well as three proteins taken from the hepatitis B virus—the large, medium, and small hepatitis B surface antigens. This assembly surrounds an inner ribonucleoprotein (RNP) particle, which contains the genome surrounded by about 200 molecules of hepatitis D antigen (HDAg) for each genome. The central region of HDAg has been shown to bind RNA. Several interactions are also mediated by a coiled-coil region at the N terminus of HDAg. The HDV genome is negative sense , single-stranded, closed circular RNA ; with a genome of approximately 1700 nucleotides, HDV is the smallest "virus" known to infect animals. It has been proposed that HDV may have originated from a class of plant pathogens called viroids , which are much smaller than viruses. Its genome is unique among animal viruses because of its high GC nucleotide content. Its nucleotide sequence is about 70% self-complementary, allowing the genome to form a partially double-stranded, rod-like RNA structure. HDV strains are highly divergent; fusions of different strains exist and sequences had been deposited in public databases employing different start sites for the circular viral RNA involved. This had resulted in something of chaos with respect to molecular classification of this virus, a situation which has been resolved recently with the adoption of a proposed reference genome and a uniform classification system. Like hepatitis B, HDV gains entry into liver cells via the sodium taurocholate cotransporting polypeptide (NTCP) bile transporter. HDV recognizes its receptor via the N-terminal domain of the large hepatitis B surface antigen, HBsAg . Mapping by mutagenesis of this domain has shown that amino acid residues 9–15 make up the receptor-binding site. After entering the hepatocyte, the virus is uncoated and the nucleocapsid translocated to the nucleus due to a signal in HDAg Since the HDV genome does not code for an RNA polymerase to replicate the virus' genome, the virus makes use of the host cellular RNA polymerases . Initially thought to use just RNA polymerase II, now RNA polymerases I and III have also been shown to be involved in HDV replication. Normally RNA polymerase II utilizes DNA as a template and produces mRNA. Consequently, if HDV indeed utilizes RNA polymerase II during replication, it would be the only known animal pathogen capable of using a DNA-dependent polymerase as an RNA-dependent polymerase. [ citation needed ] The RNA polymerases treat the RNA genome as double-stranded DNA due to the folded rod-like structure it is in. Three forms of RNA are made; circular genomic RNA, circular complementary antigenomic RNA, and a linear polyadenylated antigenomic RNA, which is the mRNA containing the open reading frame for the HDAg. Synthesis of antigenomic RNA occurs in the nucleolus, mediated by RNA polymerase I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA polymerase II. HDV RNA is synthesized first as linear RNA that contains many copies of the genome. The genomic and antigenomic RNA contain a sequence of 85 nucleotides, the hepatitis delta virus ribozyme , that acts as a ribozyme , which self-cleaves the linear RNA into monomers. These monomers are then ligated to form circular RNA. A significant difference between viroids and HDV is that, while viroids produce no proteins, HDV is known to produce one protein, namely HDAg. It comes in two forms; a 27kDa large-HDAg, and a small-HDAg of 24kDa. The N-terminals of the two forms are identical, they differ by 19 more amino acids in the C-terminal of the large HDAg. Both isoforms are produced from the same reading frame which contains an UAG stop codon at codon 196, which normally produces only the small-HDAg. However, editing by cellular enzyme adenosine deaminase acting on RNA (ADAR) changes the stop codon to UGG, allowing the large-HDAg to be produced. Despite having 90% identical sequences, these two proteins play diverging roles during the course of an infection. HDAg-S is produced in the early stages of an infection and enters the nucleus and supports viral replication. HDAg-L, in contrast, is produced during the later stages of an infection, acts as an inhibitor of viral replication, and is required for assembly of viral particles. Thus RNA editing by the cellular enzymes is critical to the virus' life cycle because it regulates the balance between viral replication and virion assembly. [ citation needed ]The HDV envelope protein has three of the HBV surface proteins anchored to it. The S region of the genome is most commonly expressed and its main function is to assemble subviral particles. HDV antigen proteins combine with the viral genome to form a ribonucleoprotein (RNP) which when enveloped with the subviral particles can form viral-like particles that are almost identical to mature HDV, but they are not infectious. Researchers had concluded that the determinant of infectivity of HDV was within the N-terminal pre-S1 domain of the large protein (L). It was found to be a mediator in binding to the cellular receptor. Researchers Georges Abou Jaoudé and Camille Sureau published an article in 2005 that studied the role of the antigenic loop, found in HDV envelope proteins, in the infectivity of the virus. The antigenic loop, like the N-terminal pre-S1 domain of the large protein, is exposed at the virion surface. Jaoudé and Sureau's study provided evidence that the antigenic loop may be an important factor in HDV entry into the host cell and by mutating parts of the antigenic loop, the infectivity of HDV may be minimized. The routes of transmission of hepatitis D are similar to those for hepatitis B. Infection is largely restricted to persons at high risk of hepatitis B infection, particularly injecting drug users and persons receiving clotting factor concentrates. Worldwide more than 15 million people are co-infected. HDV is rare in most developed countries , and is mostly associated with intravenous drug use . However, HDV is much more common in the immediate Mediterranean region, sub-Saharan Africa, the Middle East, and the northern part of South America. In all, about 20 million people may be infected with HDV. As previously stated, patients previously diagnosed with hepatitis B are at risk for hepatitis D infection. Hepatitis D infection risk increases if a person uses injecting drugs, is a hemophiliac, if they are a hemodialysis patient, or through sexual contact with other infected persons.Vaccination against hepatitis B protects against hepatitis D viral infection as hepatitis D requires hepatitis B viral infection to be present in order to infect and replicate in people. Universal vaccination against hepatitis B virus is recommended by the World Health Organization . The hepatitis B vaccine is routinely given soon after birth (usually within 24 hours) to protect against hepatitis B and D viral infection. Latex or polyurethane condoms have been shown to prevent the transmission of hepatitis B, and most likely hepatitis D viral infection. Women who are pregnant or trying to become pregnant should undergo testing for HBV to know if they carry the virus, this will allow prevention strategies to be implemented during the birth of the child. The CDC recommends that all women who are pregnant be tested for hepatitis B viral infection and that all infants of women with HBV infection be given hepatitis B immune globulin (HBIG) and the hepatitis B vaccine within 12 hours of birth to prevent transmission of the virus from mother to child. Those who get tattoos or body piercings should do so using sterile equipment to prevent the transmission of hepatitis B and D via infected bodily fluids. Hepatitis B and D can also be transmitted from contaminated needles, so those who inject drugs should seek help to stop drug use or use sterile needles and avoid sharing needles with others. Those with hepatitis B or D should also not share razors or other personal care items which may have been contaminated by potentially infectious bodily fluids. Screening for hepatits D requires testing for anti-HDV antibodies, which indicate past exposure to the virus or current infection. If anti-HDV antibodies are present, then active HDV infection is confirmed by measuring hepatitis D RNA levels. Testing for HDV is only indicated in those who are hepatitis B surface antigen positive (those who have had previous or active infection with hepatitis B) as HDV requires hepatitis B viral infection to infect people. Non-invasive measures of liver fibrosis, such as the biomarker based FibroTest or non-invasive liver imaging such as transient elastography (also known as the FibroScan) have not been validated as quantitative measures of liver fibrosis in those with chronic hepatitis D infection. In those with whom liver fibrosis or cirrhosis is suspected, a liver biopsy is usually needed. Current established treatments for chronic hepatitis D include conventional or pegylated interferon alpha therapy. Evidence suggests that pegylated interferon alpha is effective in reducing the viral load and the effect of the disease during the time the drug is given, but the benefit generally stops if the drug is discontinued. The efficiency of this treatment does not usually exceed about 20%, and late relapse after therapy has been reported. In May 2020, the Committee for Medicinal Products for Human Use of the European Medicines Agency approved the antiviral Hepcludex ( bulevirtide ) to treat hepatitis D. Bulevirtide binds and inactivates the sodium/bile acid cotransporter , blocking hepatitis D virus (as well as hepatitis B virus) from entering hepatocytes . Bulevirtide may be given with pegylated interferon alpha as the two are thought to have a synergistic effect, leading to greater treatment response rates. In patients with HDV-related compensated Cirrhosis and clinically significant portal hypertension, the treatment with ( bulevirtide ) was safe, well tolerated and has led to a significant improvement in biochemical variables and an increase in liver function parameters. Other treatments for hepatitis D which are currently under development include pegylated interferon lambda (λ), which binds to receptors on the hepatocyte surface leading to an intracellular signaling cascade via the JAK-STAT signaling pathway and activation of anti-viral cell mediated immunity. The prenylation inhibitor lonafarnib prevents hepatitis D viral particle assembly by inhibiting the farnesylation of the L-HDAg. REP2139-Ca is a nucleic acid polymer that prevents the release of hepatitis B surface antigen (which is required for assembly of hepatitis D viral particles). Superinfections, in which hepatitis D viral infection occurs in someone who has chronic hepatitis B (as opposed to co-infection, in which a person is infected with hepatitis B and D simultaneously), are more likely to progress to chronic hepatitis D and are associated with a worse prognosis. 90% of cases of chronic hepatitis D infection are thought to be due to superinfection in those already with hepatitis B. Hepatitis B and D co-infection is likely to lead to acute hepatitis, but is usually self limited with regards to the hepatitis D infection. Chronic hepatitis B and D is associated with a worse prognosis than chronic hepatitis B alone. Infection with both viruses is characterized by a poor prognosis with 75% of those with chronic hepatitis D developing liver cirrhosis within 15 years and a much higher risk of developing liver cancer. Persistent HDV viremia is the most important risk factor for disease progression in those with co-infection or superinfection. Other factors that are responsible for a poor prognosis in chronic hepatitis D include male sex, older age at time of infection, alcohol use, diabetes , obesity and immunodeficiency . HDV is prevalent worldwide. However, the prevalence is decreasing in many higher income countries due to hepatitis B vaccination programs (although rates remain high in some groups such as those who inject drugs or immigrants from HDV endemic reigions). Infection with HDV is a major medical scourge in low income regions of the globe in which HBV prevalence remains high. Currently the Amazon basin and low income regions of Asia and Africa have high rates of HDV, owing to concurrently high rates of HBV. Globally, five percent of those with chronic hepatitis B infection also have hepatitis D and 12.5% of people with HIV are also co-infected with hepatitis D. Hepatitis D virus was first reported in 1977 as a nuclear antigen in patients infected with HBV who had severe liver disease. This nuclear antigen was then thought to be a hepatitis B antigen and was called the delta antigen. Subsequent experiments in chimpanzees showed that the hepatitis delta antigen (HDAg) was a structural part of a pathogen that required HBV infection to produce a complete viral particle. The entire genome was cloned and sequenced in 1986. It was subsequently placed in its own genus: Deltavirus . Lábrea fever is a lethal tropical infection discovered in the 1950s in the city of Lábrea , in the Brazilian Amazon basin , where it occurs mostly in the area south of the Amazon River, in the states of Acre , Amazonas , and Rondônia . The disease has also been diagnosed in Colombia and Peru. It is now known to be a coinfection or superinfection of hepatitis B (HBV) with hepatitis D. Lábrea fever has a sudden onset, with jaundice , anorexia (lack of appetite), hematemesis ( vomiting of blood), headache , fever and severe prostration . Death occurs by acute liver failure (ALF). In the last phase, neurological symptoms such as agitation, delirium , convulsions and hemorrhagic coma commonly appear. These symptoms arise from a fulminant hepatitis which may kill in less than a week, and which characteristically affects children and young adults, and more males than females. It is accompanied also by an encephalitis in many cases. The disease is highly lethal: in a study carried out in 1986 at Boca do Acre , also in the Amazon, 39 patients out of 44 died in the acute phase of the disease. Survivors may develop chronic disease. [ citation needed ] The main discovery of delta virus and HBV association was done by Gilberta Bensabath , of the Instituto Evandro Chagas , of Belém , state of Pará , and her collaborators. Infected patients show extensive destruction of liver tissue, with steatosis of a particular type (microsteatosis, characterized by small fat droplets inside the cells), and infiltration of large numbers of inflammatory cells called morula cells , comprised mainly by macrophages containing delta virus antigens . In the 1987 Boca do Acre study, scientists did an epidemiological survey and reported delta virus infection in 24% of asymptomatic HBV carriers, 29% of acute nonfulminant hepatitis B cases, 74% of fulminant hepatitis B cases, and 100% of chronic hepatitis B cases. The delta virus seems to be endemic in the Amazon region. Lábrea fever is a lethal tropical infection discovered in the 1950s in the city of Lábrea , in the Brazilian Amazon basin , where it occurs mostly in the area south of the Amazon River, in the states of Acre , Amazonas , and Rondônia . The disease has also been diagnosed in Colombia and Peru. It is now known to be a coinfection or superinfection of hepatitis B (HBV) with hepatitis D. Lábrea fever has a sudden onset, with jaundice , anorexia (lack of appetite), hematemesis ( vomiting of blood), headache , fever and severe prostration . Death occurs by acute liver failure (ALF). In the last phase, neurological symptoms such as agitation, delirium , convulsions and hemorrhagic coma commonly appear. These symptoms arise from a fulminant hepatitis which may kill in less than a week, and which characteristically affects children and young adults, and more males than females. It is accompanied also by an encephalitis in many cases. The disease is highly lethal: in a study carried out in 1986 at Boca do Acre , also in the Amazon, 39 patients out of 44 died in the acute phase of the disease. Survivors may develop chronic disease. [ citation needed ] The main discovery of delta virus and HBV association was done by Gilberta Bensabath , of the Instituto Evandro Chagas , of Belém , state of Pará , and her collaborators. Infected patients show extensive destruction of liver tissue, with steatosis of a particular type (microsteatosis, characterized by small fat droplets inside the cells), and infiltration of large numbers of inflammatory cells called morula cells , comprised mainly by macrophages containing delta virus antigens . In the 1987 Boca do Acre study, scientists did an epidemiological survey and reported delta virus infection in 24% of asymptomatic HBV carriers, 29% of acute nonfulminant hepatitis B cases, 74% of fulminant hepatitis B cases, and 100% of chronic hepatitis B cases. The delta virus seems to be endemic in the Amazon region. Three genotypes (I–III) were originally described. Genotype I has been isolated in Europe, North America, Africa and some Asia. Genotype II has been found in Japan, Taiwan, and Yakutia (Russia). Genotype III has been found exclusively in South America (Peru, Colombia, and Venezuela). Some genomes from Taiwan and the Okinawa islands have been difficult to type but have been placed in genotype 2. However it is now known that there are at least 8 genotypes of this virus (HDV-1 to HDV-8). Phylogenetic studies suggest an African origin for this pathogen. An analysis of 36 strains of genotype 3 estimated that the most recent common ancestor of these strains originated around 1930. This genotype spread exponentially from early 1950s to the 1970s in South America. The substitution rate was estimated to be 1.07 × 10 −3 substitutions per site per year. Another study found an overall evolution rate of 3.18 × 10 −3 substitutions per site per year. The mutation rate varied with position : the hypervariable region evolved faster (4.55 × 10 −3 substitutions per site per year) than the hepatitis delta antigen coding region (2.60 × 10 −3 substitutions per site per year) and the autocatalytic region (1.11 × 10 −3 substitutions per site per year). A third study suggested a mutation rate between 9.5 × 10 −3 to 1.2 × 10 −3 substitutions/site/year. Genotypes, with the exception of type 1, appear to be restricted to certain geographical areas: HDV-2 (previously HDV-IIa) is found in Japan, Taiwan and Yakutia; HDV-4 (previously HDV-IIb) in Japan and Taiwan; HDV-3 in the Amazonian region; HDV-5, HDV-6, HDV-7 and HDV-8 in Africa. Genotype 8 has also been isolated from South America. This genotype is usually only found in Africa and may have been imported into South America during the slave trade. HDV-specific CD8+ T cells can control the virus, but it has been found HDV mutates to escape detection by CD8+ T cells. A few other viruses with similarity to HDV have been described in species other than humans. Unlike HDV, none of them depend on a Hepadnaviridae (HBV family) virus to replicate. These agents have rod-like structure, a delta antigen, and a ribozyme. HDV and all such relatives are classified in their own realm , Ribozyviria , by the International Committee on Taxonomy of Viruses .

Wiki

Acute hemorrhagic fever syndrome

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Internal bleeding

Internal bleeding (also called internal haemorrhage ) is a loss of blood from a blood vessel that collects inside the body, and is not usually visible from the outside. It can be a serious medical emergency but the extent of severity depends on bleeding rate and location of the bleeding (e.g. head, torso, extremities). Severe internal bleeding into the chest , abdomen , pelvis , or thighs can cause hemorrhagic shock or death if proper medical treatment is not received quickly. Internal bleeding is a medical emergency and should be treated immediately by medical professionals. Signs and symptoms of internal bleeding may vary based on location, presence of injury or trauma, and severity of bleeding. Common symptoms of blood loss may include: Lightheadedness Fatigue Urinating less than usual Confusion Fast heart rate Pale and/or cold skin Thirst Generalized weakness Visible signs of internal bleeding include: Blood in the urine Dark black stools Bright red stools Bloody noses Bruising Throwing up blood Of note, it is possible to have internal bleeding without any of the above symptoms, and pain may or may not be present. A patient may lose more than 30% of their blood volume before there are changes in their vital signs or level of consciousness. This is called hemorrhagic or hypovolemic shock , which is a type of shock that occurs when there is not enough blood to reach organs in the body. Internal bleeding can be caused by a broad number of things. We can break these up into three large categories: Trauma, or direct injury to blood vessels within the body cavity Genetic and acquired conditions, along with various medications, that result in an increased bleeding risk Other The most common cause of death in trauma is bleeding . Death from trauma accounts for 1.5 million of the 1.9 million deaths per year due to bleeding. There are two types of trauma: penetrating trauma and blunt trauma . A number of pathological conditions and diseases can lead to internal bleeding. These include: Internal bleeding could be a result of complications following surgery or other medical procedures. Some medications may also increase a person's risk for bleeding, such as anticoagulant drugs or antiplatelet drugs in the treatment of coronary artery disease . The most common cause of death in trauma is bleeding . Death from trauma accounts for 1.5 million of the 1.9 million deaths per year due to bleeding. There are two types of trauma: penetrating trauma and blunt trauma . A number of pathological conditions and diseases can lead to internal bleeding. These include:Internal bleeding could be a result of complications following surgery or other medical procedures. Some medications may also increase a person's risk for bleeding, such as anticoagulant drugs or antiplatelet drugs in the treatment of coronary artery disease . Blood loss can be estimated based on heart rate, blood pressure, respiratory rate, and mental status. Blood is circulated throughout the body and all major organ systems through a closed loop system. When there is damage to the blood vessel or the blood is thinner than the physiologic consistency, blood can exit the vessel which disrupts this close-looped system. The autonomic nervous system (ANS) responds in two large ways as an attempt to compensate for the opening in the system. These two actions are easily monitored by checking the heart rate and blood pressure. Blood pressure will initially decrease due to the loss of blood. This is where the ANS comes in and attempts to compensate by contracting the muscles that surround these vessels. As a result, a person who is bleeding internally may initially have a normal blood pressure. When the blood pressure falls below the normal range, this is called hypotension . The heart will start to pump faster causing the heart rate to increase, as an attempt to get blood delivered to vital organ systems faster. When the heart beats faster than the healthy and normal range, this is called tachycardia . If the bleeding is not controlled or stopped, a patient will experience tachycardia and hypotension, which altogether is a state of shock, called hemorrhagic shock . Advanced trauma life support (ATLS) by the American College of Surgeons separates hemorrhagic shock into four categories. Slightly anxious Mildly anxious Cool, clammy skin with delayed capillary refill Altered mental status (anxious, confused) Decreased urine output Significantly altered mental status (confused, lethargic) Cool, clammy skin with delayed capillary refill Significantly decreased or absent urine output Assessing circulation occurs after assessing the patient's airway and breathing ( ABC (medicine) ). If internal bleeding is suspected, a patient's circulatory system is assessed through palpation of pulses and doppler ultrasonography . It is important to examine the person for visible signs that may suggest the presence of internal bleeding and/or the source of the bleed. Some of these signs may include: If internal bleeding is suspected a FAST exam may be performed to look for bleeding in the abdomen. If the patient has stable vital signs , they may undergo diagnostic imaging such as a CT scan . If the patient has unstable vital signs, they may not undergo diagnostic imaging and instead may receive immediate medical or surgical treatment. Blood loss can be estimated based on heart rate, blood pressure, respiratory rate, and mental status. Blood is circulated throughout the body and all major organ systems through a closed loop system. When there is damage to the blood vessel or the blood is thinner than the physiologic consistency, blood can exit the vessel which disrupts this close-looped system. The autonomic nervous system (ANS) responds in two large ways as an attempt to compensate for the opening in the system. These two actions are easily monitored by checking the heart rate and blood pressure. Blood pressure will initially decrease due to the loss of blood. This is where the ANS comes in and attempts to compensate by contracting the muscles that surround these vessels. As a result, a person who is bleeding internally may initially have a normal blood pressure. When the blood pressure falls below the normal range, this is called hypotension . The heart will start to pump faster causing the heart rate to increase, as an attempt to get blood delivered to vital organ systems faster. When the heart beats faster than the healthy and normal range, this is called tachycardia . If the bleeding is not controlled or stopped, a patient will experience tachycardia and hypotension, which altogether is a state of shock, called hemorrhagic shock . Advanced trauma life support (ATLS) by the American College of Surgeons separates hemorrhagic shock into four categories. Slightly anxious Mildly anxious Cool, clammy skin with delayed capillary refill Altered mental status (anxious, confused) Decreased urine output Significantly altered mental status (confused, lethargic) Cool, clammy skin with delayed capillary refill Significantly decreased or absent urine output Assessing circulation occurs after assessing the patient's airway and breathing ( ABC (medicine) ). If internal bleeding is suspected, a patient's circulatory system is assessed through palpation of pulses and doppler ultrasonography . It is important to examine the person for visible signs that may suggest the presence of internal bleeding and/or the source of the bleed. Some of these signs may include:If internal bleeding is suspected a FAST exam may be performed to look for bleeding in the abdomen. If the patient has stable vital signs , they may undergo diagnostic imaging such as a CT scan . If the patient has unstable vital signs, they may not undergo diagnostic imaging and instead may receive immediate medical or surgical treatment. Management of internal bleeding depends on the cause and severity of the bleed. Internal bleeding is a medical emergency and should be treated immediately by medical professionals . If a patient has low blood pressure ( hypotension ), intravenous fluids can be used until they can receive a blood transfusion . In order to replace blood loss quickly and with large amounts of IV fluids or blood, patients may need a central venous catheter . Patients with severe bleeding need to receive large quantities of replacement blood via a blood transfusion . As soon as the clinician recognizes that the patient may have a severe, continuing hemorrhage requiring more than 4 units in 1 hour or 10 units in 6 hours, they should initiate a massive transfusion protocol . The massive transfusion protocol replaces red blood cells , plasma , and platelets in varying ratios based on the cause of the bleeding (traumatic vs. non-traumatic). It is crucial to stop the internal bleeding immediately (achieve hemostasis ) after identifying its cause. The longer it takes to achieve hemostasis in people with traumatic causes (e.g. pelvic fracture ) and non-traumatic causes (e.g. gastrointestinal bleeding , ruptured abdominal aortic aneurysm ), the higher the death rate is. Unlike with external bleeding, most internal bleeding cannot be controlled by applying pressure to the site of injury. Internal bleeding in the thorax and abdominal cavity (including both the intraperitoneal and retroperitoneal space ) cannot be controlled with direct pressure (compression). A patient with acute internal bleeding in the thorax after trauma should be diagnosed, resuscitated, and stabilized in the Emergency Department in less than 10 minutes before undergoing surgery to reduce the risk of death from internal bleeding. A patient with acute internal bleeding in the abdomen or pelvis after trauma may require use of a REBOA device to slow the bleeding. The REBOA has also been used for non-traumatic causes of internal bleeding, including bleeding during childbirth and gastrointestinal bleeding . Internal bleeding from a bone fracture in the arms or legs may be partially controlled with direct pressure using a tourniquet . After tourniquet placement, the patient may need immediate surgery to find the bleeding blood vessel . Internal bleeding where the torso meets the extremities ("junctional sites" such as the axilla or groin ) cannot be controlled with a tourniquet; however there is an FDA approved device known as an Abdominal Aortic and Junctional Tourniquet (AAJT) designed for proximal aortic control, although very few studies examining its use have been published. For bleeding at junctional sites, a dressing with a blood clotting agent ( hemostatic dressing ) should be applied. A campaign is to improve the care of the bleeding known as Stop The Bleed campaign is also taking place. If a patient has low blood pressure ( hypotension ), intravenous fluids can be used until they can receive a blood transfusion . In order to replace blood loss quickly and with large amounts of IV fluids or blood, patients may need a central venous catheter . Patients with severe bleeding need to receive large quantities of replacement blood via a blood transfusion . As soon as the clinician recognizes that the patient may have a severe, continuing hemorrhage requiring more than 4 units in 1 hour or 10 units in 6 hours, they should initiate a massive transfusion protocol . The massive transfusion protocol replaces red blood cells , plasma , and platelets in varying ratios based on the cause of the bleeding (traumatic vs. non-traumatic). It is crucial to stop the internal bleeding immediately (achieve hemostasis ) after identifying its cause. The longer it takes to achieve hemostasis in people with traumatic causes (e.g. pelvic fracture ) and non-traumatic causes (e.g. gastrointestinal bleeding , ruptured abdominal aortic aneurysm ), the higher the death rate is. Unlike with external bleeding, most internal bleeding cannot be controlled by applying pressure to the site of injury. Internal bleeding in the thorax and abdominal cavity (including both the intraperitoneal and retroperitoneal space ) cannot be controlled with direct pressure (compression). A patient with acute internal bleeding in the thorax after trauma should be diagnosed, resuscitated, and stabilized in the Emergency Department in less than 10 minutes before undergoing surgery to reduce the risk of death from internal bleeding. A patient with acute internal bleeding in the abdomen or pelvis after trauma may require use of a REBOA device to slow the bleeding. The REBOA has also been used for non-traumatic causes of internal bleeding, including bleeding during childbirth and gastrointestinal bleeding . Internal bleeding from a bone fracture in the arms or legs may be partially controlled with direct pressure using a tourniquet . After tourniquet placement, the patient may need immediate surgery to find the bleeding blood vessel . Internal bleeding where the torso meets the extremities ("junctional sites" such as the axilla or groin ) cannot be controlled with a tourniquet; however there is an FDA approved device known as an Abdominal Aortic and Junctional Tourniquet (AAJT) designed for proximal aortic control, although very few studies examining its use have been published. For bleeding at junctional sites, a dressing with a blood clotting agent ( hemostatic dressing ) should be applied. A campaign is to improve the care of the bleeding known as Stop The Bleed campaign is also taking place.

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Acute hemorrhagic fever syndrome

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Viral hepatitis

Viral hepatitis is liver inflammation due to a viral infection . It may present in acute form as a recent infection with relatively rapid onset, or in chronic form, typically progressing from a long-lasting asymptomatic condition up to a decompensated hepatic disease and hepatocellular carcinoma (HCC). The most common causes of viral hepatitis are the five unrelated hepatotropic viruses hepatitis A , B , C , D , and E . Other viruses can also cause liver inflammation, including cytomegalovirus , Epstein–Barr virus , and yellow fever . There also have been scores of recorded cases of viral hepatitis caused by herpes simplex virus. Viral hepatitis is either transmitted through contaminated food or water (A, E) or via blood and body fluids (B, C). The viruses transmitted through water and food are mostly self-limited, resulting in acute illness with full resolution. The blood borne viruses (B, C) can cause both acute and chronic liver disease and can be transmitted from mother to child during birth, through contact with body fluids during sex, unsafe injections and through unscreened blood transfusions. The most common types of hepatitis can be prevented or treated. Hepatitis A and hepatitis B can be prevented by vaccination. Effective treatments for hepatitis C are available but costly. In 2013, about 1.5 million people died from viral hepatitis, most commonly due to hepatitis B and C. East Asia, in particular Mongolia , is the region most affected. The most common cause of hepatitis is viral. Although the effects of various viruses are all classified under the disease hepatitis , these viruses are not all related. [ citation needed ]Hepatitis A or infectious jaundice is caused by hepatitis A virus (HAV), a picornavirus transmitted by the fecal-oral route often associated with ingestion of contaminated food . It causes an acute form of hepatitis and does not have a chronic stage. A patient's immune system makes antibodies against HAV that confer immunity against future infection. People with hepatitis A are advised to rest, stay hydrated and avoid alcohol. A vaccine is available that will prevent HAV infection for up to 10 years. Hepatitis A can be spread through personal contact, consumption of raw sea food, or drinking contaminated water . This occurs primarily in third world countries . Strict personal hygiene and the avoidance of raw and unpeeled foods can help prevent an infection. Infected people excrete HAV with their feces two weeks before and one week after the appearance of jaundice . The time between the infection and the start of the illness averages 28 days. (ranging from 15 to 50 days), Most patients recover fully within 2 months, although approximately 15% of affected people may experience continuous or relapsing symptoms from six months to a year following initial diagnosis . Hepatitis B is caused by the hepatitis B virus, a hepadnavirus that can cause both acute and chronic hepatitis. Chronic hepatitis develops in the 15% of adults who are unable to eliminate the virus after an initial infection. Identified methods of transmission include contact with blood, blood transfusion (now rare), unsanitary tattoos, sex (through sexual intercourse or contact with bodily fluids), or mother-to-child by breast feeding ; [ citation needed ] there is minimal evidence of transplacental crossing . However, in about half of cases the source of infection cannot be determined. Blood contact can occur by sharing syringes in intravenous drug use, shaving accessories such as razor blades, or touching wounds on infected persons. Needle-exchange programmes have been created in many countries as a form of prevention. [ citation needed ] Patients with chronic hepatitis B have antibodies against the virus, but not enough to clear the infected liver cells . The continued production of virus and countervailing antibodies is a likely cause of the immune complex disease seen in these patients. A vaccine is available to prevent infection for life. Hepatitis B infections result in 500,000 to 1,200,000 deaths per year worldwide due to the complications of chronic hepatitis, cirrhosis , and hepatocellular carcinoma (HCC). Hepatitis B is endemic in a number of (mainly South-East Asian) countries, making cirrhosis and hepatocellular carcinoma big killers. There are eight treatment options approved by the U.S. Food and Drug Administration (FDA) available for persons with a chronic hepatitis B infection: alpha-interferon , pegylated interferon , adefovir , entecavir , telbivudine , lamivudine , tenofovir disoproxil and tenofovir alafenamide with a 65% rate of sustained response. [ citation needed ] Hepatitis C (originally "non-A non-B hepatitis") is caused by hepatitis C virus (HCV), an RNA virus of the family Flaviviridae . HCV can be transmitted through contact with blood (including through sexual contact if the two parties' blood is mixed) and can also cross the placenta . Hepatitis C usually leads to chronic hepatitis, culminating in cirrhosis in some people. It usually remains asymptomatic for decades. Patients with hepatitis C are susceptible to severe hepatitis if they contract either hepatitis A or B, so all persons with hepatitis C should be immunized against hepatitis A and hepatitis B if they are not already immune, and avoid alcohol. HCV can lead to the development of hepatocellular carcinoma , however, only a minority of HCV-infected individuals develop cancer (1–4% annually), suggesting a complex interplay between viral gene expression and host and environmental factors to promote carcinogenesis. The risk is increased two-fold with active HBV coinfection and a 21% increase in mortality compared to those with latent HBV and HCV. HCV viral levels can be reduced to undetectable levels by a combination of interferon and the antiviral drug ribavirin . The genotype of the virus is the primary determinant of the rate of response to this treatment regimen, with genotype 1 being the most resistant. [ citation needed ] Hepatitis C is the most common chronic bloodborne infection in the United States, and the leading cause of liver tranplants. Hepatitis D is caused by the hepatitis D virus (HDV), or hepatitis delta virus; it belongs to the genus Deltavirus . HDV is similar to a satellite virus as it can only propagate in the presence of the hepatitis B virus, depending on the helper function of HBV for its replication and expression. It has no independent life cycle, but can survive and replicate as long as HBV infection persists in the host body. It can only cause infection when encapsulated by hepatitis B virus surface antigens. The vaccine for hepatitis B protects against hepatitis D virus because of the latter's dependence on the presence of hepatitis B virus for it to replicate. Hepatitis E is caused by the Hepatitis E virus (HEV), from the family Hepeviridae. It produces symptoms similar to hepatitis A , although it can take a fulminant course in some patients, particularly pregnant women (mortality rate about 20%); chronic infections may occur in immune-compromised patients. It is more prevalent in the Indian subcontinent . The virus is feco-orally transmitted and is usually self-limited. [ citation needed ] Hepatitis F virus (HFV) is a hypothetical virus linked to certain cases of hepatitis. Several hepatitis F virus candidates emerged in the 1990s, but none of these reports have been substantiated. [ citation needed ] The GB virus C is a virus that is probably spread by blood and sexual contact. It was initially identified as Hepatitis G virus. There is very little evidence that this virus causes hepatitis, as it does not appear to replicate primarily in the liver. It is now classified as GB virus C. In 2022, several hundred cases of acute hepatitis of probable infectious origin were reported worldwide. As of May 2023, the virus causing these cases has not been identified, but an adenovirus is suspected. Hepatitis A or infectious jaundice is caused by hepatitis A virus (HAV), a picornavirus transmitted by the fecal-oral route often associated with ingestion of contaminated food . It causes an acute form of hepatitis and does not have a chronic stage. A patient's immune system makes antibodies against HAV that confer immunity against future infection. People with hepatitis A are advised to rest, stay hydrated and avoid alcohol. A vaccine is available that will prevent HAV infection for up to 10 years. Hepatitis A can be spread through personal contact, consumption of raw sea food, or drinking contaminated water . This occurs primarily in third world countries . Strict personal hygiene and the avoidance of raw and unpeeled foods can help prevent an infection. Infected people excrete HAV with their feces two weeks before and one week after the appearance of jaundice . The time between the infection and the start of the illness averages 28 days. (ranging from 15 to 50 days), Most patients recover fully within 2 months, although approximately 15% of affected people may experience continuous or relapsing symptoms from six months to a year following initial diagnosis . Hepatitis B is caused by the hepatitis B virus, a hepadnavirus that can cause both acute and chronic hepatitis. Chronic hepatitis develops in the 15% of adults who are unable to eliminate the virus after an initial infection. Identified methods of transmission include contact with blood, blood transfusion (now rare), unsanitary tattoos, sex (through sexual intercourse or contact with bodily fluids), or mother-to-child by breast feeding ; [ citation needed ] there is minimal evidence of transplacental crossing . However, in about half of cases the source of infection cannot be determined. Blood contact can occur by sharing syringes in intravenous drug use, shaving accessories such as razor blades, or touching wounds on infected persons. Needle-exchange programmes have been created in many countries as a form of prevention. [ citation needed ] Patients with chronic hepatitis B have antibodies against the virus, but not enough to clear the infected liver cells . The continued production of virus and countervailing antibodies is a likely cause of the immune complex disease seen in these patients. A vaccine is available to prevent infection for life. Hepatitis B infections result in 500,000 to 1,200,000 deaths per year worldwide due to the complications of chronic hepatitis, cirrhosis , and hepatocellular carcinoma (HCC). Hepatitis B is endemic in a number of (mainly South-East Asian) countries, making cirrhosis and hepatocellular carcinoma big killers. There are eight treatment options approved by the U.S. Food and Drug Administration (FDA) available for persons with a chronic hepatitis B infection: alpha-interferon , pegylated interferon , adefovir , entecavir , telbivudine , lamivudine , tenofovir disoproxil and tenofovir alafenamide with a 65% rate of sustained response. [ citation needed ]Hepatitis C (originally "non-A non-B hepatitis") is caused by hepatitis C virus (HCV), an RNA virus of the family Flaviviridae . HCV can be transmitted through contact with blood (including through sexual contact if the two parties' blood is mixed) and can also cross the placenta . Hepatitis C usually leads to chronic hepatitis, culminating in cirrhosis in some people. It usually remains asymptomatic for decades. Patients with hepatitis C are susceptible to severe hepatitis if they contract either hepatitis A or B, so all persons with hepatitis C should be immunized against hepatitis A and hepatitis B if they are not already immune, and avoid alcohol. HCV can lead to the development of hepatocellular carcinoma , however, only a minority of HCV-infected individuals develop cancer (1–4% annually), suggesting a complex interplay between viral gene expression and host and environmental factors to promote carcinogenesis. The risk is increased two-fold with active HBV coinfection and a 21% increase in mortality compared to those with latent HBV and HCV. HCV viral levels can be reduced to undetectable levels by a combination of interferon and the antiviral drug ribavirin . The genotype of the virus is the primary determinant of the rate of response to this treatment regimen, with genotype 1 being the most resistant. [ citation needed ] Hepatitis C is the most common chronic bloodborne infection in the United States, and the leading cause of liver tranplants. Hepatitis D is caused by the hepatitis D virus (HDV), or hepatitis delta virus; it belongs to the genus Deltavirus . HDV is similar to a satellite virus as it can only propagate in the presence of the hepatitis B virus, depending on the helper function of HBV for its replication and expression. It has no independent life cycle, but can survive and replicate as long as HBV infection persists in the host body. It can only cause infection when encapsulated by hepatitis B virus surface antigens. The vaccine for hepatitis B protects against hepatitis D virus because of the latter's dependence on the presence of hepatitis B virus for it to replicate. Hepatitis E is caused by the Hepatitis E virus (HEV), from the family Hepeviridae. It produces symptoms similar to hepatitis A , although it can take a fulminant course in some patients, particularly pregnant women (mortality rate about 20%); chronic infections may occur in immune-compromised patients. It is more prevalent in the Indian subcontinent . The virus is feco-orally transmitted and is usually self-limited. [ citation needed ]Hepatitis F virus (HFV) is a hypothetical virus linked to certain cases of hepatitis. Several hepatitis F virus candidates emerged in the 1990s, but none of these reports have been substantiated. [ citation needed ]The GB virus C is a virus that is probably spread by blood and sexual contact. It was initially identified as Hepatitis G virus. There is very little evidence that this virus causes hepatitis, as it does not appear to replicate primarily in the liver. It is now classified as GB virus C. In 2022, several hundred cases of acute hepatitis of probable infectious origin were reported worldwide. As of May 2023, the virus causing these cases has not been identified, but an adenovirus is suspected. Hepatitis C virus (HCV) can cause acute and chronic infections that are a major cause of hepatocellular carcinoma (HCC), advanced hepatic fibrosis and cirrhosis. [ citation needed ] HCC is a major cause of death in patients with chronic HCV infection. Regarding the pathogenesis of HCC associated with HCV, that virus may play direct or indirect roles. A major risk for the development of HCC is persistent infection with HCV, and the highest risk for HCC development is associated with co-infection of HBV with HDV, HCV or HIV. Risk factors that can lead to the development of HCC in those with chronic HCV include synchronous liver diseases, viral genotype, diabetes mellitus, and obesity. Lifestyle factors such as liver steatosis, smoking, and alcohol use can accelerate progression to HCC and liver decompensation in patients with HCV. The purpose of HCV treatment is to eliminate the infection, reduce the transmission to other people and decrease the risk of HCC development. The virus first known to cause hepatitis was the yellow fever virus , a mosquito-borne flavivirus . Other viruses than can cause hepatitis include: Additionally, a casual role between the virus KIs-V and hepatitis is suspected based on a 2011 study that isolated KIs-V from four patients with raised serum alanine transferases without other known cause.

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Babesiosis

Babesiosis or piroplasmosis is a malaria -like parasitic disease caused by infection with a eukaryotic parasite in the order Piroplasmida , typically a Babesia or Theileria , in the phylum Apicomplexa . Human babesiosis transmission via tick bite is most common in the Northeastern and Midwestern United States and parts of Europe, and sporadic throughout the rest of the world. It occurs in warm weather. People can get infected with Babesia parasites by the bite of an infected tick , by getting a blood transfusion from an infected donor of blood products, or by congenital transmission (an infected mother to her baby). Ticks transmit the human strain of babesiosis, so it often presents with other tick-borne illnesses such as Lyme disease . After trypanosomes , Babesia is thought to be the second-most common blood parasite of mammals. They can have major adverse effects on the health of domestic animals in areas without severe winters. In cattle, the disease is known as Texas cattle fever or redwater . Half of all children and a quarter of previously healthy adults with Babesia infection are asymptomatic. When people do develop symptoms, the most common are fever and hemolytic anemia , symptoms that are similar to those of malaria. People with symptoms usually become ill 1 to 4 weeks after the bite, or 1 to 9 weeks after transfusion of contaminated blood products. A person infected with babesiosis gradually develops malaise and fatigue, followed by a fever. Hemolytic anemia, in which red blood cells are destroyed and removed from the blood, also develops. Chills, sweats, and thrombocytopenia are also common symptoms. Symptoms may last from several days to several months. [ citation needed ] Less common symptoms and physical exam findings of mild-to-moderate babesiosis: In more severe cases, symptoms similar to malaria occur, with fevers up to 40.5 °C (105 °F), shaking chills, and severe anemia (hemolytic anemia). Organ failure may follow, including adult respiratory distress syndrome. Sepsis in people who have had a splenectomy can occur rapidly, consistent with overwhelming post-splenectomy infection . Severe cases are also more likely to occur in the very young, very old, and persons with immunodeficiency , such as HIV/AIDS patients. [ citation needed ] A reported increase in human babesiosis diagnoses in the 2000s is thought to be caused by more widespread testing and higher numbers of people with immunodeficiencies coming in contact with ticks, the disease vector. Little is known about the occurrence of Babesia species in malaria- endemic areas, where Babesia can easily be misdiagnosed as Plasmodium . Human patients with repeat babesiosis infection may exhibit premunity . Babesia species are in the phylum Apicomplexa , which also has the protozoan parasites that cause malaria , toxoplasmosis , and cryptosporidiosis . Four clades of Babesia species infect humans. The main species in each clade are: [ citation needed ]Babesia parasites reproduce in red blood cells , where they can be seen as cross-shaped inclusions (four merozoites asexually budding, but attached together forming a structure looking like a " Maltese cross ") and cause hemolytic anemia, quite similar to malaria. Unlike the Plasmodium parasites that cause malaria, Babesia species lack an exoerythrocytic phase, so the liver is usually not affected. [ citation needed ] In nonhuman animals, Babesia canis rossi , Babesia bigemina , and Babesia bovis cause particularly severe forms of the disease, including a severe haemolytic anaemia, with positive erythrocyte-in-saline-agglutination test indicating an immune-mediated component to the haemolysis. Common sequelae include haemoglobinuria "red-water", disseminated intravascular coagulation, and "cerebral babesiosis" caused by sludging of erythrocytes in cerebral capillaries. [ citation needed ] In bovine species, the organism causes hemolytic anemia, so an infected animal shows pale mucous membranes initially. As the levels of bilirubin (a byproduct of red blood cell lysis) continue to increase, the visible mucous membranes become yellow in color (icterus) due to the failure of the liver to metabolize the excess bilirubin. Hemoglobinuria is seen due to excretion of red-blood-cell lysis byproducts via the kidneys. Fever of 40.5 °C (105 °F) develops due to release of inflammatory byproducts. [ citation needed ]Only specialized laboratories can adequately diagnose Babesia infection in humans, so Babesia infections are considered highly under-reported. It develops in patients who live in or travel to an endemic area or receive a contaminated blood transfusion within the preceding 9 weeks, so this aspect of the medical history is vital. Babesiosis may be suspected when a person with such an exposure history develops persistent fevers and hemolytic anemia. The definitive diagnostic test is the identification of parasites on a Giemsa-stained thin-film blood smear . So-called "Maltese cross formations" on the blood film are diagnostic ( pathognomonic ) of babesiosis, since they are not seen in malaria, the primary differential diagnosis. Careful examination of multiple smears may be necessary, since Babesia may infect less than 1% of circulating red blood cells, thus be easily overlooked. Serologic testing for antibodies against Babesia (both IgG and IgM ) can detect low-level infection in cases with a high clinical suspicion, but negative blood film examinations. Serology is also useful for differentiating babesiosis from malaria in cases where people are at risk for both infections. Since detectable antibody responses require about a week after infection to develop, serologic testing may be falsely negative early in the disease course. A polymerase chain reaction (PCR) test has been developed for the detection of Babesia from the peripheral blood. PCR may be at least as sensitive and specific as blood-film examination in diagnosing babesiosis, though it is also significantly more expensive. Most often, PCR testing is used in conjunction with blood film examination and possibly serologic testing . Other laboratory findings include decreased numbers of red blood cells and platelets on complete blood count . [ citation needed ] In animals, babesiosis is suspected by observation of clinical signs (hemoglobinuria and anemia) in animals in endemic areas. Diagnosis is confirmed by observation of merozoites on thin film blood smear examined at maximum magnification under oil using Romonovski stains (methylene blue and eosin). This is a routine part of the veterinary examination of dogs and ruminants in regions where babesiosis is endemic. [ citation needed ] Babesia canis and B. bigemina are "large Babesia species" that form paired merozoites in the erythrocytes, commonly described as resembling "two pears hanging together", rather than the "Maltese cross" of the "small Babesia species". Their merozoites are around twice the size of small ones. [ citation needed ] Cerebral babesiosis is suspected in vivo when neurological signs (often severe) are seen in cattle that are positive for B. bovis on blood smear, but this has yet to be proven scientifically. Outspoken red discoloration of the grey matter post mortem further strengthens suspicion of cerebral babesiosis. Diagnosis is confirmed post mortem by observation of Babesia -infected erythrocytes sludged in the cerebral cortical capillaries in a brain smear. [ citation needed ]Treatment of asymptomatic carriers should be considered if parasites are still detected after 3 months. In mild-to-moderate babesiosis, the treatment of choice is a combination of atovaquone and azithromycin . This regimen is preferred to clindamycin and quinine because it has fewer side effects. The standard course is 7 to 10 days, but this is extended to at least 6 weeks in people with relapsing disease. Even mild cases are recommended to be treated to decrease the chance of inadvertently transmitting the infection by donating blood. In severe babesiosis, the combination of clindamycin and quinine is preferred. In life-threatening cases, exchange transfusion is performed. In this procedure, the infected red blood cells are removed and replaced with uninfected ones. [ citation needed ] Imidocarb is a drug used for treatment of babesiosis in dogs. Extracts of the poisonous, bulbous plant Boophone disticha are used in the folk medicine of South Africa to treat equine babesiosis. B. disticha is a member of the daffodil family Amaryllidaceae and has also been used in preparations employed as arrow poisons , hallucinogens , and in embalming . The plant is rich in alkaloids , some of which display an action similar to that of scopolamine . Babesiosis is a vector-borne illness usually transmitted by Ixodes scapularis ticks . B. microti uses the same tick vector as Lyme disease, and may occur in conjunction with Lyme. The organism can also be transmitted by blood transfusion. Ticks of domestic animals , especially Rhipicephalus (Boophilus) microplus and R. (B.) decoloratus transmit several species of Babesia to livestock, causing considerable economic losses to farmers in tropical and subtropical regions. [ citation needed ] In the United States, the majority of babesiosis cases are caused by B. microti , and occur in the Northeast and northern Midwest from May through October. Areas with especially high rates include eastern Long Island , Fire Island , Nantucket Island , and Martha's Vineyard . The Centers for Disease Control and Prevention now requires state health departments to report infections using Form OMB No. 0920-0728 . In 2014, Rhode Island had an incidence of 16.3 reported infections per 100,000 people. In Europe, B. divergens is the primary cause of infectious babesiosis and is transmitted by I. ricinus . Babesiosis has emerged in Lower Hudson Valley, New York, since 2001. In Australia, one locally-acquired case of B. microti has been reported, which was fatal. A subsequent investigation found no additional evidence of human Babesiosis in over 7000 patient samples, leading the authors to conclude that Babesiosis was rare in Australia. A similar disease in cattle, commonly known as tick fever, is spread by Babesia bovis and B. bigemina in the introduced cattle tick Rhipicephalus microplus . This disease is found in eastern and northern Australia. A table of isolated cases of babesiosis, which may be underestimated given how widely distributed the tick vectors are in temperate latitudes. A table of isolated cases of babesiosis, which may be underestimated given how widely distributed the tick vectors are in temperate latitudes. The disease is named for the genus of the causative organism, which was named after the Romanian bacteriologist Victor Babeș . In 1888, Victor Babeș identified the microorganisms in red blood cells as the cause of febrile hemoglobinuria in cattle. In 1893, Theobald Smith and Frederick Kilborne discovered that a tick was the vector for transmission in Texas cattle. The agent was B. bigemina . This was the first demonstration that an arthropod could act as a disease vector to transmit an infectious agent to a vertebrate host. [ citation needed ] In 1957, the first human case was documented in a splenectomized Croatian herdsman. The agent was B. divergens . In 1969, the first case was reported in an immunocompetent individual on Nantucket Island. The agent was B. microti , and the vector was the tick I. scapularis . [ citation needed ] Equine babesiosis (caused by the protozoan Theileria equi ) is also known as piroplasmosis (from the Latin piro , meaning pear + Greek plasma , a thing formed). Veterinary treatment of babesiosis does not normally use antibiotics. In livestock and animals, diminazen (Berenil), imidocarb , or trypan blue would be the drugs of choice for treatment of B. canis rossi (dogs in Africa), B. bovis , and B. bigemina (cattle in Southern Africa). In acute cases in cattle, blood transfusion may be carried out. A vaccine is effective against B. canis canis (dogs in the Mediterranean region), but is ineffective against B. c. rossi . B. imitans causes a mild form of the disease that frequently resolves without treatment (dogs in Southeast Asia). [ citation needed ]

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Infective endocarditis

Infective endocarditis is an infection of the inner surface of the heart , usually the valves . Signs and symptoms may include fever , small areas of bleeding into the skin , heart murmur , feeling tired, and low red blood cell count . Complications may include backward blood flow in the heart , heart failure – the heart struggling to pump a sufficient amount of blood to meet the body's needs, abnormal electrical conduction in the heart , stroke , and kidney failure . The cause is typically a bacterial infection and less commonly a fungal infection . Risk factors include valvular heart disease , including rheumatic disease , congenital heart disease , artificial valves , hemodialysis , intravenous drug use , and electronic pacemakers . The bacteria most commonly involved are streptococci or staphylococci . Diagnosis is suspected based on symptoms and supported by blood cultures or ultrasound of the heart. There is also a noninfective form of endocarditis . The usefulness of antibiotics following dental procedures for prevention is unclear. Some recommend them for people at high risk. Treatment is generally with intravenous antibiotics . The choice of antibiotics is based on the results of blood cultures. Occasionally heart surgery is required. The number of people affected is about 5 per 100,000 per year. Rates, however, vary between regions of the world. Infective endocarditis occurs in males more often than in females. The risk of death among those infected is about 25%. Without treatment, it is almost universally fatal. Improved diagnosis and treatment options have significantly enhanced the life expectancy of patients with infective endocarditis, particularly with congenital heart disease. Infective endocarditis is divided into the three categories of acute, subacute, and chronic based on the duration of symptoms. Acute infective endocarditis refers to the presence of signs and symptoms of infective endocarditis that are present for days up to six weeks. If these signs and symptoms persist for more than six weeks but less than three months, this is subacute infective endocarditis. Chronic infective endocarditis refers to the presence of such signs and symptoms when they persist for more than three months. This classification is now discouraged, because the ascribed associations (in terms of organism and prognosis) were not strong enough to be relied upon clinically. The terms short incubation (meaning less than about six weeks) and long incubation (greater than about six weeks) are preferred. Infective endocarditis may also be classified as culture-positive or culture-negative . By far the most common cause of "culture-negative" endocarditis is prior administration of antibiotics and can occur in up to 31% of cases. Sometimes microorganisms can take a longer period of time to grow in the culture media, for example Cutibacterium spp. and the HACEK bacteria group. Some organisms are said to be fastidious because they have demanding growth requirements. Some examples include pathogens like Aspergillus species, Brucella species, Coxiella burnetii , Chlamydia species. Due to delay in growth and identification in these cases, patients may be erroneously classified as "culture-negative" endocarditis. Endocarditis can also be classified by the side of the heart affected: Another form of endocarditis is healthcare-associated endocarditis when the infecting organism is believed to be transmitted in a health care setting like hospital, dialysis unit or a residential nursing home. Nosocomial endocarditis is a form of healthcare associated endocarditis in which the infective organism is acquired during a stay in a hospital and it is usually secondary to presence of intravenous catheters, total parenteral nutrition lines, pacemakers , etc. Finally, the distinction between native-valve endocarditis and prosthetic-valve endocarditis is clinically important. Prosthetic valve endocarditis can be early (within 1 year of surgery) or late (> 1 year following valvular surgery). Prosthetic valve endocarditis is commonly caused by Staphylococcus epidermidis as it is capable of growing as a biofilm on plastic surfaces. Cutibacterium acnes almost exclusively causes endocarditis on prosthetic heart valves. Infective endocarditis may also be classified as culture-positive or culture-negative . By far the most common cause of "culture-negative" endocarditis is prior administration of antibiotics and can occur in up to 31% of cases. Sometimes microorganisms can take a longer period of time to grow in the culture media, for example Cutibacterium spp. and the HACEK bacteria group. Some organisms are said to be fastidious because they have demanding growth requirements. Some examples include pathogens like Aspergillus species, Brucella species, Coxiella burnetii , Chlamydia species. Due to delay in growth and identification in these cases, patients may be erroneously classified as "culture-negative" endocarditis. Endocarditis can also be classified by the side of the heart affected:Another form of endocarditis is healthcare-associated endocarditis when the infecting organism is believed to be transmitted in a health care setting like hospital, dialysis unit or a residential nursing home. Nosocomial endocarditis is a form of healthcare associated endocarditis in which the infective organism is acquired during a stay in a hospital and it is usually secondary to presence of intravenous catheters, total parenteral nutrition lines, pacemakers , etc. Finally, the distinction between native-valve endocarditis and prosthetic-valve endocarditis is clinically important. Prosthetic valve endocarditis can be early (within 1 year of surgery) or late (> 1 year following valvular surgery). Prosthetic valve endocarditis is commonly caused by Staphylococcus epidermidis as it is capable of growing as a biofilm on plastic surfaces. Cutibacterium acnes almost exclusively causes endocarditis on prosthetic heart valves. Many microorganisms can cause infective endocarditis. These are generally isolated by blood culture , where the patient's blood is drawn and any growth is noted and identified. The term bacterial endocarditis (BE) commonly is used, reflecting the fact that most cases of IE are due to bacteria; however, infective endocarditis (IE) has become the preferred term. Staphylococcus aureus is the leading cause of infective endocarditis in most parts of the world and is responsible for about 31% of cases. Staphylococcus aureus is the most common cause of endocarditis in people who use intravenous drugs. Viridans streptococci and Enterococci are the second and third most common organisms responsible for infective endocarditis. Viridans streptococci are a common cause of infective endocarditis in South America. Other Streptococci are also a frequent cause. Infective endocarditis due to Streptococcus bovis occurs more commonly in Europe than in North America. HACEK group of bacteria are also rare causes of infective endocarditis in North America. The viridans group includes S. oralis , S. mitis , S. sanguis , S. gordonii and S. parasanguis . The primary habitats for these organisms are the oral cavity and upper respiratory tract. These bacteria are present in the normal oral flora and enter the bloodstream due to disruption of tissues in the mouth when dental surgical procedures are performed (tooth extractions) or genitourinary manipulation. Similarly, HACEK organisms are a group of bacteria that live on the dental gums and can be seen with people who inject drugs who contaminate their needles with saliva. Patients may also have a history of poor dental hygiene or pre-existing valvular disease. Viridans alpha-hemolytic streptococci , that are present in the mouth, are the most frequently isolated microorganisms when the infection is acquired in a community setting. In contrast, Staphylococcus bloodstream infections are frequently acquired in a health care setting where they can enter the bloodstream through procedures that cause breaks in the integrity of skin, such as surgery, catheterization, or during access of long term indwelling catheters or secondary to intravenous injection of recreational drugs. [ citation needed ] Enterococcus can enter the bloodstream as a consequence of abnormalities in the gastrointestinal or genitourinary tracts. [ citation needed ] Some organisms, when isolated, give valuable clues to the cause, as they tend to be specific. Multiple case reports of infective endocarditis caused by unusual organisms have been published. Cutibacterium spp., which are normal skin flora, have been responsible for infective endocarditis, preferably in patients with prosthetic heart valves, in rare cases leading to death. Tropheryma whipplei has caused endocarditis without gastrointestinal involvement. Citrobacter koseri was found in an immunocompetent adult. Neisseria bacilliformis was found in a person with a bicuspid aortic valve . One in eight cases of infective endocarditis is thought to be caused by S. viridans infection associated with dental procedures such as cleaning or tooth extraction [ obsolete source ] . This was thought to be more clinically significant than it is [ citation needed ] . However, it is important that a dentist or a dental hygienist be told of any heart problems before commencing treatment. Prophylactic antibiotics were regularly administered to patients with certain heart conditions as a precaution, although this practice has changed in the US, with new American Heart Association guidelines released in 2007, and in the UK as of March 2008 due to new NICE guidelines. Fungal endocarditis (FE) is often fatal and one of the most serious forms of infective endocarditis. The types of fungi most seen associated with this disease are: Candida albicans is found as a spherical or oval budding yeast . It is associated with endocarditis in people who inject drugs, patients with prosthetic valves , and immunocompromised patients. It forms biofilms around thick-walled resting structures like prosthetic heart valves and additionally colonizes and penetrates endothelial walls. C. albicans is responsible for 24-46% of all the cases of FE, and its mortality rate is 46.6–50%. Other fungi demonstrated to cause endocarditis are Histoplasma capsulatum and Aspergillus . Aspergillus contributes to roughly 25% of FE cases. Endocarditis with Tricosporon asahii has also been reported in a case report. Risk factors for infective endocarditis are based on the premise that in a healthy individual, bacteremia (bacteria entering the bloodstream) is cleared quickly with no adverse consequences. However, if a heart valve is damaged, the bacteria can attach themselves to the valve, resulting in infective endocarditis. Additionally, in individuals with weakened immune systems, the concentration of bacteria in the blood can reach levels high enough to increase the probability that some will attach to the valve. Some significant risk factors are listed here: Staphylococcus aureus is the leading cause of infective endocarditis in most parts of the world and is responsible for about 31% of cases. Staphylococcus aureus is the most common cause of endocarditis in people who use intravenous drugs. Viridans streptococci and Enterococci are the second and third most common organisms responsible for infective endocarditis. Viridans streptococci are a common cause of infective endocarditis in South America. Other Streptococci are also a frequent cause. Infective endocarditis due to Streptococcus bovis occurs more commonly in Europe than in North America. HACEK group of bacteria are also rare causes of infective endocarditis in North America. The viridans group includes S. oralis , S. mitis , S. sanguis , S. gordonii and S. parasanguis . The primary habitats for these organisms are the oral cavity and upper respiratory tract. These bacteria are present in the normal oral flora and enter the bloodstream due to disruption of tissues in the mouth when dental surgical procedures are performed (tooth extractions) or genitourinary manipulation. Similarly, HACEK organisms are a group of bacteria that live on the dental gums and can be seen with people who inject drugs who contaminate their needles with saliva. Patients may also have a history of poor dental hygiene or pre-existing valvular disease. Viridans alpha-hemolytic streptococci , that are present in the mouth, are the most frequently isolated microorganisms when the infection is acquired in a community setting. In contrast, Staphylococcus bloodstream infections are frequently acquired in a health care setting where they can enter the bloodstream through procedures that cause breaks in the integrity of skin, such as surgery, catheterization, or during access of long term indwelling catheters or secondary to intravenous injection of recreational drugs. [ citation needed ] Enterococcus can enter the bloodstream as a consequence of abnormalities in the gastrointestinal or genitourinary tracts. [ citation needed ] Some organisms, when isolated, give valuable clues to the cause, as they tend to be specific. Multiple case reports of infective endocarditis caused by unusual organisms have been published. Cutibacterium spp., which are normal skin flora, have been responsible for infective endocarditis, preferably in patients with prosthetic heart valves, in rare cases leading to death. Tropheryma whipplei has caused endocarditis without gastrointestinal involvement. Citrobacter koseri was found in an immunocompetent adult. Neisseria bacilliformis was found in a person with a bicuspid aortic valve . One in eight cases of infective endocarditis is thought to be caused by S. viridans infection associated with dental procedures such as cleaning or tooth extraction [ obsolete source ] . This was thought to be more clinically significant than it is [ citation needed ] . However, it is important that a dentist or a dental hygienist be told of any heart problems before commencing treatment. Prophylactic antibiotics were regularly administered to patients with certain heart conditions as a precaution, although this practice has changed in the US, with new American Heart Association guidelines released in 2007, and in the UK as of March 2008 due to new NICE guidelines.One in eight cases of infective endocarditis is thought to be caused by S. viridans infection associated with dental procedures such as cleaning or tooth extraction [ obsolete source ] . This was thought to be more clinically significant than it is [ citation needed ] . However, it is important that a dentist or a dental hygienist be told of any heart problems before commencing treatment. Prophylactic antibiotics were regularly administered to patients with certain heart conditions as a precaution, although this practice has changed in the US, with new American Heart Association guidelines released in 2007, and in the UK as of March 2008 due to new NICE guidelines.Fungal endocarditis (FE) is often fatal and one of the most serious forms of infective endocarditis. The types of fungi most seen associated with this disease are: Candida albicans is found as a spherical or oval budding yeast . It is associated with endocarditis in people who inject drugs, patients with prosthetic valves , and immunocompromised patients. It forms biofilms around thick-walled resting structures like prosthetic heart valves and additionally colonizes and penetrates endothelial walls. C. albicans is responsible for 24-46% of all the cases of FE, and its mortality rate is 46.6–50%. Other fungi demonstrated to cause endocarditis are Histoplasma capsulatum and Aspergillus . Aspergillus contributes to roughly 25% of FE cases. Endocarditis with Tricosporon asahii has also been reported in a case report. Risk factors for infective endocarditis are based on the premise that in a healthy individual, bacteremia (bacteria entering the bloodstream) is cleared quickly with no adverse consequences. However, if a heart valve is damaged, the bacteria can attach themselves to the valve, resulting in infective endocarditis. Additionally, in individuals with weakened immune systems, the concentration of bacteria in the blood can reach levels high enough to increase the probability that some will attach to the valve. Some significant risk factors are listed here: Damaged valves and endocardium contribute to the development of infective endocarditis. Specifically, the damaged part of a heart valve forms a local blood clot , a condition known as non-bacterial thrombotic endocarditis (NBTE) . The platelet and fibrin deposits that form as part of the blood clotting process allow bacteria to take hold and form vegetations . As previously mentioned, the body has no direct methods of combating valvular vegetations because the valves do not have a dedicated blood supply. This combination of damaged valves, bacterial growth, and lack of a strong immune response results in infective endocarditis. [ citation needed ] Damage to the valves and endocardium can be caused by: The risk factors for infective endocarditis provide a more extensive list of conditions that can damage the heart.In general, the Duke criteria should be fulfilled in order to establish the diagnosis of endocarditis. Although the Duke criteria are widely used, they have significant limitations. For example, the sensitivity of the Duke criteria for detecting infective endocarditis decreases when prosthetic heart valves are present. As the Duke criteria rely heavily on the results of echocardiography, research has addressed when to order an echocardiogram by using signs and symptoms to predict occult endocarditis among people who inject drugs and among non drug-abusing patients. However, this research is over twenty years old and it is possible that changes in the epidemiology of endocarditis and bacteria such as staphylococci make the following estimates incorrect. The blood tests C reactive protein (CRP) and procalcitonin have not been found to be particularly useful in helping make or rule out the diagnosis. Echocardiography is the main type of diagnostic imaging used to establish the diagnosis of infective endocarditis. There are two main types of echocardiography used to assist with the diagnosis of IE: transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE). The transthoracic echocardiogram has a sensitivity and specificity of approximately 65% and 95% if the echocardiographer believes there is 'probable' or 'almost certain' evidence of endocarditis. However, in endocarditis involving a prosthetic valve, TTE has a sensitivity of approximately 50%, whereas TEE has a sensitivity exceeding 90%. The TEE also has an important diagnostic role when the TTE does not reveal IE but diagnostic suspicion remains high, since TEE is more sensitive for infective endocarditis and is better able to characterize infection-related damage to the heart valves and surrounding tissues. Guidelines support the initial use of TTE over TEE in people with abnormal blood cultures, a new heart murmur, and suspected infective endocarditis. TEE is the preferred initial form of imaging in people with suspected infective endocarditis who have a moderate to high pretest probability of infective endocarditis, including people with prosthetic heart valves, blood cultures growing Staphylococcus , or have an intracardiac device (such as a pacemaker ). Established in 1994 by the Duke Endocarditis Service and revised in 2000, the Duke criteria are a collection of major and minor criteria used to establish a diagnosis of infective endocarditis. According to the Duke criteria, diagnosis of infective endocarditis can be definite, possible, or rejected. A diagnosis of infective endocarditis is definite if either the following pathological or clinical criteria are met: One of these pathological criteria: Histology or culture of cardiac vegetation, embolized vegetation, or intracardiac abscess from the heart finds microorganisms Active endocarditis One of these combinations of clinical criteria Two major clinical criteria One major and three minor criteria Five minor criteria Diagnosis of infective endocarditis is possible if one of the following combinations of clinical criteria is met: One major and one minor criteria Three minor criteria are fulfilled Positive blood culture with typical IE microorganism, defined as one of the following: Evidence of endocardial involvement with positive echocardiogram is defined as Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation, or Abscess, or New partial dehiscence of prosthetic valve or new valvular regurgitation (worsening or changing of preexisting murmur not sufficient) Updated (2023) Modified Duke Criteria for Infective Endocarditis: Infective endocarditis (IE) is a life-threatening condition and the Duke criteria (established in 1994 and revised in 2000) has been fundamental for the diagnosis of the disease. However, the landscape of micro-biology, diagnostics, epidemiology, and treatment for lE has evolved significantly over the years. The 2023 modified Duke criteria address these changes: https://medicalstudyhub.com/updated-2023-modified-duke-criteria-for-infective-endocarditis/ Among people who do not use intravenous drugs and have a fever in the emergency department , there is a less than 5% chance of occult endocarditis. Mellors in 1987 found no cases of endocarditis nor of staphylococcal bacteremia among 135 febrile patients in the emergency room . The upper confidence interval for 0% of 135 is 5%, so for statistical reasons alone, there is up to a 5% chance of endocarditis among these patients. In contrast, Leibovici found that among 113 non-selected adults admitted to the hospital because of fever there were two cases (1.8% with 95%CI: 0% to 7%) of endocarditis. Among people who do use intravenous drugs and have a fever in the emergency department, there is about a 10% to 15% prevalence of endocarditis. This estimate is not substantially changed by whether the doctor believes the patient has a trivial explanation for their fever. Weisse found that 13% of 121 patients had endocarditis. Marantz also found a prevalence of endocarditis of 13% among such patients in the emergency department with fever. Samet found a 6% incidence among 283 such patients, but after excluding patients with initially apparent major illness to explain the fever (including 11 cases of manifest endocarditis), there was a 7% prevalence of endocarditis. During the Opioid epidemic in the United States , hospitals observed an increase in stroke associated with infective endocarditis. Among people with staphylococcal bacteremia (SAB), one study found a 29% prevalence of endocarditis in community-acquired SAB versus 5% in nosocomial SAB. However, only 2% of strains were resistant to methicillin and so these numbers may be low in areas of higher resistance. [ citation needed ]Echocardiography is the main type of diagnostic imaging used to establish the diagnosis of infective endocarditis. There are two main types of echocardiography used to assist with the diagnosis of IE: transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE). The transthoracic echocardiogram has a sensitivity and specificity of approximately 65% and 95% if the echocardiographer believes there is 'probable' or 'almost certain' evidence of endocarditis. However, in endocarditis involving a prosthetic valve, TTE has a sensitivity of approximately 50%, whereas TEE has a sensitivity exceeding 90%. The TEE also has an important diagnostic role when the TTE does not reveal IE but diagnostic suspicion remains high, since TEE is more sensitive for infective endocarditis and is better able to characterize infection-related damage to the heart valves and surrounding tissues. Guidelines support the initial use of TTE over TEE in people with abnormal blood cultures, a new heart murmur, and suspected infective endocarditis. TEE is the preferred initial form of imaging in people with suspected infective endocarditis who have a moderate to high pretest probability of infective endocarditis, including people with prosthetic heart valves, blood cultures growing Staphylococcus , or have an intracardiac device (such as a pacemaker ). Established in 1994 by the Duke Endocarditis Service and revised in 2000, the Duke criteria are a collection of major and minor criteria used to establish a diagnosis of infective endocarditis. According to the Duke criteria, diagnosis of infective endocarditis can be definite, possible, or rejected. A diagnosis of infective endocarditis is definite if either the following pathological or clinical criteria are met: One of these pathological criteria: Histology or culture of cardiac vegetation, embolized vegetation, or intracardiac abscess from the heart finds microorganisms Active endocarditis One of these combinations of clinical criteria Two major clinical criteria One major and three minor criteria Five minor criteria Diagnosis of infective endocarditis is possible if one of the following combinations of clinical criteria is met: One major and one minor criteria Three minor criteria are fulfilled Positive blood culture with typical IE microorganism, defined as one of the following: Evidence of endocardial involvement with positive echocardiogram is defined as Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation, or Abscess, or New partial dehiscence of prosthetic valve or new valvular regurgitation (worsening or changing of preexisting murmur not sufficient) Updated (2023) Modified Duke Criteria for Infective Endocarditis: Infective endocarditis (IE) is a life-threatening condition and the Duke criteria (established in 1994 and revised in 2000) has been fundamental for the diagnosis of the disease. However, the landscape of micro-biology, diagnostics, epidemiology, and treatment for lE has evolved significantly over the years. The 2023 modified Duke criteria address these changes: https://medicalstudyhub.com/updated-2023-modified-duke-criteria-for-infective-endocarditis/Positive blood culture with typical IE microorganism, defined as one of the following: Evidence of endocardial involvement with positive echocardiogram is defined as Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation, or Abscess, or New partial dehiscence of prosthetic valve or new valvular regurgitation (worsening or changing of preexisting murmur not sufficient)Updated (2023) Modified Duke Criteria for Infective Endocarditis: Infective endocarditis (IE) is a life-threatening condition and the Duke criteria (established in 1994 and revised in 2000) has been fundamental for the diagnosis of the disease. However, the landscape of micro-biology, diagnostics, epidemiology, and treatment for lE has evolved significantly over the years. The 2023 modified Duke criteria address these changes: https://medicalstudyhub.com/updated-2023-modified-duke-criteria-for-infective-endocarditis/Among people who do not use intravenous drugs and have a fever in the emergency department , there is a less than 5% chance of occult endocarditis. Mellors in 1987 found no cases of endocarditis nor of staphylococcal bacteremia among 135 febrile patients in the emergency room . The upper confidence interval for 0% of 135 is 5%, so for statistical reasons alone, there is up to a 5% chance of endocarditis among these patients. In contrast, Leibovici found that among 113 non-selected adults admitted to the hospital because of fever there were two cases (1.8% with 95%CI: 0% to 7%) of endocarditis. Among people who do use intravenous drugs and have a fever in the emergency department, there is about a 10% to 15% prevalence of endocarditis. This estimate is not substantially changed by whether the doctor believes the patient has a trivial explanation for their fever. Weisse found that 13% of 121 patients had endocarditis. Marantz also found a prevalence of endocarditis of 13% among such patients in the emergency department with fever. Samet found a 6% incidence among 283 such patients, but after excluding patients with initially apparent major illness to explain the fever (including 11 cases of manifest endocarditis), there was a 7% prevalence of endocarditis. During the Opioid epidemic in the United States , hospitals observed an increase in stroke associated with infective endocarditis. Among people with staphylococcal bacteremia (SAB), one study found a 29% prevalence of endocarditis in community-acquired SAB versus 5% in nosocomial SAB. However, only 2% of strains were resistant to methicillin and so these numbers may be low in areas of higher resistance. [ citation needed ]Not all people with heart disease require antibiotics to prevent infective endocarditis. Heart diseases have been classified into high, medium and low risk of developing IE. Those falling into high risk category require IE prophylaxis before endoscopies and urinary tract procedures. Diseases listed under high risk include: Prior endocarditis Unrepaired cyanotic congenital heart diseases Completely repaired congenital heart disease in their first 6 months Prosthetic heart valves or valves repaired with any prosthetic material Incompletely repaired congenital heart diseases Cardiac transplant valvulopathy Following are the antibiotic regimens recommended by the American Heart Association for antibiotic prophylaxis: In the UK, NICE clinical guidelines no longer advise prophylaxis because there is no clinical evidence that it reduces the incidence of IE and there are negative effects (e.g. allergy and increased bacterial resistance) of taking antibiotics that may outweigh the benefits. Antibiotics were historically commonly recommended to prevent IE in those with heart problems undergoing dental procedures (known as dental antibiotic prophylaxis ). There is, however, insufficient evidence to support whether antibiotics are effective or ineffective at preventing IE when given prior to a dental procedures in people at high risk. They are less commonly recommended for this procedure. In some countries e.g. the US, high risk patients may be given prophylactic antibiotics such as penicillin or clindamycin for penicillin-allergic people prior to dental procedures. Prophylactics should be bactericidal rather than bacteriostatic . Such measures are not taken in certain countries e.g. Scotland due to the fear of antibiotic resistance . Because bacteria are the most common cause of infective endocarditis, antibiotics such as penicillin and amoxicillin (for beta lactamase -producing bacteria) are used in prophylaxis. [ citation needed ]High-dose antibiotics are the cornerstone of treatment for infective endocarditis. These antibiotics are administered by the intravenous (IV) route to maximize diffusion of antibiotic molecules into vegetation(s) from the blood filling the chambers of the heart. This is necessary because neither the heart valves nor the vegetations adhering to them are supplied by blood vessels. Antibiotics are typically continued for two to six weeks depending on the characteristics of the infection and the causative microorganisms . Antibiotic treatment lowers the risk of embolic complications in people with infective endocarditis. In acute endocarditis, due to the fulminant inflammation, empirical antibiotic therapy is started immediately after the blood has been drawn for culture to clarify the bacterial organisms responsible for the infection. This usually includes vancomycin and ceftriaxone IV infusions until the infecting organism is identified and the susceptibility report with the minimum inhibitory concentration becomes available. Once this information is available, this allows the supervising healthcare professional to modify the antimicrobial therapy to target the specific infecting microorganism. The routine use of gentamicin to treat endocarditis has fallen out of favor due to the lack of evidence to support its use (except in infections caused by Enterococcus and nutritionally variant streptococci ) and the high rate of complications. In cases of subacute endocarditis, where the person's hemodynamic status is usually stable, antibiotic treatment can be delayed until the causative microorganism can be identified. [ citation needed ] Viridans group streptococci and Streptococcus bovis are usually highly susceptible to penicillin and can be treated with penicillin or ceftriaxone. Relatively resistant strains of viridans group streptococci and Streptococcus bovis are treated with penicillin or ceftriaxone along with a shorter two-week course of an aminoglycoside during the initial phase of treatment. Highly penicillin-resistant strains of viridans group streptococci , nutritionally variant streptococci like Granulicatella sp. , Gemella sp. , Abiotrophia defectiva , and Enterococci are usually treated with a combination therapy consisting of penicillin and an aminoglycoside for the entire duration of 4–6 weeks. Some people may be treated with a relatively shorter course of treatment (two weeks) with benzyl penicillin IV if infection is caused by viridans group streptococci or Streptococcus bovis as long as the following conditions are met: Additionally, oxacillin-susceptible Staphylococcus aureus native valve endocarditis of the right side can also be treated with a short 2-week course of a beta-lactam antibiotic such as nafcillin with or without aminoglycosides. The main indication for surgical treatment is regurgitation or stenosis . In active infective endocarditis, the surgery should remove enough leaflet tissue to ensure eradication of the infectious process. Subsequent valve repair can be performed in limited disease. Replacement of the valve with a mechanical or bioprosthetic artificial heart valve is necessary in certain situations: Patients with significant valve stenosis or regurgitation causing heart failure Evidence of hemodynamic compromise in the form of elevated end-diastolic left ventricular or left atrial pressure or moderate to severe pulmonary hypertension Presence of intracardiac complications like paravalvular abscess, conduction defects or destructive penetrating lesions Recurrent septic emboli despite appropriate antibiotic treatment Large vegetations (> 10 mm) Persistently positive blood cultures despite appropriate antibiotic treatment Prosthetic valve dehiscence Relapsing infection in the presence of a prosthetic valve Abscess formation Early closure of mitral valve Infection caused by fungi or resistant Gram-negative bacteria. The guidelines were recently updated by both the American College of Cardiology and the European Society of Cardiology . There was a recent meta-analysis published that showed surgical intervention at seven days or less is associated with lower mortality. Infective endocarditis is associated with 18% in-hospital mortality. However, adult patients with congenital heart disease can have relatively lower mortality down to 5% due to younger age, right-sided endocarditis and management by multidisciplinary teams. As many as 50% of people with infective endocarditis may experience embolic complications. In developed countries , the annual incidence of infective endocarditis is 3 to 9 cases per 100,000 persons. Infective endocarditis occurs more often in men than in women. There is an increased incidence of infective endocarditis in persons 65 years of age and older, which is probably because people in this age group have a larger number of risk factors for infective endocarditis. In recent years, over one-third of infective endocarditis cases in the United States was healthcare-associated . Another trend observed in developed countries is that chronic rheumatic heart disease accounts for less than 10% of cases. Although a history of valve disease has a significant association with infective endocarditis, 50% of all cases develop in people with no known history of valvular disease. [ citation needed ]Few diseases present greater difficulties in the way of diagnosis than malignant endocarditis, difficulties which in many cases are practically insurmountable. It is no disparagement to the many skilled physicians who have put their cases upon record to say that, in fully one-half the diagnosis was made post mortem. Lazare Riviére first described infective endocarditis affecting the aortic valve in 1616. In 1806, Jean-Nicolas Corvisart coined the term vegetation to describe collections of debris found on a mitral valve affected by infective endocarditis. The British physician Joseph Hodgson was the first to describe the embolic complications of infective endocarditis in 1815. It was not until 1878 that Theodor Klebs first suggested that infective endocarditis had a microbial infectious origin. In 1909, William Osler noted that heart valves that experienced degeneration and were sclerotic or poorly functioning had a higher risk of being affected. Later, in 1924, Emanuel Libman and Benjamin Sacks described cases of vegetative endocarditis that lacked a clear microbial origin and were often associated with the autoimmune condition systemic lupus erythematosus . In 1944, physicians reported on the first successful use of penicillin to treat a case of infective endocarditis.

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Acute hemorrhagic fever syndrome

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Enoxaparin sodium

none Enoxaparin sodium , sold under the brand name Lovenox among others, is an anticoagulant medication (blood thinner). It is used to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) including during pregnancy and following certain types of surgery. It is also used in those with acute coronary syndrome (ACS) and heart attacks . It is given by injection just under the skin or into a vein . It is also used during hemodialysis . Common side effects include bleeding, fever, and swelling of the legs . Bleeding may be serious especially in those who are undergoing a spinal tap . Use during pregnancy appears to be safe for the baby. Enoxaparin is in the low molecular weight heparin family of medications. Enoxaparin was first made in 1981 and approved for medical use in 1993. It is on the World Health Organization's List of Essential Medicines . Enoxaparin is sold under several brand names and is available as a generic medication . Enoxaparin is made from heparin . In 2020, it was the 350th most commonly prescribed medication in the United States, with more than 500 thousand prescriptions. Enoxaparin has predictable absorption, bioavailability , and distribution therefore monitoring is not typically done. However, there are instances where monitoring may be beneficial for special populations, for example individuals with kidney insufficiency or those that are obese. In this case, anti-Xa units can be measured and dosing adjusted accordingly. Protamine sulfate is less effective at reversing enoxaparin compared to heparin , with a maximum neutralization of approximately 60% of the anti-factor Xa effect. Enoxaparin has predictable absorption, bioavailability , and distribution therefore monitoring is not typically done. However, there are instances where monitoring may be beneficial for special populations, for example individuals with kidney insufficiency or those that are obese. In this case, anti-Xa units can be measured and dosing adjusted accordingly. Protamine sulfate is less effective at reversing enoxaparin compared to heparin , with a maximum neutralization of approximately 60% of the anti-factor Xa effect. Uncommon (1%) Frequency under investigation The FDA issued a revision to the boxed warning for enoxaparin in October 2013. The revision recommends exercising caution regarding when spinal catheters are placed and removed in persons taking enoxaparin for spinal puncture or neuroaxial anesthesia . It may be necessary to delay anticoagulant dosing in these persons in order to decrease the risk for spinal or epidural hematomas, which can manifest as permanent or long-term paralysis . Persons at risk for hematomas may present with indwelling epidural catheters, concurrent use of medications that worsen bleeding states such as non-steroidal anti-inflammatory drugs (NSAIDs) , or a past medical history of epidural or spinal punctures, spinal injury, or spinal deformations. The FDA recommends that at-risk persons be monitored for bleeding and neurological changes. The FDA issued a revision to the boxed warning for enoxaparin in October 2013. The revision recommends exercising caution regarding when spinal catheters are placed and removed in persons taking enoxaparin for spinal puncture or neuroaxial anesthesia . It may be necessary to delay anticoagulant dosing in these persons in order to decrease the risk for spinal or epidural hematomas, which can manifest as permanent or long-term paralysis . Persons at risk for hematomas may present with indwelling epidural catheters, concurrent use of medications that worsen bleeding states such as non-steroidal anti-inflammatory drugs (NSAIDs) , or a past medical history of epidural or spinal punctures, spinal injury, or spinal deformations. The FDA recommends that at-risk persons be monitored for bleeding and neurological changes. Enoxaparin binds to and potentiates antithrombin (a circulating anticoagulant) to form a complex that irreversibly inactivates clotting factor Xa . It has less activity against factor IIa (thrombin) compared to unfractionated heparin (UFH) due to its low molecular weight. Absorption: Bioavailability (subcutaneous injection) ~ 100% Distribution: Volume of distribution (anti-Factor Xa activity) = 4.3 liters Metabolism: Enoxaparin is metabolized in the liver into low molecular weight species by either or both desulfation and depolymerization. Elimination: A single dose of a subcutaneous injection of enoxaparin has an elimination half-life of 4.5 hours. Approximately 10–40% of the active and inactive fragments from a single dose are excreted by the kidneys. Dose adjustments based on kidney function are necessary in persons with reduced kidney function. Enoxaparin belongs to the class of drugs known as low molecular weight heparins. Other drugs in this class include dalteparin , fondaparinux and tinzaparin . Enoxaparin binds to and potentiates antithrombin (a circulating anticoagulant) to form a complex that irreversibly inactivates clotting factor Xa . It has less activity against factor IIa (thrombin) compared to unfractionated heparin (UFH) due to its low molecular weight. Absorption: Bioavailability (subcutaneous injection) ~ 100% Distribution: Volume of distribution (anti-Factor Xa activity) = 4.3 liters Metabolism: Enoxaparin is metabolized in the liver into low molecular weight species by either or both desulfation and depolymerization. Elimination: A single dose of a subcutaneous injection of enoxaparin has an elimination half-life of 4.5 hours. Approximately 10–40% of the active and inactive fragments from a single dose are excreted by the kidneys. Dose adjustments based on kidney function are necessary in persons with reduced kidney function. Enoxaparin belongs to the class of drugs known as low molecular weight heparins. Other drugs in this class include dalteparin , fondaparinux and tinzaparin . In September 2016, Inhixa and Thorinane were approved for use in the European Union. Thorinane was withdrawn from the market in October 2019. In March 2017, Enoxaparin BECAT, Laboratorios ROVI (Spain) obtained marketing authorization in twenty six countries in Europe. The product is now available in Europe. In October 2020, Noromby and Noromby HP, were approved for medical use in Canada. In November 2020, Inclunox and Inclunox HP were approved for medical use in Canada. In December 2020, Redesca and Redesca HP were approved for medical use in Canada.

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Acute hemorrhagic fever syndrome

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ST elevation

ST elevation refers to a finding on an electrocardiogram wherein the trace in the ST segment is abnormally high above the baseline.The ST segment starts from the J point (termination of QRS complex and the beginning of ST segment) and ends with the T wave . The ST segment is the plateau phase, in which the majority of the myocardial cells had gone through depolarization but not repolarization . The ST segment is the isoelectric line because there is no voltage difference across cardiac muscle cell membrane during this state. Any distortion in the shape, duration, or height of the cardiac action potential can distort the ST segment. An ST elevation is considered significant if the vertical distance inside the ECG trace and the baseline at a point 0.04 seconds after the J-point is at least 0.1 mV (usually representing 1 mm or 1 small square) in a limb lead or 0.2 mV (2 mm or 2 small squares) in a precordial lead . The baseline is either the PR interval or the TP interval. This measure has a false positive rate of 15–20% (which is slightly higher in women than men) and a false negative rate of 20–30%. When there is a blockage of the coronary artery , there will be lack of oxygen supply to all three layers of cardiac muscle (transmural ischemia). The leads facing the injured cardiac muscle cells will record the action potential as ST elevation during systole while during diastole , there will be depression of the PR segment and the PT segment. Since PR and PT interval are regarded as baseline, ST segment elevation is regarded as a sign of myocardial ischemia. The opposing leads (such as V3 and V4 versus posterior leads V7–V9) always show reciprocal ST segment changes (ST elevation in one lead is followed by ST depression in the opposing lead). This is highly specific for myocardial infarction. An upsloping, convex ST segment is highly predictive of a myocardial infarction ( Pardee sign ) while a concave ST elevation is less suggestive and can be found in other non-ischaemic causes. Following infarction, ventricular aneurysm can develop, which leads to persistent ST elevation, loss of S wave, and T wave inversion. Weakening of the electrical activity of the cardiac muscles causes the decrease in height of the R wave in those leads facing it. In opposing leads, it manifests as Q wave . However, Q waves may be found in healthy individuals at lead I, aVL, V5 and V6 due to left to right depolarisation. In these conditions, there will mostly be concave ST elevations in almost all the leads except for aVR and V1. These two leads, ST depression will be seen because they are the opposing leads of the cardiac axis. PR segment depression is highly suggestive of pericarditis. R wave in most cases will be unaltered. In two weeks after pericarditis, there will be upward concave ST elevation, positive T wave, and PR depression. After several more weeks, PR and ST segments normalised with flattened T wave. At last, there will be T wave inversion which will take weeks or months to vanish. When there is a blockage of the coronary artery , there will be lack of oxygen supply to all three layers of cardiac muscle (transmural ischemia). The leads facing the injured cardiac muscle cells will record the action potential as ST elevation during systole while during diastole , there will be depression of the PR segment and the PT segment. Since PR and PT interval are regarded as baseline, ST segment elevation is regarded as a sign of myocardial ischemia. The opposing leads (such as V3 and V4 versus posterior leads V7–V9) always show reciprocal ST segment changes (ST elevation in one lead is followed by ST depression in the opposing lead). This is highly specific for myocardial infarction. An upsloping, convex ST segment is highly predictive of a myocardial infarction ( Pardee sign ) while a concave ST elevation is less suggestive and can be found in other non-ischaemic causes. Following infarction, ventricular aneurysm can develop, which leads to persistent ST elevation, loss of S wave, and T wave inversion. Weakening of the electrical activity of the cardiac muscles causes the decrease in height of the R wave in those leads facing it. In opposing leads, it manifests as Q wave . However, Q waves may be found in healthy individuals at lead I, aVL, V5 and V6 due to left to right depolarisation. In these conditions, there will mostly be concave ST elevations in almost all the leads except for aVR and V1. These two leads, ST depression will be seen because they are the opposing leads of the cardiac axis. PR segment depression is highly suggestive of pericarditis. R wave in most cases will be unaltered. In two weeks after pericarditis, there will be upward concave ST elevation, positive T wave, and PR depression. After several more weeks, PR and ST segments normalised with flattened T wave. At last, there will be T wave inversion which will take weeks or months to vanish. The topology and distribution of the affected areas depend on the underlying condition. Thus, ST elevation may be present on all or some leads of ECG. [ citation needed ] It can be associated with:

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Acute hemorrhagic fever syndrome

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Sepsis

Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system . Common signs and symptoms include fever , increased heart rate , increased breathing rate , and confusion . There may also be symptoms related to a specific infection, such as a cough with pneumonia , or painful urination with a kidney infection . The very young, old, and people with a weakened immune system may have no symptoms of a specific infection, and the body temperature may be low or normal instead of having a fever . Severe sepsis causes poor organ function or blood flow. The presence of low blood pressure , high blood lactate , or low urine output may suggest poor blood flow. Septic shock is low blood pressure due to sepsis that does not improve after fluid replacement . Sepsis is caused by many organisms including bacteria, viruses and fungi. Common locations for the primary infection include the lungs, brain, urinary tract , skin, and abdominal organs . Risk factors include being very young or old, a weakened immune system from conditions such as cancer or diabetes , major trauma , and burns . Previously, a sepsis diagnosis required the presence of at least two systemic inflammatory response syndrome (SIRS) criteria in the setting of presumed infection. In 2016, a shortened sequential organ failure assessment score (SOFA score), known as the quick SOFA score (qSOFA), replaced the SIRS system of diagnosis. qSOFA criteria for sepsis include at least two of the following three: increased breathing rate, change in the level of consciousness, and low blood pressure. Sepsis guidelines recommend obtaining blood cultures before starting antibiotics; however, the diagnosis does not require the blood to be infected . Medical imaging is helpful when looking for the possible location of the infection. Other potential causes of similar signs and symptoms include anaphylaxis , adrenal insufficiency , low blood volume , heart failure , and pulmonary embolism . Sepsis requires immediate treatment with intravenous fluids and antimicrobials . Ongoing care often continues in an intensive care unit . If an adequate trial of fluid replacement is not enough to maintain blood pressure, then the use of medications that raise blood pressure becomes necessary. Mechanical ventilation and dialysis may be needed to support the function of the lungs and kidneys, respectively. A central venous catheter and an arterial catheter may be placed for access to the bloodstream and to guide treatment. Other helpful measurements include cardiac output and superior vena cava oxygen saturation . People with sepsis need preventive measures for deep vein thrombosis , stress ulcers , and pressure ulcers unless other conditions prevent such interventions. Some people might benefit from tight control of blood sugar levels with insulin . The use of corticosteroids is controversial, with some reviews finding benefit, and others not. Disease severity partly determines the outcome. The risk of death from sepsis is as high as 30%, while for severe sepsis it is as high as 50%, and septic shock 80%. Sepsis affected about 49 million people in 2017, with 11 million deaths (1 in 5 deaths worldwide). In the developed world , approximately 0.2 to 3 people per 1000 are affected by sepsis yearly, resulting in about a million cases per year in the United States. Rates of disease have been increasing. Some data indicate that sepsis is more common among males than females, however, other data show a greater prevalence of the disease among women. Descriptions of sepsis date back to the time of Hippocrates . In addition to symptoms related to the actual cause, people with sepsis may have a fever , low body temperature , rapid breathing , a fast heart rate , confusion , and edema . Early signs include a rapid heart rate, decreased urination , and high blood sugar . Signs of established sepsis include confusion, metabolic acidosis (which may be accompanied by a faster breathing rate that leads to respiratory alkalosis ), low blood pressure due to decreased systemic vascular resistance , higher cardiac output , and disorders in blood-clotting that may lead to organ failure. Fever is the most common presenting symptom in sepsis, but fever may be absent in some people such as the elderly or those who are immunocompromised. The drop in blood pressure seen in sepsis can cause lightheadedness and is part of the criteria for septic shock . Oxidative stress is observed in septic shock, with circulating levels of copper and vitamin C being decreased. Diastolic blood pressure falls during the early stages of sepsis, causing a widening/increasing of pulse pressure , which is the difference between the systolic and diastolic blood pressures. If sepsis becomes severe and hemodynamic compromise advances, the systolic pressure also decreases, causing a narrowing/decreasing of pulse pressure. A pulse pressure of over 70 mmHg in patients with sepsis is correlated with an increased chance of survival. A widened pulse pressure is also correlated with an increased chance that someone with sepsis will benefit from and respond to IV fluids . Infections leading to sepsis are usually bacterial but may be fungal , parasitic or viral . Gram-positive bacteria were the primary cause of sepsis before the introduction of antibiotics in the 1950s. After the introduction of antibiotics, gram-negative bacteria became the predominant cause of sepsis from the 1960s to the 1980s. After the 1980s, gram-positive bacteria, most commonly staphylococci , are thought to cause more than 50% of cases of sepsis. Other commonly implicated bacteria include Streptococcus pyogenes , Escherichia coli , Pseudomonas aeruginosa , and Klebsiella species. Fungal sepsis accounts for approximately 5% of severe sepsis and septic shock cases; the most common cause of fungal sepsis is an infection by Candida species of yeast , a frequent hospital-acquired infection . The most common causes for parasitic sepsis are Plasmodium (which leads to malaria ), Schistosoma and Echinococcus . The most common sites of infection resulting in severe sepsis are the lungs, the abdomen, and the urinary tract. Typically, 50% of all sepsis cases start as an infection in the lungs. In one-third to one-half of cases, the source of infection is unclear. Sepsis is caused by a combination of factors related to the particular invading pathogen(s) and to the status of the immune system of the host. The early phase of sepsis characterized by excessive inflammation (sometimes resulting in a cytokine storm ) may be followed by a prolonged period of decreased functioning of the immune system . Either of these phases may prove fatal. On the other hand, systemic inflammatory response syndrome (SIRS) occurs in people without the presence of infection, for example, in those with burns , polytrauma , or the initial state in pancreatitis and chemical pneumonitis . However, sepsis also causes similar response to SIRS. Bacterial virulence factors , such as glycocalyx and various adhesins , allow colonization, immune evasion, and establishment of disease in the host. Sepsis caused by gram-negative bacteria is thought to be largely due to a response by the host to the lipid A component of lipopolysaccharide , also called endotoxin . Sepsis caused by gram-positive bacteria may result from an immunological response to cell wall lipoteichoic acid . Bacterial exotoxins that act as superantigens also may cause sepsis. Superantigens simultaneously bind major histocompatibility complex and T-cell receptors in the absence of antigen presentation . This forced receptor interaction induces the production of pro-inflammatory chemical signals ( cytokines ) by T-cells. There are a number of microbial factors that may cause the typical septic inflammatory cascade . An invading pathogen is recognized by its pathogen-associated molecular patterns (PAMPs). Examples of PAMPs include lipopolysaccharides and flagellin in gram-negative bacteria, muramyl dipeptide in the peptidoglycan of the gram-positive bacterial cell wall, and CpG bacterial DNA . These PAMPs are recognized by the pattern recognition receptors (PRRs) of the innate immune system, which may be membrane-bound or cytosolic. There are four families of PRRs: the toll-like receptors , the C-type lectin receptors, the NOD-like receptors , and the RIG-I-like receptors . Invariably, the association of a PAMP and a PRR will cause a series of intracellular signalling cascades. Consequentially, transcription factors such as nuclear factor-kappa B and activator protein-1 , will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines. Upon detection of microbial antigens , the host systemic immune system is activated. Immune cells not only recognise pathogen-associated molecular patterns but also damage-associated molecular patterns from damaged tissues. An uncontrolled immune response is then activated because leukocytes are not recruited to the specific site of infection, but instead they are recruited all over the body. Then, an immunosuppression state ensues when the proinflammatory T helper cell 1 (TH1) is shifted to TH2, mediated by interleukin 10 , which is known as "compensatory anti-inflammatory response syndrome". The apoptosis (cell death) of lymphocytes further worsens the immunosuppression. Neutrophils , monocytes , macrophages , dendritic cells , CD4+ T cells , and B cells all undergo apoptosis, whereas regulatory T cells are more apoptosis resistant. Subsequently, multiple organ failure ensues because tissues are unable to use oxygen efficiently due to inhibition of cytochrome c oxidase . Inflammatory responses cause multiple organ dysfunction syndrome through various mechanisms as described below. Increased permeability of the lung vessels causes leaking of fluids into alveoli, which results in pulmonary edema and acute respiratory distress syndrome (ARDS). Impaired utilization of oxygen in the liver impairs bile salt transport, causing jaundice (yellowish discoloration of the skin). In kidneys, inadequate oxygenation results in tubular epithelial cell injury (of the cells lining the kidney tubules), and thus causes acute kidney injury (AKI). Meanwhile, in the heart, impaired calcium transport, and low production of adenosine triphosphate (ATP), can cause myocardial depression, reducing cardiac contractility and causing heart failure . In the gastrointestinal tract , increased permeability of the mucosa alters the microflora, causing mucosal bleeding and paralytic ileus . In the central nervous system , direct damage of the brain cells and disturbances of neurotransmissions causes altered mental status. Cytokines such as tumor necrosis factor , interleukin 1 , and interleukin 6 may activate procoagulation factors in the cells lining blood vessels , leading to endothelial damage. The damaged endothelial surface inhibits anticoagulant properties as well as increases antifibrinolysis , which may lead to intravascular clotting, the formation of blood clots in small blood vessels, and multiple organ failure . The low blood pressure seen in those with sepsis is the result of various processes, including excessive production of chemicals that dilate blood vessels such as nitric oxide , a deficiency of chemicals that constrict blood vessels such as vasopressin , and activation of ATP-sensitive potassium channels . In those with severe sepsis and septic shock, this sequence of events leads to a type of circulatory shock known as distributive shock . Bacterial virulence factors , such as glycocalyx and various adhesins , allow colonization, immune evasion, and establishment of disease in the host. Sepsis caused by gram-negative bacteria is thought to be largely due to a response by the host to the lipid A component of lipopolysaccharide , also called endotoxin . Sepsis caused by gram-positive bacteria may result from an immunological response to cell wall lipoteichoic acid . Bacterial exotoxins that act as superantigens also may cause sepsis. Superantigens simultaneously bind major histocompatibility complex and T-cell receptors in the absence of antigen presentation . This forced receptor interaction induces the production of pro-inflammatory chemical signals ( cytokines ) by T-cells. There are a number of microbial factors that may cause the typical septic inflammatory cascade . An invading pathogen is recognized by its pathogen-associated molecular patterns (PAMPs). Examples of PAMPs include lipopolysaccharides and flagellin in gram-negative bacteria, muramyl dipeptide in the peptidoglycan of the gram-positive bacterial cell wall, and CpG bacterial DNA . These PAMPs are recognized by the pattern recognition receptors (PRRs) of the innate immune system, which may be membrane-bound or cytosolic. There are four families of PRRs: the toll-like receptors , the C-type lectin receptors, the NOD-like receptors , and the RIG-I-like receptors . Invariably, the association of a PAMP and a PRR will cause a series of intracellular signalling cascades. Consequentially, transcription factors such as nuclear factor-kappa B and activator protein-1 , will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines. Upon detection of microbial antigens , the host systemic immune system is activated. Immune cells not only recognise pathogen-associated molecular patterns but also damage-associated molecular patterns from damaged tissues. An uncontrolled immune response is then activated because leukocytes are not recruited to the specific site of infection, but instead they are recruited all over the body. Then, an immunosuppression state ensues when the proinflammatory T helper cell 1 (TH1) is shifted to TH2, mediated by interleukin 10 , which is known as "compensatory anti-inflammatory response syndrome". The apoptosis (cell death) of lymphocytes further worsens the immunosuppression. Neutrophils , monocytes , macrophages , dendritic cells , CD4+ T cells , and B cells all undergo apoptosis, whereas regulatory T cells are more apoptosis resistant. Subsequently, multiple organ failure ensues because tissues are unable to use oxygen efficiently due to inhibition of cytochrome c oxidase . Inflammatory responses cause multiple organ dysfunction syndrome through various mechanisms as described below. Increased permeability of the lung vessels causes leaking of fluids into alveoli, which results in pulmonary edema and acute respiratory distress syndrome (ARDS). Impaired utilization of oxygen in the liver impairs bile salt transport, causing jaundice (yellowish discoloration of the skin). In kidneys, inadequate oxygenation results in tubular epithelial cell injury (of the cells lining the kidney tubules), and thus causes acute kidney injury (AKI). Meanwhile, in the heart, impaired calcium transport, and low production of adenosine triphosphate (ATP), can cause myocardial depression, reducing cardiac contractility and causing heart failure . In the gastrointestinal tract , increased permeability of the mucosa alters the microflora, causing mucosal bleeding and paralytic ileus . In the central nervous system , direct damage of the brain cells and disturbances of neurotransmissions causes altered mental status. Cytokines such as tumor necrosis factor , interleukin 1 , and interleukin 6 may activate procoagulation factors in the cells lining blood vessels , leading to endothelial damage. The damaged endothelial surface inhibits anticoagulant properties as well as increases antifibrinolysis , which may lead to intravascular clotting, the formation of blood clots in small blood vessels, and multiple organ failure . The low blood pressure seen in those with sepsis is the result of various processes, including excessive production of chemicals that dilate blood vessels such as nitric oxide , a deficiency of chemicals that constrict blood vessels such as vasopressin , and activation of ATP-sensitive potassium channels . In those with severe sepsis and septic shock, this sequence of events leads to a type of circulatory shock known as distributive shock . Early diagnosis is necessary to properly manage sepsis, as the initiation of rapid therapy is key to reducing deaths from severe sepsis. Some hospitals use alerts generated from electronic health records to bring attention to potential cases as early as possible. Within the first three hours of suspected sepsis, diagnostic studies should include white blood cell counts , measuring serum lactate, and obtaining appropriate cultures before starting antibiotics, so long as this does not delay their use by more than 45 minutes. To identify the causative organism(s), at least two sets of blood cultures using bottles with media for aerobic and anaerobic organisms are necessary. At least one should be drawn through the skin and one through each vascular access device (such as an IV catheter) that has been in place more than 48 hours. Bacteria are present in the blood in only about 30% of cases. Another possible method of detection is by polymerase chain reaction . If other sources of infection are suspected, cultures of these sources, such as urine, cerebrospinal fluid, wounds, or respiratory secretions, also should be obtained, as long as this does not delay the use of antibiotics. Within six hours, if blood pressure remains low despite initial fluid resuscitation of 30 mL/kg, or if initial lactate is ≥ four mmol/L (36 mg/dL), central venous pressure and central venous oxygen saturation should be measured. Lactate should be re-measured if the initial lactate was elevated. Evidence for point of care lactate measurement over usual methods of measurement, however, is poor. Within twelve hours, it is essential to diagnose or exclude any source of infection that would require emergent source control, such as a necrotizing soft tissue infection, an infection causing inflammation of the abdominal cavity lining , an infection of the bile duct , or an intestinal infarction. A pierced internal organ (free air on an abdominal X-ray or CT scan), an abnormal chest X-ray consistent with pneumonia (with focal opacification), or petechiae , purpura , or purpura fulminans may indicate the presence of an infection. [ citation needed ] Previously, SIRS criteria had been used to define sepsis. If the SIRS criteria are negative, it is very unlikely the person has sepsis; if it is positive, there is just a moderate probability that the person has sepsis. According to SIRS, there were different levels of sepsis: sepsis, severe sepsis, and septic shock. The definition of SIRS is shown below: In 2016 a new consensus was reached to replace screening by systemic inflammatory response syndrome (SIRS) with the sequential organ failure assessment ( SOFA score ) and the abbreviated version ( qSOFA ). The three criteria for the qSOFA score include a respiratory rate greater than or equal to 22 breaths per minute, systolic blood pressure 100 mmHg or less and altered mental status. Sepsis is suspected when 2 of the qSOFA criteria are met. The SOFA score was intended to be used in the intensive care unit (ICU) where it is administered upon admission to the ICU and then repeated every 48 hours, whereas the qSOFA could be used outside the ICU. Some advantages of the qSOFA score are that it can be administered quickly and does not require labs. However, the American College of Chest Physicians (CHEST) raised concerns that qSOFA and SOFA criteria may lead to delayed diagnosis of serious infection, leading to delayed treatment. Although SIRS criteria can be too sensitive and not specific enough in identifying sepsis, SOFA also has its limitations and is not intended to replace the SIRS definition. qSOFA has also been found to be poorly sensitive though decently specific for the risk of death with SIRS possibly better for screening. NOTE - Surviving Sepsis Campaign 2021 Guidelines recommends "against using qSOFA compared with SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock". Examples of end-organ dysfunction include the following: More specific definitions of end-organ dysfunction exist for SIRS in pediatrics. Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience. Biomarkers can help diagnosis because they can point to the presence or severity of sepsis, although their exact role in the management of sepsis remains undefined. A 2013 review concluded moderate-quality evidence exists to support the use of the procalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS. The same review found the sensitivity of the test to be 77% and the specificity to be 79%. The authors suggested that procalcitonin may serve as a helpful diagnostic marker for sepsis, but cautioned that its level alone does not definitively make the diagnosis. More current literature recommends utilizing the PCT to direct antibiotic therapy for improved antibiotic stewardship and better patient outcomes. A 2012 systematic review found that soluble urokinase-type plasminogen activator receptor (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis. This same review concluded, however, that SuPAR has prognostic value, as higher SuPAR levels are associated with an increased rate of death in those with sepsis. Serial measurement of lactate levels (approximately every 4 to 6 hours) may guide treatment and is associated with lower mortality in sepsis. The differential diagnosis for sepsis is broad and has to examine (to exclude) the non-infectious conditions that may cause the systemic signs of SIRS: alcohol withdrawal , acute pancreatitis , burns , pulmonary embolism , thyrotoxicosis , anaphylaxis , adrenal insufficiency , and neurogenic shock . Hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis (HLH) may have similar symptoms and are on the differential diagnosis. In common clinical usage, neonatal sepsis refers to a bacterial blood stream infection in the first month of life, such as meningitis , pneumonia , pyelonephritis , or gastroenteritis , but neonatal sepsis also may be due to infection with fungi, viruses, or parasites. Criteria with regard to hemodynamic compromise or respiratory failure are not useful because they present too late for intervention. [ citation needed ]Previously, SIRS criteria had been used to define sepsis. If the SIRS criteria are negative, it is very unlikely the person has sepsis; if it is positive, there is just a moderate probability that the person has sepsis. According to SIRS, there were different levels of sepsis: sepsis, severe sepsis, and septic shock. The definition of SIRS is shown below: In 2016 a new consensus was reached to replace screening by systemic inflammatory response syndrome (SIRS) with the sequential organ failure assessment ( SOFA score ) and the abbreviated version ( qSOFA ). The three criteria for the qSOFA score include a respiratory rate greater than or equal to 22 breaths per minute, systolic blood pressure 100 mmHg or less and altered mental status. Sepsis is suspected when 2 of the qSOFA criteria are met. The SOFA score was intended to be used in the intensive care unit (ICU) where it is administered upon admission to the ICU and then repeated every 48 hours, whereas the qSOFA could be used outside the ICU. Some advantages of the qSOFA score are that it can be administered quickly and does not require labs. However, the American College of Chest Physicians (CHEST) raised concerns that qSOFA and SOFA criteria may lead to delayed diagnosis of serious infection, leading to delayed treatment. Although SIRS criteria can be too sensitive and not specific enough in identifying sepsis, SOFA also has its limitations and is not intended to replace the SIRS definition. qSOFA has also been found to be poorly sensitive though decently specific for the risk of death with SIRS possibly better for screening. NOTE - Surviving Sepsis Campaign 2021 Guidelines recommends "against using qSOFA compared with SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock". Examples of end-organ dysfunction include the following: More specific definitions of end-organ dysfunction exist for SIRS in pediatrics. Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience. Biomarkers can help diagnosis because they can point to the presence or severity of sepsis, although their exact role in the management of sepsis remains undefined. A 2013 review concluded moderate-quality evidence exists to support the use of the procalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS. The same review found the sensitivity of the test to be 77% and the specificity to be 79%. The authors suggested that procalcitonin may serve as a helpful diagnostic marker for sepsis, but cautioned that its level alone does not definitively make the diagnosis. More current literature recommends utilizing the PCT to direct antibiotic therapy for improved antibiotic stewardship and better patient outcomes. A 2012 systematic review found that soluble urokinase-type plasminogen activator receptor (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis. This same review concluded, however, that SuPAR has prognostic value, as higher SuPAR levels are associated with an increased rate of death in those with sepsis. Serial measurement of lactate levels (approximately every 4 to 6 hours) may guide treatment and is associated with lower mortality in sepsis. The differential diagnosis for sepsis is broad and has to examine (to exclude) the non-infectious conditions that may cause the systemic signs of SIRS: alcohol withdrawal , acute pancreatitis , burns , pulmonary embolism , thyrotoxicosis , anaphylaxis , adrenal insufficiency , and neurogenic shock . Hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis (HLH) may have similar symptoms and are on the differential diagnosis. In common clinical usage, neonatal sepsis refers to a bacterial blood stream infection in the first month of life, such as meningitis , pneumonia , pyelonephritis , or gastroenteritis , but neonatal sepsis also may be due to infection with fungi, viruses, or parasites. Criteria with regard to hemodynamic compromise or respiratory failure are not useful because they present too late for intervention. [ citation needed ]Early recognition and focused management may improve the outcomes in sepsis. Current professional recommendations include a number of actions ("bundles") to be followed as soon as possible after diagnosis. Within the first three hours, someone with sepsis should have received antibiotics and, intravenous fluids if there is evidence of either low blood pressure or other evidence for inadequate blood supply to organs (as evidenced by a raised level of lactate); blood cultures also should be obtained within this time period. After six hours the blood pressure should be adequate, close monitoring of blood pressure and blood supply to organs should be in place, and the lactate should be measured again if initially it was raised. A related bundle, the " Sepsis Six ", is in widespread use in the United Kingdom ; this requires the administration of antibiotics within an hour of recognition, blood cultures, lactate, and hemoglobin determination, urine output monitoring, high-flow oxygen, and intravenous fluids. Apart from the timely administration of fluids and antibiotics , the management of sepsis also involves surgical drainage of infected fluid collections and appropriate support for organ dysfunction. This may include hemodialysis in kidney failure , mechanical ventilation in lung dysfunction, transfusion of blood products , and drug and fluid therapy for circulatory failure. Ensuring adequate nutrition—preferably by enteral feeding , but if necessary, by parenteral nutrition —is important during prolonged illness. Medication to prevent deep vein thrombosis and gastric ulcers also may be used. Two sets of blood cultures (aerobic and anaerobic) are recommended without delaying the initiation of antibiotics. Cultures from other sites such as respiratory secretions, urine, wounds, cerebrospinal fluid, and catheter insertion sites (in-situ more than 48 hours) are recommended if infections from these sites are suspected. In severe sepsis and septic shock, broad-spectrum antibiotics (usually two, a β-lactam antibiotic with broad coverage, or broad-spectrum carbapenem combined with fluoroquinolones , macrolides , or aminoglycosides ) are recommended. The choice of antibiotics is important in determining the survival of the person. Some recommend they be given within one hour of making the diagnosis, stating that for every hour of delay in the administration of antibiotics, there is an associated 6% rise in mortality. Others did not find a benefit with early administration. Several factors determine the most appropriate choice for the initial antibiotic regimen. These factors include local patterns of bacterial sensitivity to antibiotics, whether the infection is thought to be a hospital or community-acquired infection, and which organ systems are thought to be infected. Antibiotic regimens should be reassessed daily and narrowed if appropriate. Treatment duration is typically 7–10 days with the type of antibiotic used directed by the results of cultures. If the culture result is negative, antibiotics should be de-escalated according to the person's clinical response or stopped altogether if an infection is not present to decrease the chances that the person is infected with multiple drug resistance organisms. In case of people having a high risk of being infected with multiple drug resistant organisms such as Pseudomonas aeruginosa , Acinetobacter baumannii , the addition of an antibiotic specific to the gram-negative organism is recommended. For methicillin-resistant Staphylococcus aureus (MRSA), vancomycin or teicoplanin is recommended. For Legionella infection, addition of macrolide or fluoroquinolone is chosen. If fungal infection is suspected, an echinocandin , such as caspofungin or micafungin , is chosen for people with severe sepsis, followed by triazole ( fluconazole and itraconazole ) for less ill people. Prolonged antibiotic prophylaxis is not recommended in people who has SIRS without any infectious origin such as acute pancreatitis and burns unless sepsis is suspected. Once-daily dosing of aminoglycoside is sufficient to achieve peak plasma concentration for a clinical response without kidney toxicity. Meanwhile, for antibiotics with low volume distribution (vancomycin, teicoplanin, colistin), a loading dose is required to achieve an adequate therapeutic level to fight infections. Frequent infusions of beta-lactam antibiotics without exceeding total daily dose would help to keep the antibiotics level above minimum inhibitory concentration (MIC), thus providing a better clinical response. Giving beta-lactam antibiotics continuously may be better than giving them intermittently. Access to therapeutic drug monitoring is important to ensure adequate drug therapeutic level while at the same time preventing the drug from reaching toxic level. The Surviving Sepsis Campaign has recommended 30 mL/kg of fluid to be given in adults in the first three hours followed by fluid titration according to blood pressure, urine output, respiratory rate, and oxygen saturation with a target mean arterial pressure (MAP) of 65 mmHg. In children an initial amount of 20 mL/kg is reasonable in shock. In cases of severe sepsis and septic shock where a central venous catheter is used to measure blood pressures dynamically, fluids should be administered until the central venous pressure reaches 8–12 mmHg. Once these goals are met, the central venous oxygen saturation (ScvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the ScvO2 is less than 70%, blood may be given to reach a hemoglobin of 10 g/dL and then inotropes are added until the ScvO2 is optimized. In those with acute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given carefully. Crystalloid solution is recommended as the fluid of choice for resuscitation. Albumin can be used if a large amount of crystalloid is required for resuscitation. Crystalloid solutions shows little difference with hydroxyethyl starch in terms of risk of death. Starches also carry an increased risk of acute kidney injury , and need for blood transfusion. Various colloid solutions (such as modified gelatin) carry no advantage over crystalloid. Albumin also appears to be of no benefit over crystalloids. The Surviving Sepsis Campaign recommended packed red blood cells transfusion for hemoglobin levels below 70 g/L if there is no myocardial ischemia , hypoxemia , or acute bleeding. In a 2014 trial, blood transfusions to keep target hemoglobin above 70 or 90 g/L did not make any difference to survival rates; meanwhile, those with a lower threshold of transfusion received fewer transfusions in total. Erythropoietin is not recommended in the treatment of anemia with septic shock because it may precipitate blood clotting events. Fresh frozen plasma transfusion usually does not correct the underlying clotting abnormalities before a planned surgical procedure. However, platelet transfusion is suggested for platelet counts below (10 × 10 9 /L) without any risk of bleeding, or (20 × 10 9 /L) with high risk of bleeding, or (50 × 10 9 /L) with active bleeding, before a planned surgery or an invasive procedure. IV immunoglobulin is not recommended because its beneficial effects are uncertain. Monoclonal and polyclonal preparations of intravenous immunoglobulin (IVIG) do not lower the rate of death in newborns and adults with sepsis. Evidence for the use of IgM -enriched polyclonal preparations of IVIG is inconsistent. On the other hand, the use of antithrombin to treat disseminated intravascular coagulation is also not useful. Meanwhile, the blood purification technique (such as hemoperfusion , plasma filtration, and coupled plasma filtration adsorption) to remove inflammatory mediators and bacterial toxins from the blood also does not demonstrate any survival benefit for septic shock. If the person has been sufficiently fluid resuscitated but the mean arterial pressure is not greater than 65 mmHg, vasopressors are recommended. Norepinephrine (noradrenaline) is recommended as the initial choice. Delaying initiation of vasopressor therapy during septic shock is associated with increased mortality. Norepinephrine is often used as a first-line treatment for hypotensive septic shock because evidence shows that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours. Norepinephrine raises blood pressure through a vasoconstriction effect, with little effect on stroke volume and heart rate. In some people, the required dose of vasopressor needed to increase the mean arterial pressure can become exceedingly high that it becomes toxic. In order to reduce the required dose of vasopressor, epinephrine may be added. Epinephrine is not often used as a first-line treatment for hypotensive shock because it reduces blood flow to the abdominal organs and increases lactate levels. Vasopressin can be used in septic shock because studies have shown that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours. However, vasopressin reduces blood flow to the heart, finger/toes, and abdominal organs, resulting in a lack of oxygen supply to these tissues. Dopamine is typically not recommended. Although dopamine is useful to increase the stroke volume of the heart, it causes more abnormal heart rhythms than norepinephrine and also has an immunosuppressive effect. Dopamine is not proven to have protective properties on the kidneys. Dobutamine can also be used in hypotensive septic shock to increase cardiac output and correct blood flow to the tissues. Dobutamine is not used as often as epinephrine due to its associated side effects, which include reducing blood flow to the gut. Additionally, dobutamine increases the cardiac output by abnormally increasing the heart rate. The use of steroids in sepsis is controversial. Studies do not give a clear picture as to whether and when glucocorticoids should be used. The 2016 Surviving Sepsis Campaign recommends low dose hydrocortisone only if both intravenous fluids and vasopressors are not able to adequately treat septic shock. The 2021 Surviving Sepsis Campaign recommends IV corticosteroids for adults with septic shock who have an ongoing requirement for vasopressor therapy . A 2019 Cochrane review found low-quality evidence of benefit, as did two 2019 reviews. During critical illness, a state of adrenal insufficiency and tissue resistance to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency . Treatment with corticosteroids might be most beneficial in those with septic shock and early severe ARDS, whereas its role in others such as those with pancreatitis or severe pneumonia is unclear. However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. Neither ACTH stimulation testing nor random cortisol levels are recommended to confirm the diagnosis. The method of stopping glucocorticoid drugs is variable, and it is unclear whether they should be slowly decreased or simply abruptly stopped. However, the 2016 Surviving Sepsis Campaign recommended to taper steroids when vasopressors are no longer needed. A target tidal volume of 6 mL/kg of predicted body weight (PBW) and a plateau pressure less than 30 cm H 2 O is recommended for those who require ventilation due to sepsis-induced severe ARDS. High positive end expiratory pressure (PEEP) is recommended for moderate to severe ARDS in sepsis as it opens more lung units for oxygen exchange. Predicted body weight is calculated based on sex and height, and tools for this are available. Recruitment maneuvers may be necessary for severe ARDS by briefly raising the transpulmonary pressure. It is recommended that the head of the bed be raised if possible to improve ventilation. However, β2 adrenergic receptor agonists are not recommended to treat ARDS because it may reduce survival rates and precipitate abnormal heart rhythms . A spontaneous breathing trial using continuous positive airway pressure (CPAP), T piece, or inspiratory pressure augmentation can be helpful in reducing the duration of ventilation. Minimizing intermittent or continuous sedation is helpful in reducing the duration of mechanical ventilation. General anesthesia is recommended for people with sepsis who require surgical procedures to remove the infective source. Usually, inhalational and intravenous anesthetics are used. Requirements for anesthetics may be reduced in sepsis. Inhalational anesthetics can reduce the level of proinflammatory cytokines, altering leukocyte adhesion and proliferation, inducing apoptosis (cell death) of the lymphocytes, possibly with a toxic effect on mitochondrial function. Although etomidate has a minimal effect on the cardiovascular system, it is often not recommended as a medication to help with intubation in this situation due to concerns it may lead to poor adrenal function and an increased risk of death. The small amount of evidence there is, however, has not found a change in the risk of death with etomidate. Paralytic agents are not suggested for use in sepsis cases in the absence of ARDS , as a growing body of evidence points to reduced durations of mechanical ventilation , ICU and hospital stays. However, paralytic use in ARDS cases remains controversial. When appropriately used, paralytics may aid successful mechanical ventilation, however, evidence has also suggested that mechanical ventilation in severe sepsis does not improve oxygen consumption and delivery. Source control refers to physical interventions to control a focus of infection and reduce conditions favorable to microorganism growth or host defense impairment, such as drainage of pus from an abscess . It is one of the oldest procedures for control of infections, giving rise to the Latin phrase Ubi pus, ibi evacua , and remains important despite the emergence of more modern treatments. Early goal directed therapy (EGDT) is an approach to the management of severe sepsis during the initial 6 hours after diagnosis. It is a step-wise approach, with the physiologic goal of optimizing cardiac preload, afterload, and contractility. It includes giving early antibiotics. EGDT also involves monitoring of hemodynamic parameters and specific interventions to achieve key resuscitation targets which include maintaining a central venous pressure between 8–12 mmHg, a mean arterial pressure of between 65 and 90 mmHg, a central venous oxygen saturation (ScvO 2 ) greater than 70% and a urine output of greater than 0.5 mL/kg/hour. The goal is to optimize oxygen delivery to tissues and achieve a balance between systemic oxygen delivery and demand. An appropriate decrease in serum lactate may be equivalent to ScvO 2 and easier to obtain. In the original trial, early goal-directed therapy was found to reduce mortality from 46.5% to 30.5% in those with sepsis, and the Surviving Sepsis Campaign has been recommending its use. However, three more recent large randomized control trials (ProCESS, ARISE, and ProMISe), did not demonstrate a 90-day mortality benefit of early goal-directed therapy when compared to standard therapy in severe sepsis. It is likely that some parts of EGDT are more important than others. Following these trials the use of EGDT is still considered reasonable. Neonatal sepsis can be difficult to diagnose as newborns may be asymptomatic. If a newborn shows signs and symptoms suggestive of sepsis, antibiotics are immediately started and are either changed to target a specific organism identified by diagnostic testing or discontinued after an infectious cause for the symptoms has been ruled out. Despite early intervention, death occurs in 13% of children who develop septic shock, with the risk partly based on other health problems. For those without multiple organ system failures or who require only one inotropic agent, mortality is low. Treating fever in sepsis, including people in septic shock, has not been associated with any improvement in mortality over a period of 28 days. Treatment of fever still occurs for other reasons. A 2012 Cochrane review concluded that N-acetylcysteine does not reduce mortality in those with SIRS or sepsis and may even be harmful. Recombinant activated protein C ( drotrecogin alpha ) was originally introduced for severe sepsis (as identified by a high APACHE II score), where it was thought to confer a survival benefit. However, subsequent studies showed that it increased adverse events—bleeding risk in particular—and did not decrease mortality. It was removed from sale in 2011. Another medication known as eritoran also has not shown benefit. In those with high blood sugar levels, insulin to bring it down to 7.8–10 mmol/L (140–180 mg/dL) is recommended with lower levels potentially worsening outcomes. Glucose levels taken from capillary blood should be interpreted with care because such measurements may not be accurate. If a person has an arterial catheter, arterial blood is recommended for blood glucose testing. Intermittent or continuous renal replacement therapy may be used if indicated. However, sodium bicarbonate is not recommended for a person with lactic acidosis secondary to hypoperfusion. Low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), and mechanical prophylaxis with intermittent pneumatic compression devices are recommended for any person with sepsis at moderate to high risk of venous thromboembolism . Stress ulcer prevention with proton-pump inhibitor (PPI) and H2 antagonist are useful in a person with risk factors of developing upper gastrointestinal bleeding (UGIB) such as on mechanical ventilation for more than 48 hours, coagulation disorders, liver disease, and renal replacement therapy. Achieving partial or full enteral feeding (delivery of nutrients through a feeding tube ) is chosen as the best approach to provide nutrition for a person who is contraindicated for oral intake or unable to tolerate orally in the first seven days of sepsis when compared to intravenous nutrition . However, omega-3 fatty acids are not recommended as immune supplements for a person with sepsis or septic shock. The usage of prokinetic agents such as metoclopramide , domperidone , and erythromycin are recommended for those who are septic and unable to tolerate enteral feeding. However, these agents may precipitate prolongation of the QT interval and consequently provoke a ventricular arrhythmia such as torsades de pointes . The usage of prokinetic agents should be reassessed daily and stopped if no longer indicated. People in sepsis may have micronutrient deficiencies, including low levels of vitamin C. Reviews mention that an intake of 3.0 g/day, which requires intravenous administration, may needed to maintain normal plasma concentrations in people with sepsis or severe burn injury. Sepsis mortality is reduced with administration of intravenous vitamin C. Two sets of blood cultures (aerobic and anaerobic) are recommended without delaying the initiation of antibiotics. Cultures from other sites such as respiratory secretions, urine, wounds, cerebrospinal fluid, and catheter insertion sites (in-situ more than 48 hours) are recommended if infections from these sites are suspected. In severe sepsis and septic shock, broad-spectrum antibiotics (usually two, a β-lactam antibiotic with broad coverage, or broad-spectrum carbapenem combined with fluoroquinolones , macrolides , or aminoglycosides ) are recommended. The choice of antibiotics is important in determining the survival of the person. Some recommend they be given within one hour of making the diagnosis, stating that for every hour of delay in the administration of antibiotics, there is an associated 6% rise in mortality. Others did not find a benefit with early administration. Several factors determine the most appropriate choice for the initial antibiotic regimen. These factors include local patterns of bacterial sensitivity to antibiotics, whether the infection is thought to be a hospital or community-acquired infection, and which organ systems are thought to be infected. Antibiotic regimens should be reassessed daily and narrowed if appropriate. Treatment duration is typically 7–10 days with the type of antibiotic used directed by the results of cultures. If the culture result is negative, antibiotics should be de-escalated according to the person's clinical response or stopped altogether if an infection is not present to decrease the chances that the person is infected with multiple drug resistance organisms. In case of people having a high risk of being infected with multiple drug resistant organisms such as Pseudomonas aeruginosa , Acinetobacter baumannii , the addition of an antibiotic specific to the gram-negative organism is recommended. For methicillin-resistant Staphylococcus aureus (MRSA), vancomycin or teicoplanin is recommended. For Legionella infection, addition of macrolide or fluoroquinolone is chosen. If fungal infection is suspected, an echinocandin , such as caspofungin or micafungin , is chosen for people with severe sepsis, followed by triazole ( fluconazole and itraconazole ) for less ill people. Prolonged antibiotic prophylaxis is not recommended in people who has SIRS without any infectious origin such as acute pancreatitis and burns unless sepsis is suspected. Once-daily dosing of aminoglycoside is sufficient to achieve peak plasma concentration for a clinical response without kidney toxicity. Meanwhile, for antibiotics with low volume distribution (vancomycin, teicoplanin, colistin), a loading dose is required to achieve an adequate therapeutic level to fight infections. Frequent infusions of beta-lactam antibiotics without exceeding total daily dose would help to keep the antibiotics level above minimum inhibitory concentration (MIC), thus providing a better clinical response. Giving beta-lactam antibiotics continuously may be better than giving them intermittently. Access to therapeutic drug monitoring is important to ensure adequate drug therapeutic level while at the same time preventing the drug from reaching toxic level. The Surviving Sepsis Campaign has recommended 30 mL/kg of fluid to be given in adults in the first three hours followed by fluid titration according to blood pressure, urine output, respiratory rate, and oxygen saturation with a target mean arterial pressure (MAP) of 65 mmHg. In children an initial amount of 20 mL/kg is reasonable in shock. In cases of severe sepsis and septic shock where a central venous catheter is used to measure blood pressures dynamically, fluids should be administered until the central venous pressure reaches 8–12 mmHg. Once these goals are met, the central venous oxygen saturation (ScvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the ScvO2 is less than 70%, blood may be given to reach a hemoglobin of 10 g/dL and then inotropes are added until the ScvO2 is optimized. In those with acute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given carefully. Crystalloid solution is recommended as the fluid of choice for resuscitation. Albumin can be used if a large amount of crystalloid is required for resuscitation. Crystalloid solutions shows little difference with hydroxyethyl starch in terms of risk of death. Starches also carry an increased risk of acute kidney injury , and need for blood transfusion. Various colloid solutions (such as modified gelatin) carry no advantage over crystalloid. Albumin also appears to be of no benefit over crystalloids. The Surviving Sepsis Campaign recommended packed red blood cells transfusion for hemoglobin levels below 70 g/L if there is no myocardial ischemia , hypoxemia , or acute bleeding. In a 2014 trial, blood transfusions to keep target hemoglobin above 70 or 90 g/L did not make any difference to survival rates; meanwhile, those with a lower threshold of transfusion received fewer transfusions in total. Erythropoietin is not recommended in the treatment of anemia with septic shock because it may precipitate blood clotting events. Fresh frozen plasma transfusion usually does not correct the underlying clotting abnormalities before a planned surgical procedure. However, platelet transfusion is suggested for platelet counts below (10 × 10 9 /L) without any risk of bleeding, or (20 × 10 9 /L) with high risk of bleeding, or (50 × 10 9 /L) with active bleeding, before a planned surgery or an invasive procedure. IV immunoglobulin is not recommended because its beneficial effects are uncertain. Monoclonal and polyclonal preparations of intravenous immunoglobulin (IVIG) do not lower the rate of death in newborns and adults with sepsis. Evidence for the use of IgM -enriched polyclonal preparations of IVIG is inconsistent. On the other hand, the use of antithrombin to treat disseminated intravascular coagulation is also not useful. Meanwhile, the blood purification technique (such as hemoperfusion , plasma filtration, and coupled plasma filtration adsorption) to remove inflammatory mediators and bacterial toxins from the blood also does not demonstrate any survival benefit for septic shock. If the person has been sufficiently fluid resuscitated but the mean arterial pressure is not greater than 65 mmHg, vasopressors are recommended. Norepinephrine (noradrenaline) is recommended as the initial choice. Delaying initiation of vasopressor therapy during septic shock is associated with increased mortality. Norepinephrine is often used as a first-line treatment for hypotensive septic shock because evidence shows that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours. Norepinephrine raises blood pressure through a vasoconstriction effect, with little effect on stroke volume and heart rate. In some people, the required dose of vasopressor needed to increase the mean arterial pressure can become exceedingly high that it becomes toxic. In order to reduce the required dose of vasopressor, epinephrine may be added. Epinephrine is not often used as a first-line treatment for hypotensive shock because it reduces blood flow to the abdominal organs and increases lactate levels. Vasopressin can be used in septic shock because studies have shown that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours. However, vasopressin reduces blood flow to the heart, finger/toes, and abdominal organs, resulting in a lack of oxygen supply to these tissues. Dopamine is typically not recommended. Although dopamine is useful to increase the stroke volume of the heart, it causes more abnormal heart rhythms than norepinephrine and also has an immunosuppressive effect. Dopamine is not proven to have protective properties on the kidneys. Dobutamine can also be used in hypotensive septic shock to increase cardiac output and correct blood flow to the tissues. Dobutamine is not used as often as epinephrine due to its associated side effects, which include reducing blood flow to the gut. Additionally, dobutamine increases the cardiac output by abnormally increasing the heart rate. The use of steroids in sepsis is controversial. Studies do not give a clear picture as to whether and when glucocorticoids should be used. The 2016 Surviving Sepsis Campaign recommends low dose hydrocortisone only if both intravenous fluids and vasopressors are not able to adequately treat septic shock. The 2021 Surviving Sepsis Campaign recommends IV corticosteroids for adults with septic shock who have an ongoing requirement for vasopressor therapy . A 2019 Cochrane review found low-quality evidence of benefit, as did two 2019 reviews. During critical illness, a state of adrenal insufficiency and tissue resistance to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency . Treatment with corticosteroids might be most beneficial in those with septic shock and early severe ARDS, whereas its role in others such as those with pancreatitis or severe pneumonia is unclear. However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. Neither ACTH stimulation testing nor random cortisol levels are recommended to confirm the diagnosis. The method of stopping glucocorticoid drugs is variable, and it is unclear whether they should be slowly decreased or simply abruptly stopped. However, the 2016 Surviving Sepsis Campaign recommended to taper steroids when vasopressors are no longer needed. A target tidal volume of 6 mL/kg of predicted body weight (PBW) and a plateau pressure less than 30 cm H 2 O is recommended for those who require ventilation due to sepsis-induced severe ARDS. High positive end expiratory pressure (PEEP) is recommended for moderate to severe ARDS in sepsis as it opens more lung units for oxygen exchange. Predicted body weight is calculated based on sex and height, and tools for this are available. Recruitment maneuvers may be necessary for severe ARDS by briefly raising the transpulmonary pressure. It is recommended that the head of the bed be raised if possible to improve ventilation. However, β2 adrenergic receptor agonists are not recommended to treat ARDS because it may reduce survival rates and precipitate abnormal heart rhythms . A spontaneous breathing trial using continuous positive airway pressure (CPAP), T piece, or inspiratory pressure augmentation can be helpful in reducing the duration of ventilation. Minimizing intermittent or continuous sedation is helpful in reducing the duration of mechanical ventilation. General anesthesia is recommended for people with sepsis who require surgical procedures to remove the infective source. Usually, inhalational and intravenous anesthetics are used. Requirements for anesthetics may be reduced in sepsis. Inhalational anesthetics can reduce the level of proinflammatory cytokines, altering leukocyte adhesion and proliferation, inducing apoptosis (cell death) of the lymphocytes, possibly with a toxic effect on mitochondrial function. Although etomidate has a minimal effect on the cardiovascular system, it is often not recommended as a medication to help with intubation in this situation due to concerns it may lead to poor adrenal function and an increased risk of death. The small amount of evidence there is, however, has not found a change in the risk of death with etomidate. Paralytic agents are not suggested for use in sepsis cases in the absence of ARDS , as a growing body of evidence points to reduced durations of mechanical ventilation , ICU and hospital stays. However, paralytic use in ARDS cases remains controversial. When appropriately used, paralytics may aid successful mechanical ventilation, however, evidence has also suggested that mechanical ventilation in severe sepsis does not improve oxygen consumption and delivery. Source control refers to physical interventions to control a focus of infection and reduce conditions favorable to microorganism growth or host defense impairment, such as drainage of pus from an abscess . It is one of the oldest procedures for control of infections, giving rise to the Latin phrase Ubi pus, ibi evacua , and remains important despite the emergence of more modern treatments. Early goal directed therapy (EGDT) is an approach to the management of severe sepsis during the initial 6 hours after diagnosis. It is a step-wise approach, with the physiologic goal of optimizing cardiac preload, afterload, and contractility. It includes giving early antibiotics. EGDT also involves monitoring of hemodynamic parameters and specific interventions to achieve key resuscitation targets which include maintaining a central venous pressure between 8–12 mmHg, a mean arterial pressure of between 65 and 90 mmHg, a central venous oxygen saturation (ScvO 2 ) greater than 70% and a urine output of greater than 0.5 mL/kg/hour. The goal is to optimize oxygen delivery to tissues and achieve a balance between systemic oxygen delivery and demand. An appropriate decrease in serum lactate may be equivalent to ScvO 2 and easier to obtain. In the original trial, early goal-directed therapy was found to reduce mortality from 46.5% to 30.5% in those with sepsis, and the Surviving Sepsis Campaign has been recommending its use. However, three more recent large randomized control trials (ProCESS, ARISE, and ProMISe), did not demonstrate a 90-day mortality benefit of early goal-directed therapy when compared to standard therapy in severe sepsis. It is likely that some parts of EGDT are more important than others. Following these trials the use of EGDT is still considered reasonable. Neonatal sepsis can be difficult to diagnose as newborns may be asymptomatic. If a newborn shows signs and symptoms suggestive of sepsis, antibiotics are immediately started and are either changed to target a specific organism identified by diagnostic testing or discontinued after an infectious cause for the symptoms has been ruled out. Despite early intervention, death occurs in 13% of children who develop septic shock, with the risk partly based on other health problems. For those without multiple organ system failures or who require only one inotropic agent, mortality is low. Treating fever in sepsis, including people in septic shock, has not been associated with any improvement in mortality over a period of 28 days. Treatment of fever still occurs for other reasons. A 2012 Cochrane review concluded that N-acetylcysteine does not reduce mortality in those with SIRS or sepsis and may even be harmful. Recombinant activated protein C ( drotrecogin alpha ) was originally introduced for severe sepsis (as identified by a high APACHE II score), where it was thought to confer a survival benefit. However, subsequent studies showed that it increased adverse events—bleeding risk in particular—and did not decrease mortality. It was removed from sale in 2011. Another medication known as eritoran also has not shown benefit. In those with high blood sugar levels, insulin to bring it down to 7.8–10 mmol/L (140–180 mg/dL) is recommended with lower levels potentially worsening outcomes. Glucose levels taken from capillary blood should be interpreted with care because such measurements may not be accurate. If a person has an arterial catheter, arterial blood is recommended for blood glucose testing. Intermittent or continuous renal replacement therapy may be used if indicated. However, sodium bicarbonate is not recommended for a person with lactic acidosis secondary to hypoperfusion. Low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), and mechanical prophylaxis with intermittent pneumatic compression devices are recommended for any person with sepsis at moderate to high risk of venous thromboembolism . Stress ulcer prevention with proton-pump inhibitor (PPI) and H2 antagonist are useful in a person with risk factors of developing upper gastrointestinal bleeding (UGIB) such as on mechanical ventilation for more than 48 hours, coagulation disorders, liver disease, and renal replacement therapy. Achieving partial or full enteral feeding (delivery of nutrients through a feeding tube ) is chosen as the best approach to provide nutrition for a person who is contraindicated for oral intake or unable to tolerate orally in the first seven days of sepsis when compared to intravenous nutrition . However, omega-3 fatty acids are not recommended as immune supplements for a person with sepsis or septic shock. The usage of prokinetic agents such as metoclopramide , domperidone , and erythromycin are recommended for those who are septic and unable to tolerate enteral feeding. However, these agents may precipitate prolongation of the QT interval and consequently provoke a ventricular arrhythmia such as torsades de pointes . The usage of prokinetic agents should be reassessed daily and stopped if no longer indicated. People in sepsis may have micronutrient deficiencies, including low levels of vitamin C. Reviews mention that an intake of 3.0 g/day, which requires intravenous administration, may needed to maintain normal plasma concentrations in people with sepsis or severe burn injury. Sepsis mortality is reduced with administration of intravenous vitamin C. Sepsis will prove fatal in approximately 24.4% of people, and septic shock will prove fatal in 34.7% of people within 30 days (32.2% and 38.5% after 90 days). Lactate is a useful method of determining prognosis, with those who have a level greater than 4 mmol/L having a mortality of 40% and those with a level of less than 2 mmol/L having a mortality of less than 15%. There are a number of prognostic stratification systems, such as APACHE II and Mortality in Emergency Department Sepsis. APACHE II factors in the person's age, underlying condition, and various physiologic variables to yield estimates of the risk of dying of severe sepsis. Of the individual covariates, the severity of the underlying disease most strongly influences the risk of death. Septic shock is also a strong predictor of short- and long-term mortality. Case-fatality rates are similar for culture-positive and culture-negative severe sepsis. The Mortality in Emergency Department Sepsis (MEDS) score is simpler and useful in the emergency department environment. Some people may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most people with sepsis makes the incidence of this difficult to quantify or to study. Sepsis causes millions of deaths globally each year and is the most common cause of death in people who have been hospitalized. The number of new cases worldwide of sepsis is estimated to be 18 million cases per year. In the United States sepsis affects approximately 3 in 1,000 people, and severe sepsis contributes to more than 200,000 deaths per year. Sepsis occurs in 1–2% of all hospitalizations and accounts for as much as 25% of ICU bed utilization. Due to it rarely being reported as a primary diagnosis (often being a complication of cancer or other illness), the incidence, mortality, and morbidity rates of sepsis are likely underestimated. A study of U.S. states found approximately 651 hospital stays per 100,000 population with a sepsis diagnosis in 2010. It is the second-leading cause of death in non-coronary intensive care unit (ICU) and the tenth-most-common cause of death overall (the first being heart disease). Children under 12 months of age and elderly people have the highest incidence of severe sepsis. Among people from the U.S. who had multiple sepsis hospital admissions in 2010, those who were discharged to a skilled nursing facility or long-term care following the initial hospitalization were more likely to be readmitted than those discharged to another form of care. A study of 18 U.S. states found that, amongst people with Medicare in 2011, sepsis was the second most common principal reason for readmission within 30 days. Several medical conditions increase a person's susceptibility to infection and developing sepsis. Common sepsis risk factors include age (especially the very young and old); conditions that weaken the immune system such as cancer , diabetes , or the absence of a spleen ; and major trauma and burns . From 1979 to 2000, data from the United States National Hospital Discharge Survey showed that the incidence of sepsis increased fourfold, to 240 cases per 100,000 population, with a higher incidence in men when compared to women. However, the global prevalence of sepsis has been estimated to be higher in women. During the same time frame, the in-hospital case fatality rate was reduced from 28% to 18%. However, according to the nationwide inpatient sample from the United States, the incidence of severe sepsis increased from 200 per 10,000 population in 2003 to 300 cases in 2007 for population aged more than 18 years. The incidence rate is particularly high among infants, with an incidence of 500 cases per 100,000 population. Mortality related to sepsis increases with age, from less than 10% in the age group of 3 to 5 years to 60% by sixth decade of life. The increase in the average age of the population, alongside the presence of more people with chronic diseases or on immunosuppressive medications , and also the increase in the number of invasive procedures being performed, has led to an increased rate of sepsis. The term "σήψις" (sepsis) was introduced by Hippocrates in the fourth century BC, and it meant the process of decay or decomposition of organic matter. In the eleventh century, Avicenna used the term "blood rot" for diseases linked to severe purulent process. Though severe systemic toxicity had already been observed, it was only in the 19th century that the specific term – sepsis – was used for this condition. The terms "septicemia", also spelled "septicaemia", and "blood poisoning" referred to the microorganisms or their toxins in the blood. The International Statistical Classification of Diseases and Related Health Problems (ICD) version 9, which was in use in the US until 2013, used the term septicemia with numerous modifiers for different diagnoses, such as "Streptococcal septicemia". All those diagnoses have been converted to sepsis, again with modifiers, in ICD-10 , such as "Sepsis due to streptococcus". The current terms are dependent on the microorganism that is present: bacteremia if bacteria are present in the blood at abnormal levels and are the causative issue, viremia for viruses , and fungemia for a fungus . By the end of the 19th century, it was widely believed that microbes produced substances that could injure the mammalian host and that soluble toxins released during infection caused the fever and shock that were commonplace during severe infections. Pfeiffer coined the term endotoxin at the beginning of the 20th century to denote the pyrogenic principle associated with Vibrio cholerae . It was soon realized that endotoxins were expressed by most and perhaps all gram-negative bacteria . The lipopolysaccharide character of enteric endotoxins was elucidated in 1944 by Shear. The molecular character of this material was determined by Luderitz et al. in 1973. It was discovered in 1965 that a strain of C3H/HeJ mouse was immune to the endotoxin-induced shock. The genetic locus for this effect was dubbed Lps . These mice were also found to be hyper susceptible to infection by gram-negative bacteria. These observations were finally linked in 1998 by the discovery of the toll-like receptor gene 4 (TLR 4). Genetic mapping work, performed over a period of five years, showed that TLR4 was the sole candidate locus within the Lps critical region; this strongly implied that a mutation within TLR4 must account for the lipopolysaccharide resistance phenotype. The defect in the TLR4 gene that led to the endotoxin resistant phenotype was discovered to be due to a mutation in the cytoplasm . Controversy occurred in the scientific community over the use of mouse models in research into sepsis in 2013 when scientists published a review of the mouse immune system compared to the human immune system and showed that on a systems level, the two worked very differently; the authors noted that as of the date of their article over 150 clinical trials of sepsis had been conducted in humans, almost all of them supported by promising data in mice and that all of them had failed. The authors called for abandoning the use of mouse models in sepsis research; others rejected that but called for more caution in interpreting the results of mouse studies, and more careful design of preclinical studies. One approach is to rely more on studying biopsies and clinical data from people who have had sepsis, to try to identify biomarkers and drug targets for intervention. Sepsis was the most expensive condition treated in United States' hospital stays in 2013, at an aggregate cost of $23.6 billion for nearly 1.3 million hospitalizations. Costs for sepsis hospital stays more than quadrupled since 1997 with an 11.5 percent annual increase. By payer, it was the most costly condition billed to Medicare and the uninsured, the second-most costly billed to Medicaid , and the fourth-most costly billed to private insurance . A large international collaboration entitled the " Surviving Sepsis Campaign " was established in 2002 to educate people about sepsis and to improve outcomes with sepsis. The Campaign has published an evidence-based review of management strategies for severe sepsis, with the aim to publish a complete set of guidelines in subsequent years. The guidelines were updated in 2016 and again in 2021. Sepsis Alliance is a charitable organization that was created to raise sepsis awareness among both the general public and healthcare professionals. Sepsis was the most expensive condition treated in United States' hospital stays in 2013, at an aggregate cost of $23.6 billion for nearly 1.3 million hospitalizations. Costs for sepsis hospital stays more than quadrupled since 1997 with an 11.5 percent annual increase. By payer, it was the most costly condition billed to Medicare and the uninsured, the second-most costly billed to Medicaid , and the fourth-most costly billed to private insurance . A large international collaboration entitled the " Surviving Sepsis Campaign " was established in 2002 to educate people about sepsis and to improve outcomes with sepsis. The Campaign has published an evidence-based review of management strategies for severe sepsis, with the aim to publish a complete set of guidelines in subsequent years. The guidelines were updated in 2016 and again in 2021. Sepsis Alliance is a charitable organization that was created to raise sepsis awareness among both the general public and healthcare professionals. Some authors suggest that initiating sepsis by the normally mutualistic (or neutral) members of the microbiome may not always be an accidental side effect of the deteriorating host immune system. Rather it is often an adaptive microbial response to a sudden decline of host survival chances. Under this scenario, the microbe species provoking sepsis benefit from monopolizing the future cadaver, utilizing its biomass as decomposers , and then transmitted through soil or water to establish mutualistic relations with new individuals. The bacteria Streptococcus pneumoniae , Escherichia coli , Proteus spp., Pseudomonas aeruginosa , Staphylococcus aureus , Klebsiella spp., Clostridium spp., Lactobacillus spp., Bacteroides spp. and the fungi Candida spp. are all capable of such a high level of phenotypic plasticity . Evidently, not all cases of sepsis arise through such adaptive microbial strategy switches. Paul E. Marik 's "Marik protocol", also known as the "HAT" protocol, proposed a combination of hydrocortisone , vitamin C , and thiamine as a treatment for preventing sepsis for people in intensive care . Marik's own initial research, published in 2017, showed a dramatic evidence of benefit, leading to the protocol becoming popular among intensive care physicians, especially after the protocol received attention on social media and National Public Radio , leading to criticism of science by press conference from the wider medical community. Subsequent independent research failed to replicate Marik's positive results, indicating the possibility that they had been compromised by bias. A systematic review of trials in 2021 found that the claimed benefits of the protocol could not be confirmed. Another more recent review found that "HAT therapy significantly reduced the duration of vasopressor use and improved the SOFA score but appeared not to have significant benefits in other outcomes for patients with sepsis." Overall, the evidence for any role for vitamin C in the treatment of sepsis remains unclear as of 2021 [ update ] .

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Acute hemorrhagic fever syndrome

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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.

Wiki

Acute hemorrhagic fever syndrome

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Hematemesis

Hematemesis is the vomiting of blood . It can be confused with hemoptysis (coughing up blood) or epistaxis (nosebleed), which are more common. The source is generally the upper gastrointestinal tract , typically above the suspensory muscle of duodenum . It may be caused by ulcers, tumors of the stomach or esophagus, varices, prolonged and vigorous retching, gastroenteritis, ingested blood (from bleeding in the mouth , nose , or throat ), or certain drugs. [ citation needed ] Hematemesis is treated as a medical emergency, with treatments based on the amount of blood loss. Investigations include endoscopy . Any blood loss may be corrected with intravenous fluids and blood transfusions . Patients may need to avoid taking anything by mouth . [ citation needed ]Hematemesis is the vomiting of blood . This is usually vomit that contains bright red blood. Coffee ground vomiting is similar to hematemesis, but is distinct in not involving bright red blood. Hematemesis must be differentiated from hemoptysis (coughing up blood) and epistaxis (nosebleed). Both of these are more common conditions. These may be difficult to distinguish.Hematemesis may be caused by:The source of vomited blood is usually from the upper gastrointestinal tract . This can include the esophagus , stomach , and parts of the small intestine . This may be the suspensory muscle of duodenum . Hematemesis tends to occur only after significant blood loss. Hematemesis may be investigated with endoscopy of the upper gastrointestinal tract . Barium meal may also be used. Hematemesis is treated as a medical emergency . The most vital distinction is whether there is blood loss sufficient to cause shock . Correct management is required in such conditions. It is required to perform all tests such as endoscopy before medication. A platelet test is also an important test in such conditions. Medicines such as painkillers or antibiotics, e.g. ciprofloxacin, could decrease platelet count which can lead to thrombocytopenia (when the body does not have sufficient platelets in the blood and cannot form clots). In such conditions wrong medication or management could be deadly. Blood transfusion is required in such conditions if the body loses more than 20 percent of body blood volume. Severe loss makes it impossible for the heart to pump a sufficient amount of blood to the body. In such conditions unmaintained blood volume could lead to hypovolemic shock (hypovolemic shock could lead to damage of body organs e.g. kidney, brain, or gangrene of arms or legs). An untreated patient could develop cerebral atrophy. [ citation needed ] In cases that do not involve shock , treatment may involve proton pump inhibitors (such as omeprazole ) to treat stomach ulcers if they are present. This is given until endoscopy can be arranged. Blood transfusions may be given if the level of hemoglobin in the blood is extremely low, that is less than 8.0 g/dL or 4.5–5.0 mmol/L. A patient may be kept nothing by mouth (or no eating or drinking). Adequate venous access (such as with large-bore cannulas or a central venous catheter ) is generally obtained, in case the patient develops a further bleed and becomes unstable. In a "hemodynamically significant" case of hematemesis, there may be shock . Resuscitation is an immediate priority to prevent death. Intravenous fluids and blood transfusions can be given, preferably by large-bore intravenous cannula. The patient is prepared for emergency endoscopy, which is typically done in a operating theatre . Surgical opinion is usually sought in case the source of bleeding cannot be identified endoscopically, and laparotomy is necessary. Securing the airway is a top priority in hematemesis patients, especially those with a disturbed conscious level (hepatic encephalopathy in esophageal varices patient). This may be achieved with a cuffed endotracheal tube . Octreotide may be used if bleeding may be caused by varices . Hematemesis, melena , and hematochezia are symptoms of acute gastrointestinal bleeding. Bleeding that brings the patient to the physician is a potential emergency and must be considered as such until its seriousness can be evaluated. The goals in managing a major acute gastrointestinal hemorrhage are to treat hypovolemia by restoring the blood volume to normal, to make a diagnosis of the bleeding site and its underlying cause, and to treat the cause of the bleeding as definitively as possible. The history should be directed toward (1) confirming the presence of bleeding; (2) estimating its amount and rapidity; (3) identifying the source and potential specific causes; and (4) eliciting the presence of serious associated diseases that might adversely affect the outcome. The information obtained is especially helpful in identifying situations that require aggressive management.In cases that do not involve shock , treatment may involve proton pump inhibitors (such as omeprazole ) to treat stomach ulcers if they are present. This is given until endoscopy can be arranged. Blood transfusions may be given if the level of hemoglobin in the blood is extremely low, that is less than 8.0 g/dL or 4.5–5.0 mmol/L. A patient may be kept nothing by mouth (or no eating or drinking). Adequate venous access (such as with large-bore cannulas or a central venous catheter ) is generally obtained, in case the patient develops a further bleed and becomes unstable.In a "hemodynamically significant" case of hematemesis, there may be shock . Resuscitation is an immediate priority to prevent death. Intravenous fluids and blood transfusions can be given, preferably by large-bore intravenous cannula. The patient is prepared for emergency endoscopy, which is typically done in a operating theatre . Surgical opinion is usually sought in case the source of bleeding cannot be identified endoscopically, and laparotomy is necessary. Securing the airway is a top priority in hematemesis patients, especially those with a disturbed conscious level (hepatic encephalopathy in esophageal varices patient). This may be achieved with a cuffed endotracheal tube . Octreotide may be used if bleeding may be caused by varices . Hematemesis, melena , and hematochezia are symptoms of acute gastrointestinal bleeding. Bleeding that brings the patient to the physician is a potential emergency and must be considered as such until its seriousness can be evaluated. The goals in managing a major acute gastrointestinal hemorrhage are to treat hypovolemia by restoring the blood volume to normal, to make a diagnosis of the bleeding site and its underlying cause, and to treat the cause of the bleeding as definitively as possible. The history should be directed toward (1) confirming the presence of bleeding; (2) estimating its amount and rapidity; (3) identifying the source and potential specific causes; and (4) eliciting the presence of serious associated diseases that might adversely affect the outcome. The information obtained is especially helpful in identifying situations that require aggressive management.

Wiki

Acute hemorrhagic fever syndrome

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Hyperthermia

Hyperthermia , also known simply as overheating , is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation . The person's body produces or absorbs more heat than it dissipates. When extreme temperature elevation occurs, it becomes a medical emergency requiring immediate treatment to prevent disability or death. [ citation needed ] Almost half a million deaths are recorded every year from hyperthermia. [ citation needed ] The most common causes include heat stroke and adverse reactions to drugs. Heat stroke is an acute temperature elevation caused by exposure to excessive heat, or combination of heat and humidity, that overwhelms the heat-regulating mechanisms of the body. The latter is a relatively rare side effect of many drugs, particularly those that affect the central nervous system . Malignant hyperthermia is a rare complication of some types of general anesthesia . Hyperthermia can also be caused by a traumatic brain injury . Hyperthermia differs from fever in that the body's temperature set point remains unchanged. The opposite is hypothermia , which occurs when the temperature drops below that required to maintain normal metabolism. The term is from Greek ὑπέρ, hyper , meaning "above", and θέρμος, thermos , meaning "heat".In humans, hyperthermia is defined as a temperature greater than 37.5–38.3 °C (99.5–100.9 °F) , depending on the reference used, that occurs without a change in the body's temperature set point . The normal human body temperature can be as high as 37.7 °C (99.9 °F) in the late afternoon. Hyperthermia requires an elevation from the temperature that would otherwise be expected. Such elevations range from mild to extreme; body temperatures above 40 °C (104 °F) can be life-threatening.An early stage of hyperthermia can be "heat exhaustion" (or "heat prostration" or "heat stress"), whose symptoms can include heavy sweating, rapid breathing and a fast, weak pulse. If the condition progresses to heat stroke, then hot, dry skin is typical as blood vessels dilate in an attempt to increase heat loss. An inability to cool the body through perspiration may cause dry skin . Hyperthermia from neurological disease may include little or no sweating , cardiovascular problems, and confusion or delirium . Other signs and symptoms vary. Accompanying dehydration can produce nausea , vomiting, headaches , and low blood pressure and the latter can lead to fainting or dizziness , especially if the standing position is assumed quickly. In severe heat stroke, confusion and aggressive behavior may be observed. Heart rate and respiration rate will increase ( tachycardia and tachypnea ) as blood pressure drops and the heart attempts to maintain adequate circulation . The decrease in blood pressure can then cause blood vessels to contract reflexively, resulting in a pale or bluish skin color in advanced cases. Young children, in particular, may have seizures . Eventually, organ failure , unconsciousness and death will result.Heat stroke occurs when thermoregulation is overwhelmed by a combination of excessive metabolic production of heat (exertion), excessive environmental heat, and insufficient or impaired heat loss, resulting in an abnormally high body temperature. In severe cases, temperatures can exceed 40 °C (104 °F) . Heat stroke may be non-exertional (classic) or exertional . Significant physical exertion in hot conditions can generate heat beyond the ability to cool, because, in addition to the heat, humidity of the environment may reduce the efficiency of the body's normal cooling mechanisms. Human heat-loss mechanisms are limited primarily to sweating (which dissipates heat by evaporation , assuming sufficiently low humidity ) and vasodilation of skin vessels (which dissipates heat by convection proportional to the temperature difference between the body and its surroundings, according to Newton's law of cooling ). Other factors, such as insufficient water intake, consuming alcohol, or lack of air conditioning , can worsen the problem. The increase in body temperature that results from a breakdown in thermoregulation affects the body biochemically. Enzymes involved in metabolic pathways within the body such as cellular respiration fail to work effectively at higher temperatures, and further increases can lead them to denature , reducing their ability to catalyse essential chemical reactions. This loss of enzymatic control affects the functioning of major organs with high energy demands such as the heart and brain. Loss of fluid and electrolytes cause heat cramps – slow muscular contraction and severe muscular spasm lasting between one and three minutes. Almost all cases of heat cramps involve vigorous physical exertion. Body temperature may remain normal or a little higher than normal and cramps are concentrated in heavily used muscles. Situational heat stroke occurs in the absence of exertion. It mostly affects the young and elderly. In the elderly in particular, it can be precipitated by medications that reduce vasodilation and sweating, such as anticholinergic drugs, antihistamines, and diuretics. In this situation, the body's tolerance for high environmental temperature may be insufficient, even at rest. Heat waves are often followed by a rise in the death rate, and these 'classical hyperthermia' deaths typically involve the elderly and infirm. This is partly because thermoregulation involves cardiovascular, respiratory and renal systems which may be inadequate for the additional stress because of the existing burden of aging and disease, further compromised by medications. During the July 1995 heatwave in Chicago, there were at least 700 heat-related deaths. The strongest risk factors were being confined to bed, and living alone, while the risk was reduced for those with working air conditioners and those with access to transportation. Even then, reported deaths may be underestimated as diagnosis can be mis-classified as stroke or heart attack. Some drugs cause excessive internal heat production. The rate of drug-induced hyperthermia is higher where use of these drugs is higher. Those working in industry, in the military, or as first responders may be required to wear personal protective equipment (PPE) against hazards such as chemical agents, gases, fire, small arms and improvised explosive devices (IEDs). PPE includes a range of hazmat suits , firefighting turnout gear , body armor and bomb suits , among others. Depending on design, the wearer may be encapsulated in a microclimate, due to an increase in thermal resistance and decrease in vapor permeability. As physical work is performed, the body's natural thermoregulation (i.e. sweating) becomes ineffective. This is compounded by increased work rates, high ambient temperature and humidity levels, and direct exposure to the sun. The net effect is that desired protection from some environmental threats inadvertently increases the threat of heat stress. The effect of PPE on hyperthermia has been noted in fighting the 2014 Ebola virus epidemic in Western Africa. Doctors and healthcare workers were only able to work for 40 minutes at a time in their protective suits, fearing heat stroke. Other rare causes of hyperthermia include thyrotoxicosis and an adrenal gland tumor, called pheochromocytoma , both of which can cause increased heat production. Damage to the central nervous system from brain hemorrhage, traumatic brain injury, status epilepticus , and other kinds of injury to the hypothalamus can also cause hyperthermia. Significant physical exertion in hot conditions can generate heat beyond the ability to cool, because, in addition to the heat, humidity of the environment may reduce the efficiency of the body's normal cooling mechanisms. Human heat-loss mechanisms are limited primarily to sweating (which dissipates heat by evaporation , assuming sufficiently low humidity ) and vasodilation of skin vessels (which dissipates heat by convection proportional to the temperature difference between the body and its surroundings, according to Newton's law of cooling ). Other factors, such as insufficient water intake, consuming alcohol, or lack of air conditioning , can worsen the problem. The increase in body temperature that results from a breakdown in thermoregulation affects the body biochemically. Enzymes involved in metabolic pathways within the body such as cellular respiration fail to work effectively at higher temperatures, and further increases can lead them to denature , reducing their ability to catalyse essential chemical reactions. This loss of enzymatic control affects the functioning of major organs with high energy demands such as the heart and brain. Loss of fluid and electrolytes cause heat cramps – slow muscular contraction and severe muscular spasm lasting between one and three minutes. Almost all cases of heat cramps involve vigorous physical exertion. Body temperature may remain normal or a little higher than normal and cramps are concentrated in heavily used muscles.Situational heat stroke occurs in the absence of exertion. It mostly affects the young and elderly. In the elderly in particular, it can be precipitated by medications that reduce vasodilation and sweating, such as anticholinergic drugs, antihistamines, and diuretics. In this situation, the body's tolerance for high environmental temperature may be insufficient, even at rest. Heat waves are often followed by a rise in the death rate, and these 'classical hyperthermia' deaths typically involve the elderly and infirm. This is partly because thermoregulation involves cardiovascular, respiratory and renal systems which may be inadequate for the additional stress because of the existing burden of aging and disease, further compromised by medications. During the July 1995 heatwave in Chicago, there were at least 700 heat-related deaths. The strongest risk factors were being confined to bed, and living alone, while the risk was reduced for those with working air conditioners and those with access to transportation. Even then, reported deaths may be underestimated as diagnosis can be mis-classified as stroke or heart attack. Some drugs cause excessive internal heat production. The rate of drug-induced hyperthermia is higher where use of these drugs is higher. Those working in industry, in the military, or as first responders may be required to wear personal protective equipment (PPE) against hazards such as chemical agents, gases, fire, small arms and improvised explosive devices (IEDs). PPE includes a range of hazmat suits , firefighting turnout gear , body armor and bomb suits , among others. Depending on design, the wearer may be encapsulated in a microclimate, due to an increase in thermal resistance and decrease in vapor permeability. As physical work is performed, the body's natural thermoregulation (i.e. sweating) becomes ineffective. This is compounded by increased work rates, high ambient temperature and humidity levels, and direct exposure to the sun. The net effect is that desired protection from some environmental threats inadvertently increases the threat of heat stress. The effect of PPE on hyperthermia has been noted in fighting the 2014 Ebola virus epidemic in Western Africa. Doctors and healthcare workers were only able to work for 40 minutes at a time in their protective suits, fearing heat stroke. Other rare causes of hyperthermia include thyrotoxicosis and an adrenal gland tumor, called pheochromocytoma , both of which can cause increased heat production. Damage to the central nervous system from brain hemorrhage, traumatic brain injury, status epilepticus , and other kinds of injury to the hypothalamus can also cause hyperthermia. A fever occurs when the core temperature is set higher, through the action of the pre-optic region of the anterior hypothalamus . For example, in response to a bacterial or viral infection, certain white blood cells within the blood will release pyrogens which have a direct effect on the anterior hypothalamus, causing body temperature to rise, much like raising the temperature setting on a thermostat . In contrast, hyperthermia occurs when the body temperature rises without a change in the heat control centers. Some of the gastrointestinal symptoms of acute exertional heatstroke, such as vomiting, diarrhea, and gastrointestinal bleeding, may be caused by barrier dysfunction and subsequent endotoxemia . Ultraendurance athletes have been found to have significantly increased plasma endotoxin levels. Endotoxin stimulates many inflammatory cytokines, which in turn may cause multiorgan dysfunction. Experimentally, monkeys treated with oral antibiotics prior to induction of heat stroke do not become endotoxemic. There is scientific support for the concept of a temperature set point; that is, maintenance of an optimal temperature for the metabolic processes that life depends on. Nervous activity in the preoptic-anterior hypothalamus of the brain triggers heat losing (sweating, etc.) or heat generating (shivering and muscle contraction, etc.) activities through stimulation of the autonomic nervous system. The pre-optic anterior hypothalamus has been shown to contain warm sensitive, cool sensitive, and temperature insensitive neurons, to determine the body's temperature setpoint. As the temperature that these neurons are exposed to rises above 37 °C (99 °F) , the rate of electrical discharge of the warm-sensitive neurons increases progressively. Cold-sensitive neurons increase their rate of electrical discharge progressively below 37 °C (99 °F) . Hyperthermia is generally diagnosed by the combination of unexpectedly high body temperature and a history that supports hyperthermia instead of a fever. Most commonly this means that the elevated temperature has occurred in a hot, humid environment (heat stroke) or in someone taking a drug for which hyperthermia is a known side effect (drug-induced hyperthermia). The presence of signs and symptoms related to hyperthermia syndromes, such as extrapyramidal symptoms characteristic of neuroleptic malignant syndrome, and the absence of signs and symptoms more commonly related to infection-related fevers, are also considered in making the diagnosis. If fever-reducing drugs lower the body temperature, even if the temperature does not return entirely to normal, then hyperthermia is excluded. When ambient temperature is excessive, humans and many other animals cool themselves below ambient by evaporative cooling of sweat (or other aqueous liquid; saliva in dogs, for example); this helps prevent potentially fatal hyperthermia. The effectiveness of evaporative cooling depends upon humidity . Wet-bulb temperature , which takes humidity into account, or more complex calculated quantities such as wet-bulb globe temperature (WBGT), which also takes solar radiation into account, give useful indications of the degree of heat stress and are used by several agencies as the basis for heat-stress prevention guidelines. (Wet-bulb temperature is essentially the lowest skin temperature attainable by evaporative cooling at a given ambient temperature and humidity.) A sustained wet-bulb temperature exceeding 35 °C (95 °F) is likely to be fatal even to fit and healthy people unclothed in the shade next to a fan; at this temperature, environmental heat gain instead of loss occurs. As of 2012 [ update ] , wet-bulb temperatures only very rarely exceeded 30 °C (86 °F) anywhere, although significant global warming may change this. In cases of heat stress caused by physical exertion, hot environments, or protective equipment, prevention or mitigation by frequent rest breaks, careful hydration, and monitoring body temperature should be attempted. However, in situations demanding one is exposed to a hot environment for a prolonged period or must wear protective equipment, a personal cooling system is required as a matter of health and safety. There are a variety of active or passive personal cooling systems; these can be categorized by their power sources and whether they are person- or vehicle-mounted. Because of the broad variety of operating conditions, these devices must meet specific requirements concerning their rate and duration of cooling, their power source, and their adherence to health and safety regulations. Among other criteria are the user's need for physical mobility and autonomy. For example, active-liquid systems operate by chilling water and circulating it through a garment; the skin surface area is thereby cooled through conduction. This type of system has proven successful in certain military, law enforcement, and industrial applications. Bomb-disposal technicians wearing special suits to protect against improvised explosive devices (IEDs) use a small, ice-based chiller unit that is strapped to one leg; a liquid-circulating garment, usually a vest, is worn over the torso to maintain a safe core body temperature. By contrast, soldiers traveling in combat vehicles can face microclimate temperatures in excess of 65 °C (149 °F) and require a multiple-user, vehicle-powered cooling system with rapid connection capabilities. Requirements for hazmat teams, the medical community, and workers in heavy industry vary further.The underlying cause must be removed. Mild hyperthemia caused by exertion on a hot day may be adequately treated through self-care measures, such as increased water consumption and resting in a cool place. Hyperthermia that results from drug exposure requires prompt cessation of that drug, and occasionally the use of other drugs as counter measures. Antipyretics (e.g., acetaminophen , aspirin , other nonsteroidal anti-inflammatory drugs ) have no role in the treatment of heatstroke because antipyretics interrupt the change in the hypothalamic set point caused by pyrogens ; they are not expected to work on a healthy hypothalamus that has been overloaded, as in the case of heatstroke. In this situation, antipyretics actually may be harmful in patients who develop hepatic , hematologic , and renal complications because they may aggravate bleeding tendencies. When body temperature is significantly elevated, mechanical cooling methods are used to remove heat and to restore the body's ability to regulate its own temperatures. Passive cooling techniques, such as resting in a cool, shady area and removing clothing can be applied immediately. Active cooling methods, such as sponging the head, neck, and trunk with cool water, remove heat from the body and thereby speed the body's return to normal temperatures. When methods such as immersion are impractical, misting the body with water and using a fan have also been shown to be effective. Sitting in a bathtub of tepid or cool water (immersion method) can remove a significant amount of heat in a relatively short period of time. It was once thought that immersion in very cold water is counterproductive, as it causes vasoconstriction in the skin and thereby prevents heat from escaping the body core. However, a British analysis of various studies stated: "this has never been proven experimentally. Indeed, a recent study using normal volunteers has shown that cooling rates were fastest when the coldest water was used." The analysis concluded that iced water immersion is the most-effective cooling technique for exertional heat stroke. No superior cooling method has been found for non-exertional heat stroke . Thus, aggressive ice-water immersion remains the gold standard for life-threatening heat stroke . When the body temperature reaches about 40 °C (104 °F) , or if the affected person is unconscious or showing signs of confusion, hyperthermia is considered a medical emergency that requires treatment in a proper medical facility. In a hospital, more aggressive cooling measures are available, including intravenous hydration , gastric lavage with iced saline , and even hemodialysis to cool the blood. Hyperthermia affects those who are unable to regulate their body heat, mainly due to environmental conditions. The main risk factor for hyperthermia is the lack of ability to sweat. People who are dehydrated or who are older may not produce the sweat they need to regulate their body temperature. High heat conditions can put certain groups at risk for hyperthermia including: physically active individuals, soldiers, construction workers, landscapers and factory workers. Some people that do not have access to cooler living conditions, like people with lower socioeconomic status, may have a difficult time fighting the heat. People are at risk for hyperthermia during high heat and dry conditions, most commonly seen in the summer. Various cases of different types of hyperthermia have been reported. A research study was published in March 2019 that looked into multiple case reports of drug induced hyperthermia. The study concluded that psychotropic drugs such as anti-psychotics, antidepressants, and anxiolytics were associated with an increased heat-related mortality as opposed to the other drugs researched (anticholinergics, diuretics, cardiovascular agents, etc.). A different study was published in June 2019 that examined the association between hyperthermia in older adults and the temperatures in the United States. Hospitalization records of elderly patients in the US between 1991 and 2006 were analyzed and concluded that cases of hyperthermia were observed to be highest in regions with arid climates. The study discussed finding a disproportionately high number of cases of hyperthermia in early seasonal heat waves indicating that people were not yet practicing proper techniques to stay cool and prevent overheating in the early presence of warm, dry weather. In urban areas people are at an increased susceptibility to hyperthermia. This is due to a phenomenon called the urban heat island effect . Since the 20th century in the United States, the north-central region (Ohio, Indiana, Illinois, Missouri, Iowa, and Nebraska) was the region with the highest morbidity resulting from hyperthermia. Northeastern states had the next highest. Regions least affected by heat wave-related hyperthermia causing death were Southern and Pacific Coastal states. Northern cities in the United States are at greater risk of hyperthermia during heat waves due to the fact that people tend to have a lower minimum mortality temperature at higher latitudes. In contrast, cities residing in lower latitudes within the continental US typically have higher thresholds for ambient temperatures. In India, hundreds die every year from summer heat waves, including more than 2,500 in the year 2015 . Later that same summer, the 2015 Pakistani heat wave killed about 2,000 people. An extreme 2003 European heat wave caused tens of thousands of deaths. Causes of hyperthermia include dehydration, use of certain medications, using cocaine and amphetamines or excessive alcohol use. Bodily temperatures greater than 37.5–38.3 °C (99.5-101.0 °F) can be diagnosed as a hyperthermic case. As body temperatures increase or excessive body temperatures persist, individuals are at a heightened risk of developing progressive conditions. Greater risk complications of hyperthermia include heat stroke, organ malfunction, organ failure, and death. There are two forms of heat stroke ; classical heatstroke and exertional heatstroke. Classical heatstroke occurs from extreme environmental conditions, such as heat waves. Those who are most commonly affected by classical heatstroke are very young, elderly or chronically ill. Exertional heatstroke appears in individuals after vigorous physical activity. Exertional heatstroke is displayed most commonly in healthy 15-50 year old people. Sweating is often present in exertional heatstroke. The associated mortality rate of heatstroke is 40 to 64%. Hyperthermia can also be deliberately induced using drugs or medical devices, and is being studied and applied in clinical routine as a treatment of some kinds of cancer . Research has shown that medically controlled hyperthermia can shrink tumours. This occurs when a high body temperature damages cancerous cells by destroying proteins and structures within each cell. Hyperthermia has also been researched to investigate whether it causes cancerous tumours to be more prone to radiation as a form of treatment; which as a result has allowed hyperthermia to be used to compliment other forms of cancer therapy. Various techniques of hyperthermia in the treatment of cancer include local or regional hyperthermia, as well as whole body techniques.

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Acute hemorrhagic fever syndrome

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Escherichia coli O157:H7

Escherichia coli O157:H7 is a serotype of the bacterial species Escherichia coli and is one of the Shiga-like toxin–producing types of E. coli . It is a cause of disease , typically foodborne illness , through consumption of contaminated and raw food, including raw milk and undercooked ground beef . Infection with this type of pathogenic bacteria may lead to hemorrhagic diarrhea , and to kidney failure; these have been reported to cause the deaths of children younger than five years of age, of elderly patients, and of patients whose immune systems are otherwise compromised. Transmission is via the fecal–oral route , and most illness has been through distribution of contaminated raw leaf green vegetables, undercooked meat and raw milk. E. coli O157:H7 infection often causes severe, acute hemorrhagic diarrhea (although nonhemorrhagic diarrhea is also possible) and abdominal cramps . Usually little or no fever is present, and the illness resolves in 5 to 10 days. It can also sometimes be asymptomatic . In some people, particularly children under five years of age, persons whose immunologies are otherwise compromised, and the elderly, the infection can cause hemolytic–uremic syndrome (HUS), in which the red blood cells are destroyed and the kidneys fail. About 2–7% of infections lead to this complication. In the United States, HUS is the principal cause of acute kidney failure in children, and most cases of HUS are caused by E. coli O157:H7. [ citation needed ]Like the other strains of the E. coli , O157:H7 is gram-negative and oxidase-negative . Unlike many other strains, it does not ferment sorbitol , which provides a basis for clinical laboratory differentiation of the strain . Strains of E. coli that express Shiga and Shiga-like toxins gained that ability via infection with a prophage containing the structural gene coding for the toxin, and nonproducing strains may become infected and produce shiga-like toxins after incubation with shiga toxin positive strains. The prophage responsible seems to have infected the strain's ancestors fairly recently, as viral particles have been observed to replicate in the host if it is stressed in some way (e.g. antibiotics). All clinical isolates of E. coli O157:H7 possess the plasmid pO157 . The periplasmic catalase is encoded on pO157 and may enhance the virulence of the bacterium by providing additional oxidative protection when infecting the host. E. coli O157:H7 non-hemorrhagic strains are converted to hemorrhagic strains by lysogenic conversion after bacteriophage infection of non-hemorrhagic cells. [ citation needed ] While it is relatively uncommon, the E. coli serotype O157:H7 can naturally be found in the intestinal contents of some cattle, goats, and even sheep. [ citation needed ] The digestive tract of cattle lack the Shiga toxin receptor globotriaosylceramide , and thus, these can be asymptomatic carriers of the bacterium. The prevalence of E. coli O157:H7 in North American feedlot cattle herds ranges from 0 to 60%. Some cattle may also be so-called "super-shedders" of the bacterium. Super-shedders may be defined as cattle exhibiting rectoanal junction colonization and excreting >10 3 to 4 CFU g −1 feces. Super-shedders have been found to constitute a small proportion of the cattle in a feedlot (90% of all E. coli O157:H7 excreted. While it is relatively uncommon, the E. coli serotype O157:H7 can naturally be found in the intestinal contents of some cattle, goats, and even sheep. [ citation needed ] The digestive tract of cattle lack the Shiga toxin receptor globotriaosylceramide , and thus, these can be asymptomatic carriers of the bacterium. The prevalence of E. coli O157:H7 in North American feedlot cattle herds ranges from 0 to 60%. Some cattle may also be so-called "super-shedders" of the bacterium. Super-shedders may be defined as cattle exhibiting rectoanal junction colonization and excreting >10 3 to 4 CFU g −1 feces. Super-shedders have been found to constitute a small proportion of the cattle in a feedlot (90% of all E. coli O157:H7 excreted. Infection with E. coli O157:H7 can come from ingestion of contaminated food or water, or oral contact with contaminated surfaces. Examples of this can be undercooked ground beef but also leafy vegetables and raw milk. Fields often become contaminated with the bacterium through irrigation processes or contaminated water naturally entering the soil. It is highly virulent , with a low infectious dose : an inoculation of fewer than 10 to 100 colony-forming units (CFU) of E. coli O157:H7 is sufficient to cause infection, compared to over a million CFU for other pathogenic E. coli strains. A stool culture can detect the bacterium. The sample is cultured on sorbitol-MacConkey (SMAC) agar , or the variant cefixime potassium tellurite sorbitol-MacConkey agar (CT-SMAC ). On SMAC agar, O157:H7 colonies appear clear due to their inability to ferment sorbitol, while the colonies of the usual sorbitol-fermenting serotypes of E. coli appear red. Sorbitol non-fermenting colonies are tested for the somatic O157 antigen before being confirmed as E. coli O157:H7. Like all cultures, diagnosis is time-consuming with this method; swifter diagnosis is possible using quick E. coli DNA extraction method plus polymerase chain reaction techniques. Newer technologies using fluorescent and antibody detection are also under development. [ citation needed ]Avoiding the consumption of, or contact with, unpasteurized dairy products, undercooked beef, uncleaned vegetables, and non disinfected water reduces the risk of an E. coli infection. Proper hand washing with water that has been treated with adequate levels of chlorine or other effective disinfectants after using the lavatory or changing a diaper, especially among children or those with diarrhea, reduces the risk of transmission. E. coli O157:H7 infection is a nationally reportable disease in the US, Great Britain, and Germany. It is also reportable in most states of Australia including Queensland. E. coli O157:H7 infection is a nationally reportable disease in the US, Great Britain, and Germany. It is also reportable in most states of Australia including Queensland. While fluid replacement and blood pressure support may be necessary to prevent death from dehydration, most patients recover without treatment in 5–10 days. There is no evidence that antibiotics improve the course of disease, and treatment with antibiotics may precipitate hemolytic–uremic syndrome (HUS). The antibiotics are thought to trigger prophage induction, and the prophages released by the dying bacteria infect other susceptible bacteria, converting them into toxin-producing forms. Antidiarrheal agents, such as loperamide (imodium), should also be avoided as they may prolong the duration of the infection. [ citation needed ] Certain novel treatment strategies, such as the use of anti-induction strategies to prevent toxin production and the use of anti-Shiga toxin antibodies, have also been proposed.The first recorded observation of E. coli O157:H7 was in 1975, in association with a sporadic case of hemorrhagic colitis , but it was not identified as pathogenic then. It was first recognized as a human pathogen following a 1982 hemorrhagic colitis outbreak in Oregon and Michigan , in which at least 47 people were sickened by eating beef hamburger patties from a fast food chain that were found to be contaminated with it. The United States Department of Agriculture banned the sale of ground beef contaminated with the O157:H7 strain in 1994. The United States Department of Agriculture banned the sale of ground beef contaminated with the O157:H7 strain in 1994. The pathogen results in an estimated 2,100 hospitalizations annually in the United States. The illness is often misdiagnosed; therefore, expensive and invasive diagnostic procedures may be performed. Patients who develop HUS often require prolonged hospitalization, dialysis , and long-term followup. The pathogen results in an estimated 2,100 hospitalizations annually in the United States. The illness is often misdiagnosed; therefore, expensive and invasive diagnostic procedures may be performed. Patients who develop HUS often require prolonged hospitalization, dialysis , and long-term followup.

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Acute hemorrhagic fever syndrome

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Notifiable diseases in the United States

In the United States, the National Notifiable Disease Surveillance System (NNDSS) is responsible for sharing information regarding notifiable diseases . As of 2020, the following are the notifiable diseases in the US as mandated by the Centers for Disease Control and Prevention : Botulism, foodborne Botulism, infant Botulism, wound Botulism, other CP-CRE, Enterobacter spp. CP-CRE, Escherichia coli (E. coli) CP-CRE, Klebsiella spp. Dengue Dengue-like illness Severe dengue Anaplasma phagocytophilum infection Ehrlichia chaffeensis infection Ehrlichia ewingii infection Undetermined human ehrlichiosis/anaplasmosis Q fever, acute Q fever, chronic Rubella, congenital syndrome Syphilis, primary Syphilis, secondary Syphilis, early non-primary non-secondary Syphilis, unknown or late Crimean-Congo hemorrhagic fever virus Ebola virus Lassa virus Lujo virus Marburg virus New World arenavirus – Guanarito virus New World arenavirus – Junin virus New World arenavirus – Machupo virus New World arenavirus – Sabia virus Zika virus disease, congenital Zika virus disease, non-congenital Zika virus infection, congenital Zika virus infection, non-congenitalCancer Carbon monoxide poisoning Lead, elevated blood levels Lead, elevated blood levels, children (<16 Years) Lead, elevated blood levels, adult (≥16 Years) Pesticide-related illness and injury, acute Silicosis Lead, elevated blood levels, children (<16 Years) Lead, elevated blood levels, adult (≥16 Years)Foodborne disease outbreak Waterborne disease outbreak

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Acute hemorrhagic fever syndrome

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List of ICD-9 codes 390–459: diseases of the circulatory system

This is a shortened version of the seventh chapter of the ICD-9: Diseases of the Circulatory System . It covers ICD codes 259 to 282 . The full chapter can be found on pages 215 to 258 of Volume 1, which contains all (sub)categories of the ICD-9. Volume 2 is an alphabetical index of Volume 1. Both volumes can be downloaded for free from the website of the World Health Organization .

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Acute hemorrhagic fever syndrome

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Rabbit hemorrhagic disease

RHDV [FRG/89] (RHDV-FRG) RCV [ITL/95] (RHDV-RCV) RCV-A1 [MIC-07/2007/AU] (RHDV-RCV-A1) RHDV [Ashington/1998/UK] (RHDV-Ash) Rabbit hemorrhagic disease ( RHD ), also known as viral hemorrhagic disease (VHD), is a highly infectious and lethal form of viral hepatitis that affects European rabbits . Some viral strains also affect hares and cottontail rabbits. Mortality rates generally range from 70 to 100 percent. The disease is caused by strains of rabbit hemorrhagic disease virus ( RHDV ), a lagovirus in the family Caliciviridae .Rabbit hemorrhagic disease virus (RHDV) is a virus in the genus Lagovirus and the family Caliciviridae . It is a nonenveloped virus with a diameter around 35–40 nm, icosahedral symmetry, and a linear positive-sense RNA genome of 6.4–8.5 kb. RHDV causes a generalized infection in rabbits that is characterized by liver necrosis, disseminated intravascular coagulation, and rapid death. Division into serotypes has been defined by a lack of cross-neutralization using specific antisera. Rabbit lagoviruses also include related caliciviruses such as European brown hare syndrome virus . RHDV appears to have evolved from a pre-existing avirulent rabbit calicivirus (RCV). Nonpathogenic rabbit caliciviruses related to, but distinct from RHDV, had been circulating, apparently harmlessly, in Europe, Australia, and New Zealand prior to the emergence of RHDV. In the course of its evolution RHDV split into six distinct genotypes, all of which are highly pathogenic. The three strains of rabbit hemorrhagic disease virus of medical significance are RHDV, RHDVa and RHDV2. RHDV (also referred to as RHDV, RHDV1, or as classical RHD) only affects adult European rabbits ( Oryctolagus cuniculus ). This virus was first reported in China in 1984, from which it spread to much of Asia, Europe, Australia, and elsewhere. A few isolated outbreaks of RHDV have occurred in the United States and Mexico, but they remained localized and were eradicated. [ citation needed ] In 2010, a new lagovirus with a distinct antigenic profile was identified in France. The new virus, named rabbit hemorrhagic disease virus type 2 (abbreviated as RHDV2 or RHDVb), also caused RHD, but exhibited distinctive genetic, antigenic, and pathogenic features. Importantly, RHDV2 killed rabbits previously vaccinated with RHDV vaccines, and affected young European rabbits, as well as hares ( Lepus spp.). All these features strongly suggest that the virus was not derived from RHDVa, but from some other unknown source. RHDV2 has since spread to the majority of Europe, as well as to Australia, Canada, and the United States. Both viruses causing RHD are extremely contagious. Transmission occurs by direct contact with infected animals, carcasses, bodily fluids (urine, feces, respiratory secretions), and hair. Surviving rabbits may be contagious for up to 2 months. Contaminated fomites such as clothing, food, cages, bedding, feeders, and water also spread the virus. Flies, fleas, and mosquitoes can carry the virus between rabbits. Predators and scavengers can also spread the virus by shedding it in their feces. Caliciviruses are highly resistant in the environment, and can survive freezing for prolonged periods. The virus can persist in infected meat for months, and for prolonged periods in decomposing carcasses. Importation of rabbit meat may be a major contributor in the spread of the virus to new geographic regions. RHD outbreaks tend to be seasonal in wild rabbit populations, where most adults have survived infection and are immune. As young kits grow up and stop nursing, they no longer receive the antibodies provided in their mother's milk and become susceptible to infection. Thus, RHD epizootics occur more often during the rabbits' breeding season. Generally, high host specificity exists among lagoviruses. Classic RHDVa only affects European rabbits, a species native to Europe and from which the domestic rabbit is descended. The new variant RHDV2 affects European rabbits, as well, but also causes fatal RHD in various Lepus species, including Sardinian Cape hares ( L. capensis mediterraneus ), Italian hares ( L. corsicanus ), and mountain hares ( L. timidus ). Reports of RHD in Sylvilagus species have been coming from the current outbreak in the United States. RHD caused by RHDV and RHDVa demonstrates high morbidity (up to 100%) and mortality (40-100%) in adult European rabbits. Young rabbits 6–8 weeks old are less likely to be infected, and kits younger than 4 weeks old do not become ill. The more recently emerged RHDV2 causes death and disease in rabbits as young as 15 days old. Mortality rates from RHDV2 are more variable at 5-70%. Initially less virulent, the pathogenicity of RHDV2 has been increasing and is now similar to that found with RHDV and RHDVa. Deaths from RHDV2 have been confirmed in rabbits previously vaccinated against RHDVa. These viruses replicate in the liver and by mechanisms not fully elucidated, trigger the mass death of hepatocytes which can in turn lead to disseminated intravascular coagulation , hepatic encephalopathy , and nephrosis . Bleeding may occur, as clotting factors and platelets are used up.The incubation period for RHDVa is 1–2 days, and for RHDV2 3–5 days. Rabbits infected with RHDV2 are more likely to show subacute or chronic signs than are those infected with RHDVa. In rabbitries, an epidemic with high mortality rates in adult and subadult rabbits is typical. If the outbreak is caused by RHDV2, then deaths also occur in young rabbits. [ citation needed ] RHD can vary in the rate clinical signs occur. In peracute cases, rabbits are usually found dead with no premonitory symptoms. Rabbits may be observed grazing normally immediately before death. In acute cases, rabbits are inactive and reluctant to move. They may develop a fever up to 42 °C (107.6 °F) and have increased heart and respiratory rates. Bloody discharge from the nose, mouth, or vulva is common, as is blood in the feces or urine. Lateral recumbency, coma, and convulsions may be observed before death. Rabbits with the acute form generally die within 12 to 36 hours from the onset of fever. Subacute to chronic RHD has a more protracted clinical course, and is more commonly noted with RHDV2 infections. Clinical signs include lethargy, anorexia, weight loss, and jaundice . Gastrointestinal dilation, cardiac arrhythmias , heart murmurs , and neurologic abnormalities can also occur. Death, if it occurs, usually happens 1–2 weeks after the onset of symptoms, and is due to liver failure. Not all rabbits exposed to RHDVa or RHDV2 become overtly ill. A small proportion of infected rabbits clears the virus without developing signs of disease. Asymptomatic carriers also occur, and can continue to shed virus for months, thereby infecting other animals. Surviving rabbits develop a strong immunity to the specific viral variant with which they were infected. A presumptive diagnosis of RHD can often be made based on clinical presentation, infection pattern within a population, and post mortem lesions. Definitive diagnosis requires detection of the virus. As most caliciviruses cannot be grown in cell culture, antibody and nucleic acid based methods of viral detection are often used. Complete blood counts from rabbits with RHD often show low levels of white blood cells and platelets, and chemistry panels show elevated liver enzymes. Evidence of liver failure may also be present, including increased bile acids and bilirubin, and decreased glucose and cholesterol. Prolonged prothrombin and activated partial thromboplastin times are typical. Urinalysis can show bilirubinuria, proteinuria, and high urinary GGT. The classic post mortem lesion seen in rabbits with RHD is extensive hepatic necrosis. Multifocal hemorrhages, splenomegaly, bronchopneumonia, pulmonary hemorrhage or edema, and myocardial necrosis may sometimes also be seen. RT-qPCR tests are a commonly used and accurate testing modality for RNA-based viruses. Other tests used include enzyme-linked immunosorbent assay , electron microscopy , immunostaining , Western blot , and in situ hybridization . The tissue of choice for molecular testing is fresh or frozen liver, as it usually contains the largest numbers of virus, but if this is not available, spleen and serum can also be used. Identification of the strain of RHDV is needed so vaccination protocols can be adjusted accordingly. [ citation needed ]A number of vaccines available against RHD are sold in countries where the disease is endemic. All provide 12 months of protection against RHD viruses. Because RHD viruses cannot normally be grown in vitro , how these vaccines are produced is affected. Inactivated RHD vaccines, including Eravac, Felavac, and Cylap, are "liver-derived", meaning that laboratory rabbits are intentionally infected with RHD and their livers and spleens harvested to make vaccines. Each rabbit used results in the production of thousands of vaccine doses. This has led to controversy among rabbit lovers, who question the ethics of some rabbits having to die to protect others but is not an issue where rabbits are primarily farmed for meat. Another method of reproducing the virus is through recombinant technology, where antigenic portions of the RHD viruses are inserted into viruses that can be grown in culture. This is the method used to create Nobivac Myxo-RHD PLUS. Vaccines against only the classic RHDVa strain are: Cylap RCD Vaccine, made by Zoetis, protects rabbits from two different strains of RHDVa (v351 and K5) that are used for wild rabbit control in Australia. CUNIPRAVAC RHD, manufactured by HIPRA , protects against the RHDVa strains found in Europe. Nobivac Myxo-RHD, made by MSD Animal Health, is a live myxoma-vectored vaccine that offers one-year duration of immunity against both RHDVa and myxomatosis . [ citation needed ] Vaccines against only the newer RHDV2 strain are: Eravac vaccine, manufactured by HIPRA, protects rabbits against RHDV2 for a year. Vaccines that protect against both RHDVa and RHDV2 strains include: Filavac VHD K C+V, manufactured by Filavie, protects against both classical RHDVa and RHDV-2. It is available in single dose and multidose vials. A soon-to-be-released vaccine from MSD Animal Health, Nobivac Myxo-RHD PLUS, is a live recombinant vector vaccine active against both RHDVa and RHDV2, as well as myxomatosis. Countries in which RHD is not considered endemic may place restrictions on importation of RHDV vaccines. Importation of these vaccines into the United States can only be done with the approval of the United States Department of Agriculture and the appropriate state veterinarian. Caliciviruses are stable in the environment and difficult to inactivate. Products commonly used for household disinfection such as Clorox and Lysol disinfecting wipes do not work against these viruses. One effective option is to wipe down surfaces with a 10% bleach solution, allowing 10 minutes of contact time before rinsing. Other disinfectants shown to work include 10% sodium hydroxide , 2% One-Stroke Environ, Virkon S, Clorox Healthcare Bleach Germicidal Wipes, Trifectant, Rescue, and hydrogen peroxide cleaners. Surface debris must always be mechanically removed prior to disinfection. A list of disinfectants that are effective against calicivirus (in this case norovirus) can be found on the Environmental Protection Agency's website. Studies have shown that many quaternary ammonium compound based disinfectants do not inactivate caliciviruses. Because of the highly infectious nature of the disease, strict quarantine is necessary when outbreaks occur. Depopulation, disinfection, vaccination, surveillance, and quarantine are the only way to properly and effectively eradicate the disease. Deceased rabbits must be removed immediately and discarded in a safe manner. Surviving rabbits should be quarantined or humanely euthanized. Test rabbits may be used to monitor the virus on vaccinated farms. A number of vaccines available against RHD are sold in countries where the disease is endemic. All provide 12 months of protection against RHD viruses. Because RHD viruses cannot normally be grown in vitro , how these vaccines are produced is affected. Inactivated RHD vaccines, including Eravac, Felavac, and Cylap, are "liver-derived", meaning that laboratory rabbits are intentionally infected with RHD and their livers and spleens harvested to make vaccines. Each rabbit used results in the production of thousands of vaccine doses. This has led to controversy among rabbit lovers, who question the ethics of some rabbits having to die to protect others but is not an issue where rabbits are primarily farmed for meat. Another method of reproducing the virus is through recombinant technology, where antigenic portions of the RHD viruses are inserted into viruses that can be grown in culture. This is the method used to create Nobivac Myxo-RHD PLUS. Vaccines against only the classic RHDVa strain are: Cylap RCD Vaccine, made by Zoetis, protects rabbits from two different strains of RHDVa (v351 and K5) that are used for wild rabbit control in Australia. CUNIPRAVAC RHD, manufactured by HIPRA , protects against the RHDVa strains found in Europe. Nobivac Myxo-RHD, made by MSD Animal Health, is a live myxoma-vectored vaccine that offers one-year duration of immunity against both RHDVa and myxomatosis . [ citation needed ] Vaccines against only the newer RHDV2 strain are: Eravac vaccine, manufactured by HIPRA, protects rabbits against RHDV2 for a year. Vaccines that protect against both RHDVa and RHDV2 strains include: Filavac VHD K C+V, manufactured by Filavie, protects against both classical RHDVa and RHDV-2. It is available in single dose and multidose vials. A soon-to-be-released vaccine from MSD Animal Health, Nobivac Myxo-RHD PLUS, is a live recombinant vector vaccine active against both RHDVa and RHDV2, as well as myxomatosis. Countries in which RHD is not considered endemic may place restrictions on importation of RHDV vaccines. Importation of these vaccines into the United States can only be done with the approval of the United States Department of Agriculture and the appropriate state veterinarian. Caliciviruses are stable in the environment and difficult to inactivate. Products commonly used for household disinfection such as Clorox and Lysol disinfecting wipes do not work against these viruses. One effective option is to wipe down surfaces with a 10% bleach solution, allowing 10 minutes of contact time before rinsing. Other disinfectants shown to work include 10% sodium hydroxide , 2% One-Stroke Environ, Virkon S, Clorox Healthcare Bleach Germicidal Wipes, Trifectant, Rescue, and hydrogen peroxide cleaners. Surface debris must always be mechanically removed prior to disinfection. A list of disinfectants that are effective against calicivirus (in this case norovirus) can be found on the Environmental Protection Agency's website. Studies have shown that many quaternary ammonium compound based disinfectants do not inactivate caliciviruses. Because of the highly infectious nature of the disease, strict quarantine is necessary when outbreaks occur. Depopulation, disinfection, vaccination, surveillance, and quarantine are the only way to properly and effectively eradicate the disease. Deceased rabbits must be removed immediately and discarded in a safe manner. Surviving rabbits should be quarantined or humanely euthanized. Test rabbits may be used to monitor the virus on vaccinated farms. RHD is primarily a disease affecting European rabbits, which are native to the Iberian Peninsula and are found in the wild in much of Western Europe. Domesticated breeds are farmed throughout the world for meat and fur, and are becoming increasingly popular pets. European rabbits have been introduced to and become feral and sometimes invasive in Australia, New Zealand, Chile, Argentina, and various islands. RHD was first reported in 1984 in the People's Republic of China. Since then, RHD has spread to over 40 countries in Africa, the Americas, Asia, Europe, and Oceania , and is endemic in most parts of the world. In 2010, a new virus variant called rabbit hemorrhagic disease virus 2 (RHDV2) emerged in France. RHDV2 has since spread from France to the rest of Europe, Great Britain, Australia, and New Zealand. Outbreaks started occurring in the United States and Vancouver Island Canada in 2019. The first reported outbreak of RHD caused by RHDVa occurred in 1984 in the Jiangsu Province of the Mainland China . The outbreak occurred in a group of Angora rabbits that had been imported from Germany . The cause of the disease was determined to be a small, nonenveloped RNA virus. An inactivated vaccine was developed that proved effective in preventing disease. In less than a year, the disease spread over an area of 50,000 km 2 in China and killed 140 million domestic rabbits. South Korea was the next country to report RHD outbreaks following the importation of rabbit fur from Mainland China. RHD has since spread to and become endemic in many countries in Asia, including India and the Middle East. [ citation needed ] From China, RHDVa spread westward to Europe. The first report of RHD in Europe came from in Italy in 1986. From there, it spread to much of Europe. Spain's first reported case was in 1988, and France, Belgium, and Scandinavia followed in 1990. Spain experienced a large die-off of wild rabbits, which in turn caused a population decline in predators that normally ate rabbits, including the Iberian lynx and Spanish imperial eagle . RHD caused by RHDVa was reported for the first time in the United Kingdom in 1992. This initial epidemic was brought under control in the late 1990s using a combination of vaccination, strict biosecurity, and good husbandry. The newer viral strain RHDV2 was first detected in England and Wales in 2014, and soon spread to Scotland and Ireland. RHD was detected for the first time in Finland in 2016. The outbreak occurred in feral European rabbits, and genetic testing identified the viral strain as RHDV2. Cases of viral transmission to domesticated pet rabbits have been confirmed, and vaccinating rabbits has been recommended. In 1991, a strain of the RHDVa virus, Czech CAPM 351RHDV, was imported to Australia under strict quarantine conditions to research the safety and usefulness of the virus if it were used as a biological control agent against Australia and New Zealand's rabbit pest problem . Testing of the virus was undertaken on Wardang Island in Spencer Gulf off the coast of the Yorke Peninsula , South Australia . In 1995, the virus escaped quarantine and subsequently killed 10 million rabbits within 8 weeks of its release. In March 2017, a new Korean strain known as RHDV K5 was successfully released in a deliberate manner after almost a decade of research. This strain was chosen in part because it functions better in cool, wet regions where the previous Calicivirus was less effective. In July 1997, after considering over 800 public submissions, the New Zealand Ministry of Health decided not to allow RHDVa to be imported into New Zealand to control rabbit populations. However, in late August, RHDVa was confirmed to have been deliberately and illegally introduced to the Cromwell area of the South Island . An unsuccessful attempt was made by New Zealand officials to control the spread of the disease. It was, however, being intentionally spread, and several farmers (notably in the Mackenzie Basin area) admitted to processing rabbits that had died from the disease in kitchen blenders for further spreading. Had the disease been introduced at a better time, control of the population would have been more effective, but it was released after breeding had commenced for the season, and rabbits under 2 weeks old at the time of the introduction were resistant to the disease. These young rabbits were, therefore, able to survive and breed rabbit numbers back up. Ten years on, rabbit populations (in the Mackenzie Basin in particular) are beginning to reach near preplague proportions once again, though they have not yet returned to pre-RHD levels. Resistance to RHD in New Zealand rabbits has led to the widespread use of Compound 1080 (Sodium fluoroacetate) . The government and department of conservation are having to increase their use of 1080 to protect reserve land from rabbits and preserve the gains made in recent years through the use of RHD. Isolated outbreaks of RHDVa in domestic rabbits have occurred in the United States, the first of which was in Iowa in 2000. In 2001, outbreaks occurred in Utah, Illinois, and New York. More recent outbreaks of RHDVa have occurred in 2005 in Indiana and 2018 in Pennsylvania. Each of these outbreaks was contained and was the result of separate but indeterminable introductions of RHDVa. RHDVa does not affect the native cottontail and jackrabbits in the United States, so the virus did not become endemic. The first report of RHDV2 virus in North America was on a farm in Québec, in 2016. In 2018, a larger outbreak occurred in feral European rabbits on Delta and Vancouver Island, British Columbia. The disease was confirmed later that year in a pet rabbit in Ohio. In July 2019, the first case of RHDV2 in Washington was confirmed in a pet rabbit from Orcas Island . RHDV2 have been reported in domestic rabbits in Washington and New York. [ citation needed ] In 2020, outbreaks of the disease in domestic rabbits, as well as cottontail rabbits and hares, have been reported in Arizona, New Mexico, Colorado, Texas, Nevada, California and Utah. Affected wildlife include mountain cottontail rabbits ( Sylvilagus nutalli ), desert cottontail rabbits ( S. audubonii ), antelope jackrabbits ( L. alleni ), and black-tailed jackrabbits ( L. californicus ). The virus circulating in the Southwest United States is distinct from the RHDV2 isolated from New York, Washington, Ohio, and British Columbia, Canada. The sources of these outbreaks are unknown. In June 2022, a case occurred in Hawaii. It was first confirmed in a neutered hare on Maui. Department of Agriculture inspectors began testing after becoming aware of 9 rabbit deaths on a Maui farm. Mexico experienced an outbreak of RHDVa in domestic rabbits from 1989 to 1991, presumably following the importation of rabbit meat from the People's Republic of China. Strict quarantine and depopulation measures were able to eradicate the virus, and the country was officially declared to be RHD-free in 1993. A second outbreak of RHD in domestic rabbits began in the state of Chihuahua in April 2020 and has since spread to Sonora, Baja California, Baja California Sur, Coahuila, and Durango. As of 2021 and 2022, a RHD outbreak occurred in Hidalgo and the Mexico City Metropolitan Area . A mass disinfectant and vaccination campaign was ordered by the Directorate of Agricultural Development and over 390 thousand rabbits have received vaccinations. It has been confirmed ever since then, that the disease is present In Central Mexico . Since 1993, RHDVa has been endemic in Cuba. Four epizootics involving domesticated rabbits were reported in 1993, 1997, 2000–2001, and 2004–2005. As consequence, thousands of rabbits have died or have been slaughtered each time. The virus is also believed to be present in Bolivia . [ citation needed ]The first reported outbreak of RHD caused by RHDVa occurred in 1984 in the Jiangsu Province of the Mainland China . The outbreak occurred in a group of Angora rabbits that had been imported from Germany . The cause of the disease was determined to be a small, nonenveloped RNA virus. An inactivated vaccine was developed that proved effective in preventing disease. In less than a year, the disease spread over an area of 50,000 km 2 in China and killed 140 million domestic rabbits. South Korea was the next country to report RHD outbreaks following the importation of rabbit fur from Mainland China. RHD has since spread to and become endemic in many countries in Asia, including India and the Middle East. [ citation needed ]The first reported outbreak of RHD caused by RHDVa occurred in 1984 in the Jiangsu Province of the Mainland China . The outbreak occurred in a group of Angora rabbits that had been imported from Germany . The cause of the disease was determined to be a small, nonenveloped RNA virus. An inactivated vaccine was developed that proved effective in preventing disease. In less than a year, the disease spread over an area of 50,000 km 2 in China and killed 140 million domestic rabbits. South Korea was the next country to report RHD outbreaks following the importation of rabbit fur from Mainland China. RHD has since spread to and become endemic in many countries in Asia, including India and the Middle East. [ citation needed ]From China, RHDVa spread westward to Europe. The first report of RHD in Europe came from in Italy in 1986. From there, it spread to much of Europe. Spain's first reported case was in 1988, and France, Belgium, and Scandinavia followed in 1990. Spain experienced a large die-off of wild rabbits, which in turn caused a population decline in predators that normally ate rabbits, including the Iberian lynx and Spanish imperial eagle . RHD caused by RHDVa was reported for the first time in the United Kingdom in 1992. This initial epidemic was brought under control in the late 1990s using a combination of vaccination, strict biosecurity, and good husbandry. The newer viral strain RHDV2 was first detected in England and Wales in 2014, and soon spread to Scotland and Ireland. RHD was detected for the first time in Finland in 2016. The outbreak occurred in feral European rabbits, and genetic testing identified the viral strain as RHDV2. Cases of viral transmission to domesticated pet rabbits have been confirmed, and vaccinating rabbits has been recommended. RHD caused by RHDVa was reported for the first time in the United Kingdom in 1992. This initial epidemic was brought under control in the late 1990s using a combination of vaccination, strict biosecurity, and good husbandry. The newer viral strain RHDV2 was first detected in England and Wales in 2014, and soon spread to Scotland and Ireland. RHD was detected for the first time in Finland in 2016. The outbreak occurred in feral European rabbits, and genetic testing identified the viral strain as RHDV2. Cases of viral transmission to domesticated pet rabbits have been confirmed, and vaccinating rabbits has been recommended. In 1991, a strain of the RHDVa virus, Czech CAPM 351RHDV, was imported to Australia under strict quarantine conditions to research the safety and usefulness of the virus if it were used as a biological control agent against Australia and New Zealand's rabbit pest problem . Testing of the virus was undertaken on Wardang Island in Spencer Gulf off the coast of the Yorke Peninsula , South Australia . In 1995, the virus escaped quarantine and subsequently killed 10 million rabbits within 8 weeks of its release. In March 2017, a new Korean strain known as RHDV K5 was successfully released in a deliberate manner after almost a decade of research. This strain was chosen in part because it functions better in cool, wet regions where the previous Calicivirus was less effective. In July 1997, after considering over 800 public submissions, the New Zealand Ministry of Health decided not to allow RHDVa to be imported into New Zealand to control rabbit populations. However, in late August, RHDVa was confirmed to have been deliberately and illegally introduced to the Cromwell area of the South Island . An unsuccessful attempt was made by New Zealand officials to control the spread of the disease. It was, however, being intentionally spread, and several farmers (notably in the Mackenzie Basin area) admitted to processing rabbits that had died from the disease in kitchen blenders for further spreading. Had the disease been introduced at a better time, control of the population would have been more effective, but it was released after breeding had commenced for the season, and rabbits under 2 weeks old at the time of the introduction were resistant to the disease. These young rabbits were, therefore, able to survive and breed rabbit numbers back up. Ten years on, rabbit populations (in the Mackenzie Basin in particular) are beginning to reach near preplague proportions once again, though they have not yet returned to pre-RHD levels. Resistance to RHD in New Zealand rabbits has led to the widespread use of Compound 1080 (Sodium fluoroacetate) . The government and department of conservation are having to increase their use of 1080 to protect reserve land from rabbits and preserve the gains made in recent years through the use of RHD. In 1991, a strain of the RHDVa virus, Czech CAPM 351RHDV, was imported to Australia under strict quarantine conditions to research the safety and usefulness of the virus if it were used as a biological control agent against Australia and New Zealand's rabbit pest problem . Testing of the virus was undertaken on Wardang Island in Spencer Gulf off the coast of the Yorke Peninsula , South Australia . In 1995, the virus escaped quarantine and subsequently killed 10 million rabbits within 8 weeks of its release. In March 2017, a new Korean strain known as RHDV K5 was successfully released in a deliberate manner after almost a decade of research. This strain was chosen in part because it functions better in cool, wet regions where the previous Calicivirus was less effective. In July 1997, after considering over 800 public submissions, the New Zealand Ministry of Health decided not to allow RHDVa to be imported into New Zealand to control rabbit populations. However, in late August, RHDVa was confirmed to have been deliberately and illegally introduced to the Cromwell area of the South Island . An unsuccessful attempt was made by New Zealand officials to control the spread of the disease. It was, however, being intentionally spread, and several farmers (notably in the Mackenzie Basin area) admitted to processing rabbits that had died from the disease in kitchen blenders for further spreading. Had the disease been introduced at a better time, control of the population would have been more effective, but it was released after breeding had commenced for the season, and rabbits under 2 weeks old at the time of the introduction were resistant to the disease. These young rabbits were, therefore, able to survive and breed rabbit numbers back up. Ten years on, rabbit populations (in the Mackenzie Basin in particular) are beginning to reach near preplague proportions once again, though they have not yet returned to pre-RHD levels. Resistance to RHD in New Zealand rabbits has led to the widespread use of Compound 1080 (Sodium fluoroacetate) . The government and department of conservation are having to increase their use of 1080 to protect reserve land from rabbits and preserve the gains made in recent years through the use of RHD. Isolated outbreaks of RHDVa in domestic rabbits have occurred in the United States, the first of which was in Iowa in 2000. In 2001, outbreaks occurred in Utah, Illinois, and New York. More recent outbreaks of RHDVa have occurred in 2005 in Indiana and 2018 in Pennsylvania. Each of these outbreaks was contained and was the result of separate but indeterminable introductions of RHDVa. RHDVa does not affect the native cottontail and jackrabbits in the United States, so the virus did not become endemic. The first report of RHDV2 virus in North America was on a farm in Québec, in 2016. In 2018, a larger outbreak occurred in feral European rabbits on Delta and Vancouver Island, British Columbia. The disease was confirmed later that year in a pet rabbit in Ohio. In July 2019, the first case of RHDV2 in Washington was confirmed in a pet rabbit from Orcas Island . RHDV2 have been reported in domestic rabbits in Washington and New York. [ citation needed ] In 2020, outbreaks of the disease in domestic rabbits, as well as cottontail rabbits and hares, have been reported in Arizona, New Mexico, Colorado, Texas, Nevada, California and Utah. Affected wildlife include mountain cottontail rabbits ( Sylvilagus nutalli ), desert cottontail rabbits ( S. audubonii ), antelope jackrabbits ( L. alleni ), and black-tailed jackrabbits ( L. californicus ). The virus circulating in the Southwest United States is distinct from the RHDV2 isolated from New York, Washington, Ohio, and British Columbia, Canada. The sources of these outbreaks are unknown. In June 2022, a case occurred in Hawaii. It was first confirmed in a neutered hare on Maui. Department of Agriculture inspectors began testing after becoming aware of 9 rabbit deaths on a Maui farm. Mexico experienced an outbreak of RHDVa in domestic rabbits from 1989 to 1991, presumably following the importation of rabbit meat from the People's Republic of China. Strict quarantine and depopulation measures were able to eradicate the virus, and the country was officially declared to be RHD-free in 1993. A second outbreak of RHD in domestic rabbits began in the state of Chihuahua in April 2020 and has since spread to Sonora, Baja California, Baja California Sur, Coahuila, and Durango. As of 2021 and 2022, a RHD outbreak occurred in Hidalgo and the Mexico City Metropolitan Area . A mass disinfectant and vaccination campaign was ordered by the Directorate of Agricultural Development and over 390 thousand rabbits have received vaccinations. It has been confirmed ever since then, that the disease is present In Central Mexico . Since 1993, RHDVa has been endemic in Cuba. Four epizootics involving domesticated rabbits were reported in 1993, 1997, 2000–2001, and 2004–2005. As consequence, thousands of rabbits have died or have been slaughtered each time. The virus is also believed to be present in Bolivia . [ citation needed ]Isolated outbreaks of RHDVa in domestic rabbits have occurred in the United States, the first of which was in Iowa in 2000. In 2001, outbreaks occurred in Utah, Illinois, and New York. More recent outbreaks of RHDVa have occurred in 2005 in Indiana and 2018 in Pennsylvania. Each of these outbreaks was contained and was the result of separate but indeterminable introductions of RHDVa. RHDVa does not affect the native cottontail and jackrabbits in the United States, so the virus did not become endemic. The first report of RHDV2 virus in North America was on a farm in Québec, in 2016. In 2018, a larger outbreak occurred in feral European rabbits on Delta and Vancouver Island, British Columbia. The disease was confirmed later that year in a pet rabbit in Ohio. In July 2019, the first case of RHDV2 in Washington was confirmed in a pet rabbit from Orcas Island . RHDV2 have been reported in domestic rabbits in Washington and New York. [ citation needed ] In 2020, outbreaks of the disease in domestic rabbits, as well as cottontail rabbits and hares, have been reported in Arizona, New Mexico, Colorado, Texas, Nevada, California and Utah. Affected wildlife include mountain cottontail rabbits ( Sylvilagus nutalli ), desert cottontail rabbits ( S. audubonii ), antelope jackrabbits ( L. alleni ), and black-tailed jackrabbits ( L. californicus ). The virus circulating in the Southwest United States is distinct from the RHDV2 isolated from New York, Washington, Ohio, and British Columbia, Canada. The sources of these outbreaks are unknown. In June 2022, a case occurred in Hawaii. It was first confirmed in a neutered hare on Maui. Department of Agriculture inspectors began testing after becoming aware of 9 rabbit deaths on a Maui farm. Mexico experienced an outbreak of RHDVa in domestic rabbits from 1989 to 1991, presumably following the importation of rabbit meat from the People's Republic of China. Strict quarantine and depopulation measures were able to eradicate the virus, and the country was officially declared to be RHD-free in 1993. A second outbreak of RHD in domestic rabbits began in the state of Chihuahua in April 2020 and has since spread to Sonora, Baja California, Baja California Sur, Coahuila, and Durango. As of 2021 and 2022, a RHD outbreak occurred in Hidalgo and the Mexico City Metropolitan Area . A mass disinfectant and vaccination campaign was ordered by the Directorate of Agricultural Development and over 390 thousand rabbits have received vaccinations. It has been confirmed ever since then, that the disease is present In Central Mexico . Since 1993, RHDVa has been endemic in Cuba. Four epizootics involving domesticated rabbits were reported in 1993, 1997, 2000–2001, and 2004–2005. As consequence, thousands of rabbits have died or have been slaughtered each time. The virus is also believed to be present in Bolivia . [ citation needed ]

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Acute hemorrhagic fever syndrome

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Incubation period

Incubation period (also known as the latent period or latency period ) is the time elapsed between exposure to a pathogenic organism, a chemical, or radiation , and when symptoms and signs are first apparent. In a typical infectious disease, the incubation period signifies the period taken by the multiplying organism to reach a threshold necessary to produce symptoms in the host. While latent or latency period may be synonymous, a distinction is sometimes made whereby the latent period is defined as the time from infection to infectiousness. Which period is shorter depends on the disease. A person may carry a disease, such as Streptococcus in the throat, without exhibiting any symptoms. Depending on the disease, the person may or may not be contagious during the incubation period. During latency, an infection is subclinical . With respect to viral infections , in incubation the virus is replicating. This is in contrast to viral latency , a form of dormancy in which the virus does not replicate. An example of latency is HIV infection. HIV may at first have no symptoms and show no signs of AIDS , despite HIV replicating in the lymphatic system and rapidly accumulating a large viral load . People with HIV in this stage may be infectious .The terms "intrinsic incubation period" and "extrinsic incubation period" are used in vector-borne diseases . The intrinsic incubation period is the time taken by an organism to complete its development in the definitive host . The extrinsic incubation period is the time taken by an organism to develop in the intermediate host . [ citation needed ] For example, once ingested by a mosquito, malaria parasites must undergo development within the mosquito before they are infectious to humans. The time required for development in the mosquito ranges from 10 to 28 days, depending on the parasite species and the temperature. This is the extrinsic incubation period of that parasite. If a female mosquito does not survive longer than the extrinsic incubation period, then she will not be able to transmit any malaria parasites. [ citation needed ] But if a mosquito successfully transfers the parasite to a human body via a bite, the parasite starts developing. The time between the injection of the parasite into the human and the development of the first symptoms of malaria is its intrinsic incubation period. The specific incubation period for a disease process is the result of multiple factors, including: [ citation needed ] Dose or inoculum of an infectious agent Route of inoculation Rate of replication of infectious agent Host susceptibility Immune responseDue to inter-individual variation, the incubation period is always expressed as a range. When possible, it is best to express the mean and the 10th and 90th percentiles, though this information is not always available. For many conditions, incubation periods are longer in adults than they are in children or infants.

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Acute hemorrhagic fever syndrome

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Hughes–Stovin syndrome

Hughes–Stovin syndrome ( HSS ) is a rare autoimmune disorder often described as inflammation in relation to blood vessels , a form of vasculitis . It is not associated with any known cause and is typically characterized by multiple aneurysms in pulmonary arteries and deep vein thromboses . It is named after the two British physicians, John Patterson Hughes and Peter George Ingle Stovin, who first described it in 1959. HSS is presumed to be a rare variant of Behçet's disease , which entails more general problems with the circulatory system . Due to its clinical similarity with Behçet's disease, it has also been referred to as 'Incomplete Behçet's disease.' Most patients are young adult males between the age of 20–40. Common clinical presentations include fever , cough, dyspnea and hemoptysis . Radiological features are similar to those of Behçet's disease. The signs and symptoms of the disease are mostly associated by the diagnostic feature of the disease, the presence of both pulmonary artery aneurysms and deep vein thromboses . Other symptoms to this disease are typically secondary to these two conditions, the common reported clinical symptoms present in patients are listed below;The pathogenesis of this syndrome is still not clear and not complete, as there has not been enough studies on it, and therefore not enough published literature. It has been presumed that the possible causes of this syndrome include presence of infections and/or possibly angiodysplasia , characterized by vascular malformation of the gut. The possibility of the disease being a consequence of infections was ruled out as the use of antibiotics did not aid patients. Angiodysplasia could be an underlying cause of Hughes-Stovin as it can account for the vascular changes. As Hughes-Stovin syndrome is clinically considered an autoimmune disorder , the primary mechanism by which it precedes is presumed to be in the same manner as other autoimmune disorders, the syndrome occurs when the body begins attacking its own cells. This syndrome yields the inflammation of blood vessels in the body due to the body's overreactive immune system targeting affected cells. This causes coagulation , forming blood clots and begins the development of pulmonary aneurysms and thrombosis.The etiology or pathophysiology of the disease remains unclear. However, in recent years, Hughes-Stovin syndrome has been found to be potentially caused by systemic venous angiitis or collagen disease. Systemic venous angiitis or vasculitis is an inflammatory disease of the blood vessels walls, secondary to autoimmune diseases. It is essentially a T helper cell driven reaction, recruited by dendritic cells . The vascular impact can affect the blood circulation in the veins and thus give rise to the syndrome of Hughes-Stovin. It can occur in any type of artery or vein and cause the underlying main symptoms prevalent in the disease. This is presumed as Behçet's disease is caused by a similar form of vasculitis, and there is heavy vascular involvement in the disease. There is no rigid set of diagnostic criteria for Hughes-Stovin. Hughes-Stovin can be discerned from similar conditions by its resemblance to vasculitis without a presenting infection. The syndrome is also identified as being associated with pulmonary/bronchial artery aneurysms and thrombophlebitis, without the known diagnostic symptoms and features of Behçet's disease (BD)." However physicians have often diagnosed Hughes-Stovin syndrome by using one or more of these techniques; Physicians have to be able to differentiate between HSS and Behçet's disease , as HSS is often clinically considered a rare variant of this disease. The way they do this is through the absence of some of the more common symptoms of Behçet's disease, mouth and genital ulcers . Therefore, in the presence of multiple pulmonary artery aneurysms (PAA) and deep vein thrombosis , physicians differentiate between HSS and Behçet's disease and ultimately rule out Behçet's disease on the basis of the absence of skin-related findings. There is currently no satisfactory treatment for this condition. Immunosuppressive therapy is the most common treatment, involving a mix of glucocorticoids and cyclophosphamide . This is most effective in the early stages and may cause remission of the aneurysms, but is ineffective once the disease has progressed. The administration of corticosteroids , a type of steroid hormones, in combination with cytotoxic agents aid in the stabilization of the pulmonary artery aneurysms. Furthermore, the presence of thrombosis typically would require anticoagulants , however, they are typically not prescribed due to the possible life-threatening rupture of the pulmonary artery aneurysms. Therefore, if anticoagulants are given, this done in extensive care and in special cases. Depending on the state of the pulmonary artery aneurysms, surgery might also be an option when the aneurysm is localized, this would improve the state of the patient. Hughes-Stovin syndrome compromises of vein dysfunctions, formation of thrombosis and pulmonary aneurysms. The disease is noted to proceed in three main clinical stages; the first stage observed is regarded as thrombophlebitis symptoms. Thrombophlebitis typically occurs in the presence of an inflammation or injury related to the veins, where a blood clot forms. It can also proceed by the occurrence of frequent coagulation caused by the body. The second clinical stage is the formation of pulmonary artery aneurysms. The mechanism of the formation of pulmonary aneurysms is typically a result of inflammation. In most cases, the third stage is associated with aneurysm ruptures and massive blood loss, possibly resulting in fatal consequences. The syndrome is often detected very late in its precedence, relatively late in the course of the disease, therefore, it is associated with a significantly high rate of mortality. This is often associated with the high risk of blood loss as a result of a rupture of the pulmonary artery aneurysms or bronchial artery hypertrophy secondary to ischemia related to the pulmonary artery occlusion . The terminal events associated with this disease are typically due to the massive hemorrhage near lungs after rupture of the aneurysms. There is some existing evidence that suggests some success in managing the disease with immunosuppressive therapy, additionally, a lung transplant might also decrease the threat the disease presents. HSS is a largely rare disorder with less than 50 published English literature or case studies, therefore, population based incidence has yet to be specified. However, the disorder has been reported to be more prevalent among men aged 12-40, the young adult bracket with much less reported female incidence. The reported cases show no preponderance for a specific geographic location as the cases vary in precedent countries. The reported cases show a diverse geographical locations of occurrence, to exemplify; North America, Africa, Europe and Asia, therefore, no geographic location preponderance as case studies have been published all over the world. There is also no reported significance of genetic background of any familial predisposition. There is less than 50 published English literature on this condition, therefore, the available research can often be limited in providing thorough information on the syndrome. Therefore, some aspects of the illness are not adequately researched due to the lack of case reports. Authors have established a focus research group to establish the necessary information on Hughes-Stovin syndrome, the research group had been called HSS International Study Group, HSSISG. The research group hopes to gather available information on the syndrome to better assess the pathogenesis of the disease, its course of action and the way it progresses. This would allow the facilitation of early diagnosis and enhance the efficiency at which the syndrome is assessed, potentially reducing the risk of mortality. Recent research further emphasizes the need of early diagnosis, as multiple research presents patients with severe cases due to neglecting treatment. Overall, the available research is limited in providing knowledge on the mechanism and course of the disease, however, multiple cited research articles present the disease as an incomplete form of Behçet's disease . Current research presume the disease proceeds in a manner similar to Behçet's disease, with similar symptoms except skin findings. Furthermore, current research heavily consists of case studies that allows us to depict the similarities of patients suffering from Hughes-Stovin syndrome. Presented research also stresses the importance of early diagnosis and treatment to improve the prognosis of the disease and prevent fatal consequences. There is a clear need for further research to further investigate genetic, etiological and pathological basis for the disease.

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Acute hemorrhagic fever syndrome

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Hemoptysis

Hemoptysis or haemoptysis is the discharge of blood or blood-stained mucus through the mouth coming from the bronchi , larynx , trachea , or lungs . It does not necessarily involve coughing. In other words, it is the airway bleeding. This can occur with lung cancer , infections such as tuberculosis , bronchitis , or pneumonia , and certain cardiovascular conditions. Hemoptysis is considered massive at 300 mL (11 imp fl oz; 10 US fl oz) . In such cases, there are always severe injuries. The primary danger comes from choking , rather than blood loss . Past history, history of present illness, family history history of tuberculosis, bronchiectasis, chronic bronchitis, mitral stenosis, etc. history of cigarette smoking , occupational diseases by exposure to silica dust, etc. Blood duration, frequency, amount Amounts of blood: large amounts of blood, or is there blood-streaked sputum Probable source of bleeding: Is the blood coughed up, or vomited? Bloody sputum color, characters: blood-streaked, fresh blood, frothy pink, bloody gelatinous. Accompanying symptoms fever, chest pain, coughing, purulent sputum, mucocutaneous bleeding, jaundice. Imaging examination chest X-ray, CT scan and 3D reconstruction images or CT virtual bronchoscopy, bronchial angiography. Laboratory tests blood test: WBC Sputum: cells and bacterial examinations, sputum culture Bronchial fiber endoscopy history of tuberculosis, bronchiectasis, chronic bronchitis, mitral stenosis, etc. history of cigarette smoking , occupational diseases by exposure to silica dust, etc. duration, frequency, amount Amounts of blood: large amounts of blood, or is there blood-streaked sputum Probable source of bleeding: Is the blood coughed up, or vomited? color, characters: blood-streaked, fresh blood, frothy pink, bloody gelatinous. fever, chest pain, coughing, purulent sputum, mucocutaneous bleeding, jaundice. chest X-ray, CT scan and 3D reconstruction images or CT virtual bronchoscopy, bronchial angiography. blood test: WBC Sputum: cells and bacterial examinations, sputum cultureThe most common causes for hemoptysis in adults are chest infections such as bronchitis or pneumonia . In children, hemoptysis is commonly caused by the presence of a foreign body in the airway . Other common causes include lung cancers and tuberculosis . Less common causes include aspergilloma , bronchiectasis , coccidioidomycosis , pulmonary embolism , pneumonic plague , and cystic fibrosis . Rarer causes include hereditary hemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome), Goodpasture's syndrome , and granulomatosis with polyangiitis . A rare cause of hemoptysis in women is endometriosis , which leads to intermittent hemoptysis coinciding with menstrual periods in 7% of women with thoracic endometriosis syndrome. Hemoptysis may be exacerbated or even caused by overtreatment with anticoagulant drugs such as warfarin . [ citation needed ] Blood-laced mucus from the sinus or nose area can sometimes be misidentified as symptomatic of hemoptysis (such secretions can be a sign of nasal or sinus cancer , but also a sinus infection ). Extensive non-respiratory injury can also cause one to cough up blood. Cardiac causes like congestive heart failure and mitral stenosis should be ruled out. The origin of blood can be identified by observing its color. Bright-red, foamy blood comes from the respiratory tract, whereas dark-red, coffee-colored blood comes from the gastrointestinal tract . Sometimes hemoptysis may be rust-colored. [ citation needed ]Although there are reports that the fatality rate is as high as 80%, the mortality rate for hospitalized hemoptysis patients is 9.4% (with n =28539), calculated from the data in the article by Kinoshita et al. This is probably the most reasonable figure considering the overwhelming number of cases. [ citation needed ] The general definition of massive hemoptysis is more than 200 ml within 24 hours, but there is a wide range in the literature (100-600 ml). Considering that the total volume of the tracheal and bronchial lumen is about 150 cc, it may be reasonable to define massive hemoptysis as 200 ml, which is a little more than 150 ml, in terms of setting the threshold for fatal hemoptysis. More than 400ml/day is not adequate for screening purposes. [ citation needed ]Treatment depends on the underlying cause. Treatments include iced saline , and topical vasoconstrictors such as adrenaline or vasopressin . Tranexamic acid was proved to improve in-hospital mortality. Selective bronchial intubation can be used to collapse the lung that is bleeding. Also, endobronchial tamponade can be used. Laser photocoagulation can be used to stop bleeding during bronchoscopy . Angiography of bronchial arteries can be performed to locate the bleeding, and it can often be embolized . Bronchial artery embolization (BAE) is the first line treatment nowadays. Surgical option is usually the last resort and can involve removal of a lung lobe or removal of the entire lung . Cough suppressants can increase the risk of choking.

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Acute hemorrhagic fever syndrome

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Enterovirus

See text Enterovirus is a genus of positive-sense single-stranded RNA viruses associated with several human and mammalian diseases. Enteroviruses are named by their transmission-route through the intestine ('enteric' meaning intestinal). Serologic studies have distinguished 71 human enterovirus serotypes on the basis of antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes on the basis of reduced or nonreciprocal cross-neutralization between variant strains. On the basis of their pathogenesis in humans and animals, the enteroviruses were originally classified into four groups, polioviruses , Coxsackie A viruses (CA), Coxsackie B viruses (CB), and echoviruses , but it was quickly realized that there were significant overlaps in the biological properties of viruses in the different groups. Enteroviruses isolated more recently are named with a system of consecutive numbers: EV-D68 , EV-B69, EV-D70, EV-A71 , etc., where genotyping is based on the VP1 capsid region. Enteroviruses affect millions of people worldwide each year and are often found in the respiratory secretions (e.g., saliva, sputum, or nasal mucus) and stool of an infected person. Historically, poliomyelitis was the most significant disease caused by an enterovirus, namely poliovirus . There are 81 non-polio and 3 polio enteroviruses that can cause disease in humans. Of the 81 non-polio types, there are 22 Coxsackie A viruses, 6 Coxsackie B viruses, 28 echoviruses, and 25 other enteroviruses. Poliovirus, as well as coxsackie and echovirus, is spread through the fecal–oral route . Infection can result in a wide variety of symptoms, including those of: mild respiratory illness ( the common cold ), hand, foot and mouth disease , acute hemorrhagic conjunctivitis , aseptic meningitis , myocarditis , severe neonatal sepsis -like disease, acute flaccid paralysis , and the related acute flaccid myelitis . Enteroviruses are members of the picornavirus family, a large and diverse group of small RNA viruses characterized by a single positive-strand genomic RNA. All enteroviruses contain a genome of approximately 7,500 bases and are known to have a high mutation rate due to low-fidelity replication and frequent recombination . After infection of the host cell, the genome is translated in a cap-independent manner into a single polyprotein , which is subsequently processed by virus-encoded proteases into the structural capsid proteins and the nonstructural proteins, which are mainly involved in the replication of the virus. RNA recombination appears to be a major driving force in the evolution of enteroviruses as well as in the shaping of their genetic architecture. The mechanism of recombination of the RNA genome likely involves template strand switching during RNA replication , a process known as copy choice recombination. RNA recombination is considered to be an adaptation for dealing with RNA genome damage and a source of genetic diversity . It is also a source of concern for vaccination strategies, because live attenuated/mutated strains used for vaccination could potentially recombine with wild-type related strains, as has been the case with circulating vaccine derived polio viruses (cVDPDs). The capsid region and especially VP1 is a recombination coldspot, and this is one of the main reasons to use this region for genotyping. However, the 5'UTR - capsid junction and the beginning of the P2 region have been observed to recombine very frequently, although recombinations do occur in the rest of the genome as well. Interestingly, the enterovirus species EV-A, EV-B, EV-C, EV-D have not been observed so far to exchange genomic regions among them, with the exception of the 5'UTR. Enteroviruses are a group of ubiquitous viruses that cause a number of infections which are usually mild. The genus picornavirus includes enteroviruses and rhinoviruses. Enterovirus A include coxsackievirus A2, A3, A4, A5, A6, A7, A8, A10, A12, A14, A16 and enterovirus A71, A76, A89, A90, A91, A92, A144, A119, A120, A121, A122 (simian virus 19), A123 (simian virus 43), A124 (simian virus 46), A125 (baboon enterovirus A13). Some viruses initially reported as novel have been found to be misidentified. Thus, coxsackievirus A23 is the same serotype as echovirus 9, and coxsackievirus A15 is the same serotype as coxsackievirus A11 and coxsackievirus A18 is the same serotype as coxsackievirus A13. [ citation needed ] Coxsackie A16 virus causes human hand, foot and mouth disease . [ citation needed ] Enterovirus B includes coxsackievirus B1,2,3,4,5,6; coxsackievirus A9; echovirus 1–33 and enterovirus B69–113. Coxsackie B viruses are found worldwide and can cause myocarditis (inflammation of the heart); pericarditis (inflammation of the sac surrounding the heart); meningitis (inflammation of the membranes that line the brain and spinal cord); and pancreatitis (inflammation of the pancreas). The Coxsackie B viruses are also reported to cause a spastic paralysis due to the degeneration of neuronal tissue and muscle injury. Infections usually occur during warm summer months with symptoms including exanthema, pleurodynia, flu-like illness consisting of fever, fatigue, malaise, myalgia, nausea, abdominal pain and vomiting. Echoviruses are a cause of many of the nonspecific viral infections that can range from minor illness to severe, potentially fatal conditions such as aseptic meningitis, encephalitis, paralysis and myocarditis. It is mainly found in the intestine, and can cause nervous disorders. Type B enteroviruses are responsible for a vast number of mild and acute infections. They have been reported to remain in the body causing persistent infections contributing to chronic diseases such as type I diabetes. Enterovirus C consists of polioviruses 1,2 and 3; coxsackieviruses A1, A11, A13, A18, A17, 20, A21, A22, A24 and enterovirus C95, C96, C99, C102, C104, C105, C109, C113, C118. The three serotypes of poliovirus, PV-1, PV-2, and PV-3 each have a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV-1 is the most common type to cause infection in humans; however, all three forms are extremely contagious spreading through person-to-person contact. Poliovirus causes Polio, or Poliomyelitis, which is a disabling and life-threatening disease that causes paresthesia, meningitis and permanent paralysis. Symptoms can include sore throat, fever, tiredness, nausea, headache and stomach pain although 72% of those that get infected will not display visible symptoms. There are two types of vaccines available to prevent polio: inactivated poliovirus vaccine given as an injection in the leg (IPV) or arm and oral poliovirus vaccine (OPV). The polio vaccine is highly efficacious giving protection to 99 out of 100 children vaccinated. Enteroviruses are capable of producing acute infections that are rapidly cleared by the adaptive immune response. However, genomic mutations which enterovirus B serotypes (such as coxsackievirus B and echovirus ) may acquire in the host during the acute phase of the infection can transform these viruses into the non-cytolytic form (also known as non-cytopathic or defective enterovirus), a form which is capable of causing persistent low-level infections in human tissues that can last indefinitely. This persistent non-cytolytic enterovirus is a mutated quasispecies , and such non-cytolytic infections have been found in the pancreas in type 1 diabetes , in chronic myocarditis and dilated cardiomyopathy , in valvular heart disease , in the muscles, intestines and brain in myalgic encephalomyelitis , and in Sjögren's syndrome . In these persistent infections, enteroviral RNA is present at low levels in the tissues (both as single-stranded viral RNA, and in the more immune resistant doubled-stranded RNA form). Some researchers believe this enteroviral RNA is just a remnant of the acute infection, although other scientists believe these persistent intracellular viral RNA infections may have pathological effects, playing a causal role their associated diseases. EV-D68 first was identified in California in 1962. Compared with other enteroviruses, it has been rarely reported in the U.S. in the past 40 years. Most people who get infected are infants, children, and teens. EV-D68 usually causes mild to severe respiratory illness; however, the full spectrum of EV-D68 illness is not well-defined. Most start with common cold symptoms of runny nose and cough. Some, but not all, may also have fever. For more severe cases, difficulty breathing, wheezing or problems catching your breath may occur. As of October 4, 2014, there has been one death in New Jersey directly linked to EV-D68, as well as one death in Rhode Island [ citation needed ] attributed to a combination of EV-D68 and sepsis caused by an infection of staphylococcus aureus. Enterovirus A71 (EV-A71) is notable as one of the major causative agents for hand, foot and mouth disease (HFMD), and is sometimes associated with severe central nervous system diseases. EV-A71 was first isolated and characterized from cases of neurological disease in California in 1969. To date, little is known about the molecular mechanisms of host response to EV-A71 infection, but increases in the level of mRNAs encoding chemokines, proteins involved in protein degradation, complement proteins, and proapoptotis proteins have been implicated. There are three serotypes of poliovirus, PV-1 , PV-2 , and PV-3 ; each with a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV-1 is the most common form encountered in nature; however, all three forms are extremely infectious . Poliovirus can affect the spinal cord and cause poliomyelitis . Polioviruses were formerly classified as a species belonging to the genus Enterovirus in the family Picornaviridae. The Poliovirus species has been eliminated from the genus Enterovirus. The following serotypes, Human poliovirus 1, Human poliovirus 2, and Human poliovirus 3, were assigned to the species Human enterovirus C, in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to Human enterovirus C. This has been ratified in April 2008. The 39th Executive Committee (EC39) of the International Committee on Taxonomy of Viruses (ICTV) met in Canada during June 2007 with new taxonomic proposals. Two of the proposals with three changes were: Proposals approved at the (EC39) meeting of 2007, were sent to members of ICTV via email for ratification and have become official taxonomy. There have been a total of 215 taxonomic proposals, which have been approved and ratified since the 8th ICTV Report of 2005. The ratification process was performed by email. The proposals were sent electronically via email on March 18, 2008, to ICTV members with a request to vote on whether to ratify the taxonomic proposals, with a 1-month deadline. The following are two of the taxonomic proposals with three changes that were ratified by ICTV members in April 2008: Picornaviruses 2005.261V.04: To remove the following species from the existing genus Enterovirus in the family Picornaviridae: Poliovirus. (Note: Poliovirus hereby loses its status as a virus species.) 2005.262V.04: To assign the following viruses to the species Human enterovirus C in the existing genus Enterovirus in the family Picornaviridae: Human poliovirus 1, Human poliovirus 2, Human poliovirus 3. (This is not strictly necessary as a taxonomic proposal because it concerns entities below the species level, but it is left in to clarify this reorganization of the Picornaviridae.) 2005.263V.04: To change the type species of the genus Enterovirus in the family Picornaviridae, from Poliovirus to Human enterovirus C. Enteroviruses are a group of ubiquitous viruses that cause a number of infections which are usually mild. The genus picornavirus includes enteroviruses and rhinoviruses. Enterovirus A include coxsackievirus A2, A3, A4, A5, A6, A7, A8, A10, A12, A14, A16 and enterovirus A71, A76, A89, A90, A91, A92, A144, A119, A120, A121, A122 (simian virus 19), A123 (simian virus 43), A124 (simian virus 46), A125 (baboon enterovirus A13). Some viruses initially reported as novel have been found to be misidentified. Thus, coxsackievirus A23 is the same serotype as echovirus 9, and coxsackievirus A15 is the same serotype as coxsackievirus A11 and coxsackievirus A18 is the same serotype as coxsackievirus A13. [ citation needed ] Coxsackie A16 virus causes human hand, foot and mouth disease . [ citation needed ] Enterovirus B includes coxsackievirus B1,2,3,4,5,6; coxsackievirus A9; echovirus 1–33 and enterovirus B69–113. Coxsackie B viruses are found worldwide and can cause myocarditis (inflammation of the heart); pericarditis (inflammation of the sac surrounding the heart); meningitis (inflammation of the membranes that line the brain and spinal cord); and pancreatitis (inflammation of the pancreas). The Coxsackie B viruses are also reported to cause a spastic paralysis due to the degeneration of neuronal tissue and muscle injury. Infections usually occur during warm summer months with symptoms including exanthema, pleurodynia, flu-like illness consisting of fever, fatigue, malaise, myalgia, nausea, abdominal pain and vomiting. Echoviruses are a cause of many of the nonspecific viral infections that can range from minor illness to severe, potentially fatal conditions such as aseptic meningitis, encephalitis, paralysis and myocarditis. It is mainly found in the intestine, and can cause nervous disorders. Type B enteroviruses are responsible for a vast number of mild and acute infections. They have been reported to remain in the body causing persistent infections contributing to chronic diseases such as type I diabetes. Enterovirus C consists of polioviruses 1,2 and 3; coxsackieviruses A1, A11, A13, A18, A17, 20, A21, A22, A24 and enterovirus C95, C96, C99, C102, C104, C105, C109, C113, C118. The three serotypes of poliovirus, PV-1, PV-2, and PV-3 each have a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV-1 is the most common type to cause infection in humans; however, all three forms are extremely contagious spreading through person-to-person contact. Poliovirus causes Polio, or Poliomyelitis, which is a disabling and life-threatening disease that causes paresthesia, meningitis and permanent paralysis. Symptoms can include sore throat, fever, tiredness, nausea, headache and stomach pain although 72% of those that get infected will not display visible symptoms. There are two types of vaccines available to prevent polio: inactivated poliovirus vaccine given as an injection in the leg (IPV) or arm and oral poliovirus vaccine (OPV). The polio vaccine is highly efficacious giving protection to 99 out of 100 children vaccinated. Enteroviruses are capable of producing acute infections that are rapidly cleared by the adaptive immune response. However, genomic mutations which enterovirus B serotypes (such as coxsackievirus B and echovirus ) may acquire in the host during the acute phase of the infection can transform these viruses into the non-cytolytic form (also known as non-cytopathic or defective enterovirus), a form which is capable of causing persistent low-level infections in human tissues that can last indefinitely. This persistent non-cytolytic enterovirus is a mutated quasispecies , and such non-cytolytic infections have been found in the pancreas in type 1 diabetes , in chronic myocarditis and dilated cardiomyopathy , in valvular heart disease , in the muscles, intestines and brain in myalgic encephalomyelitis , and in Sjögren's syndrome . In these persistent infections, enteroviral RNA is present at low levels in the tissues (both as single-stranded viral RNA, and in the more immune resistant doubled-stranded RNA form). Some researchers believe this enteroviral RNA is just a remnant of the acute infection, although other scientists believe these persistent intracellular viral RNA infections may have pathological effects, playing a causal role their associated diseases. EV-D68 first was identified in California in 1962. Compared with other enteroviruses, it has been rarely reported in the U.S. in the past 40 years. Most people who get infected are infants, children, and teens. EV-D68 usually causes mild to severe respiratory illness; however, the full spectrum of EV-D68 illness is not well-defined. Most start with common cold symptoms of runny nose and cough. Some, but not all, may also have fever. For more severe cases, difficulty breathing, wheezing or problems catching your breath may occur. As of October 4, 2014, there has been one death in New Jersey directly linked to EV-D68, as well as one death in Rhode Island [ citation needed ] attributed to a combination of EV-D68 and sepsis caused by an infection of staphylococcus aureus. Enterovirus A71 (EV-A71) is notable as one of the major causative agents for hand, foot and mouth disease (HFMD), and is sometimes associated with severe central nervous system diseases. EV-A71 was first isolated and characterized from cases of neurological disease in California in 1969. To date, little is known about the molecular mechanisms of host response to EV-A71 infection, but increases in the level of mRNAs encoding chemokines, proteins involved in protein degradation, complement proteins, and proapoptotis proteins have been implicated. There are three serotypes of poliovirus, PV-1 , PV-2 , and PV-3 ; each with a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV-1 is the most common form encountered in nature; however, all three forms are extremely infectious . Poliovirus can affect the spinal cord and cause poliomyelitis . Polioviruses were formerly classified as a species belonging to the genus Enterovirus in the family Picornaviridae. The Poliovirus species has been eliminated from the genus Enterovirus. The following serotypes, Human poliovirus 1, Human poliovirus 2, and Human poliovirus 3, were assigned to the species Human enterovirus C, in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to Human enterovirus C. This has been ratified in April 2008. The 39th Executive Committee (EC39) of the International Committee on Taxonomy of Viruses (ICTV) met in Canada during June 2007 with new taxonomic proposals. Two of the proposals with three changes were: Proposals approved at the (EC39) meeting of 2007, were sent to members of ICTV via email for ratification and have become official taxonomy. There have been a total of 215 taxonomic proposals, which have been approved and ratified since the 8th ICTV Report of 2005. The ratification process was performed by email. The proposals were sent electronically via email on March 18, 2008, to ICTV members with a request to vote on whether to ratify the taxonomic proposals, with a 1-month deadline. The following are two of the taxonomic proposals with three changes that were ratified by ICTV members in April 2008: Picornaviruses 2005.261V.04: To remove the following species from the existing genus Enterovirus in the family Picornaviridae: Poliovirus. (Note: Poliovirus hereby loses its status as a virus species.) 2005.262V.04: To assign the following viruses to the species Human enterovirus C in the existing genus Enterovirus in the family Picornaviridae: Human poliovirus 1, Human poliovirus 2, Human poliovirus 3. (This is not strictly necessary as a taxonomic proposal because it concerns entities below the species level, but it is left in to clarify this reorganization of the Picornaviridae.) 2005.263V.04: To change the type species of the genus Enterovirus in the family Picornaviridae, from Poliovirus to Human enterovirus C. Enteroviruses cause a wide range of symptoms, and while their long list of signs and symptoms should put them on the differential diagnosis list of many illnesses, they often go unnoticed. Enteroviruses can cause anything from rashes in small children, to summer colds, to encephalitis, to blurred vision, to pericarditis . Enteroviral infections have a great range in presentation and seriousness. Non polio enteroviruses cause 10–15 million infections and tens of thousands of hospitalizations in the US each year. Enteroviruses can be identified through cell culture or PCR assay, collected from fecal or respiratory specimens. Below are common enterovirus related diseases, including poliomyelitis. Encephalitis lethargica , the 1917–1926 "sleeping sickness". Enterovirus has been speculated to be connected with Type 1 diabetes . It has been proposed that type 1 diabetes is a virus-triggered autoimmune response in which the immune system attacks virus-infected cells along with the insulin-producing beta cells in the pancreas. A team working at University of Tampere, Finland identified the enterovirus Coxsackievirus B1 as possibly linked to type 1 diabetes (which is an autoimmune disease). Enteroviruses, including polioviruses, may be a cause of myalgic encephalomyelitis / chronic fatigue syndrome (CFS/ME). Encephalitis lethargica , the 1917–1926 "sleeping sickness". Enterovirus has been speculated to be connected with Type 1 diabetes . It has been proposed that type 1 diabetes is a virus-triggered autoimmune response in which the immune system attacks virus-infected cells along with the insulin-producing beta cells in the pancreas. A team working at University of Tampere, Finland identified the enterovirus Coxsackievirus B1 as possibly linked to type 1 diabetes (which is an autoimmune disease). Enteroviruses, including polioviruses, may be a cause of myalgic encephalomyelitis / chronic fatigue syndrome (CFS/ME). Most people who contract enterovirus have mild symptoms lasting about a week. Those with higher risk may have more complications, sometimes becoming fatal. The most common sign of enterovirus is a common cold . More intense symptoms of enterovirus include hypoxia , aseptic meningitis , conjunctivitis , hand, foot and mouth disease , and paralysis .Treatment for enteroviral infection is mainly supportive. In cases of pleurodynia, treatment consists of analgesics to relieve the severe pain that occurs in patients with the disease; in some severe cases, opiates may be needed. Treatment for aseptic meningitis caused by enteroviruses is also mainly symptomatic. In patients with enteroviral carditis, treatment consists of the prevention and treatment of complications such as arrhythmias , pericardial effusion , and cardiac failure . Other treatments that have been investigated for enteroviral carditis include intravenous immunoglobulin . The enterovirus genus includes the following fifteen species: These fifteen species' serotype include: Coxsackievirus Enterovirus A: serotypes CVA-2, CVA-3, CVA-4, CVA-5, CVA-6, CVA-7, CVA-8, CVA-10, CVA-12, CVA-14, and CVA-16. Enterovirus B: serotypes CVB-1, CVB-2, CVB-3, CVB-4, CVB-5, CVB-6, and CVA-9. Enterovirus C: serotypes CVA-1, CVA-11, CVA-13, CVA-17, CVA-19, CVA-20, CVA-21, CVA-22, and CVA-24. Echovirus Enterovirus B: serotypes E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-9 , E-11 through E-21, E-24, E-25, E-26, E-27, E-29, E-30, E-31, E32, and E-33. Enterovirus Enterovirus A: serotypes EV-A71 , EV-A76, EV-A89 through EV-A92, EV-A114, EV-A119, EV-A120, EV-A121, SV19, SV43, SV46, and BabEV-A13. Enterovirus B: serotypes EV-B69, EV-B73 through EV-B75, EV-B77 through EV-B88, EV-B93, EV-B97, EV-B98, EV-B100, EV-B101, EV-B106, EV-B107, EV-B110 through EV-B113, and SA5. Enterovirus C: serotypes EV-C95, EV-C96, EV-C99, EV-C102, EV-C104, EV-C105, EV-C109, EV-C113, EV-C116, EV-C117, and EV-C118. Enterovirus D: serotypes EV-D68 , EV-D70, EV-D94, EV-D111, and EV-D120. Enterovirus E: serotypes EV-E1, EV-E2, EV-E3, EV-E4, and EV-E5. Enterovirus F: serotypes EV-F1, EV-F2, EV-F3, EV-F4, EV-F5, EV-F6, and EV-F7. Enterovirus G: serotypes EV-G1 through EV-G20. Enterovirus H: serotype EV-H. Enterovirus I: serotype EV-I1 and EV-I2. Enterovirus J: serotypes: EV-J1, EV-J103, and EV-J108. Enterovirus K: serotype EV-K1 and EV-K2. Enterovirus L: serotype EV-L1. Rhinovirus Rhinovirus A: serotypes RV-A1, RV-A1B, RV-A2, RV-A7 through RV-A13, RV-A15, RV-A16, RV-A18 through RV-A25, RV-A28 through RV-A34, RV-A36, RV-A38 through RV-A41, RV-A43, RV-A45 through RV-A47, RV-A49 through RV-A51, RV-A53 through RV-A68, RV-A71, RV-A73 through RV-A78, RV-A80 through RV-A82, RV-A85, RV-A88 through RV-A90, RV-A94, RV-A96, and RV-A100 through RV-A108 Rhinovirus B: serotypes RV-B3 through RV-B6, RV-B14, RV-B17, RV-B26, RV-B27, RV-B35, RV-B37, RV-B42, RV-B48, RV-B52, RV-B69, RV-B70, RV-B72, RV-B79, RV-B83, RV-B84, RV-B86, RV-B91 through RV-B93, RV-B97, and RV-B99 through RV-B104 Rhinovirus C: serotypes RV-C1 through RV-C51, RV-C54, RV-C55, and RV-C56. Poliovirus Enterovirus C: serotypes PV-1, PV-2, and PV-3. Enterovirus A: serotypes CVA-2, CVA-3, CVA-4, CVA-5, CVA-6, CVA-7, CVA-8, CVA-10, CVA-12, CVA-14, and CVA-16. Enterovirus B: serotypes CVB-1, CVB-2, CVB-3, CVB-4, CVB-5, CVB-6, and CVA-9. Enterovirus C: serotypes CVA-1, CVA-11, CVA-13, CVA-17, CVA-19, CVA-20, CVA-21, CVA-22, and CVA-24. Enterovirus A: serotypes EV-A71 , EV-A76, EV-A89 through EV-A92, EV-A114, EV-A119, EV-A120, EV-A121, SV19, SV43, SV46, and BabEV-A13. Enterovirus B: serotypes EV-B69, EV-B73 through EV-B75, EV-B77 through EV-B88, EV-B93, EV-B97, EV-B98, EV-B100, EV-B101, EV-B106, EV-B107, EV-B110 through EV-B113, and SA5. Enterovirus C: serotypes EV-C95, EV-C96, EV-C99, EV-C102, EV-C104, EV-C105, EV-C109, EV-C113, EV-C116, EV-C117, and EV-C118. Enterovirus D: serotypes EV-D68 , EV-D70, EV-D94, EV-D111, and EV-D120. Enterovirus E: serotypes EV-E1, EV-E2, EV-E3, EV-E4, and EV-E5. Enterovirus F: serotypes EV-F1, EV-F2, EV-F3, EV-F4, EV-F5, EV-F6, and EV-F7. Enterovirus G: serotypes EV-G1 through EV-G20. Enterovirus H: serotype EV-H. Enterovirus I: serotype EV-I1 and EV-I2. Enterovirus J: serotypes: EV-J1, EV-J103, and EV-J108. Enterovirus K: serotype EV-K1 and EV-K2. Enterovirus L: serotype EV-L1. Rhinovirus A: serotypes RV-A1, RV-A1B, RV-A2, RV-A7 through RV-A13, RV-A15, RV-A16, RV-A18 through RV-A25, RV-A28 through RV-A34, RV-A36, RV-A38 through RV-A41, RV-A43, RV-A45 through RV-A47, RV-A49 through RV-A51, RV-A53 through RV-A68, RV-A71, RV-A73 through RV-A78, RV-A80 through RV-A82, RV-A85, RV-A88 through RV-A90, RV-A94, RV-A96, and RV-A100 through RV-A108 Rhinovirus B: serotypes RV-B3 through RV-B6, RV-B14, RV-B17, RV-B26, RV-B27, RV-B35, RV-B37, RV-B42, RV-B48, RV-B52, RV-B69, RV-B70, RV-B72, RV-B79, RV-B83, RV-B84, RV-B86, RV-B91 through RV-B93, RV-B97, and RV-B99 through RV-B104 Rhinovirus C: serotypes RV-C1 through RV-C51, RV-C54, RV-C55, and RV-C56.

Wiki

Acute hemorrhagic fever syndrome

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Meningitis

Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord , collectively called the meninges . The most common symptoms are fever , intense headache , vomiting and neck stiffness and occasionally photophobia . Other symptoms include confusion or altered consciousness , nausea , and an inability to tolerate light or loud noises . Young children often exhibit only nonspecific symptoms , such as irritability, drowsiness, or poor feeding. A non-blanching rash (a rash that does not fade when a glass is rolled over it) may also be present. The inflammation may be caused by infection with viruses , bacteria , fungi or parasites . Non-infectious causes include malignancy ( cancer ), subarachnoid hemorrhage , chronic inflammatory disease ( sarcoidosis ) and certain drugs . Meningitis can be life-threatening because of the inflammation's proximity to the brain and spinal cord; therefore, the condition is classified as a medical emergency . A lumbar puncture , in which a needle is inserted into the spinal canal to collect a sample of cerebrospinal fluid (CSF), can diagnose or exclude meningitis. Some forms of meningitis are preventable by immunization with the meningococcal , mumps , pneumococcal , and Hib vaccines . Giving antibiotics to people with significant exposure to certain types of meningitis may also be useful. The first treatment in acute meningitis consists of promptly giving antibiotics and sometimes antiviral drugs . Corticosteroids can also be used to prevent complications from excessive inflammation. Meningitis can lead to serious long-term consequences such as deafness , epilepsy , hydrocephalus , or cognitive deficits , especially if not treated quickly. In 2019, meningitis was diagnosed in about 7.7 million people worldwide, of whom 236,000 died, down from 433,000 deaths in 1990. With appropriate treatment, the risk of death in bacterial meningitis is less than 15%. Outbreaks of bacterial meningitis occur between December and June each year in an area of sub-Saharan Africa known as the meningitis belt . Smaller outbreaks may also occur in other areas of the world. The word meningitis comes from the Greek μῆνιγξ meninx , 'membrane', and the medical suffix -itis , 'inflammation'. In adults, the most common symptom of meningitis is a severe headache , occurring in almost 90% of cases of bacterial meningitis, followed by neck stiffness (the inability to flex the neck forward passively due to increased neck muscle tone and stiffness). The classic triad of diagnostic signs consists of neck stiffness, sudden high fever , and altered mental status ; however, all three features are present in only 44–46% of bacterial meningitis cases. If none of the three signs are present, acute meningitis is extremely unlikely. Other signs commonly associated with meningitis include photophobia (intolerance to bright light) and phonophobia (intolerance to loud noises). Small children often do not exhibit the aforementioned symptoms, and may only be irritable and look unwell. The fontanelle (the soft spot on the top of a baby's head) can bulge in infants aged up to 6 months. Other features that distinguish meningitis from less severe illnesses in young children are leg pain, cold extremities, and an abnormal skin color . Neck stiffness occurs in 70% of bacterial meningitis in adults. Other signs include the presence of positive Kernig's sign or Brudziński sign . Kernig's sign is assessed with the person lying supine , with the hip and knee flexed to 90 degrees. In a person with a positive Kernig's sign, pain limits passive extension of the knee. A positive Brudzinski's sign occurs when flexion of the neck causes involuntary flexion of the knee and hip. Although Kernig's sign and Brudzinski's sign are both commonly used to screen for meningitis, the sensitivity of these tests is limited. They do, however, have very good specificity for meningitis: the signs rarely occur in other diseases. Another test, known as the "jolt accentuation maneuver" helps determine whether meningitis is present in those reporting fever and headache. A person is asked to rapidly rotate the head horizontally; if this does not make the headache worse, meningitis is unlikely. Other problems can produce symptoms similar to those above, but from non-meningitic causes. This is called meningism or pseudomeningitis. Meningitis caused by the bacterium Neisseria meningitidis (known as "meningococcal meningitis") can be differentiated from meningitis with other causes by a rapidly spreading petechial rash , which may precede other symptoms. The rash consists of numerous small, irregular purple or red spots ("petechiae") on the trunk, lower extremities , mucous membranes, conjunctiva, and (occasionally) the palms of the hands or soles of the feet. The rash is typically non-blanching ; the redness does not disappear when pressed with a finger or a glass tumbler. Although this rash is not necessarily present in meningococcal meningitis, it is relatively specific for the disease; it does, however, occasionally occur in meningitis due to other bacteria. Other clues on the cause of meningitis may be the skin signs of hand, foot and mouth disease and genital herpes , both of which are associated with various forms of viral meningitis. Additional problems may occur in the early stage of the illness. These may require specific treatment, and sometimes indicate severe illness or worse prognosis. The infection may trigger sepsis , a systemic inflammatory response syndrome of falling blood pressure , fast heart rate , high or abnormally low temperature, and rapid breathing . Very low blood pressure may occur at an early stage, especially but not exclusively in meningococcal meningitis; this may lead to insufficient blood supply to other organs. Disseminated intravascular coagulation , the excessive activation of blood clotting , may obstruct blood flow to organs and paradoxically increase the bleeding risk. Gangrene of limbs can occur in meningococcal disease . Severe meningococcal and pneumococcal infections may result in hemorrhaging of the adrenal glands , leading to Waterhouse-Friderichsen syndrome , which is often fatal. The brain tissue may swell , pressure inside the skull may increase and the swollen brain may herniate through the skull base. This may be noticed by a decreasing level of consciousness , loss of the pupillary light reflex , and abnormal posturing . The inflammation of the brain tissue may also obstruct the normal flow of CSF around the brain ( hydrocephalus ). Seizures may occur for various reasons; in children, seizures are common in the early stages of meningitis (in 30% of cases) and do not necessarily indicate an underlying cause. Seizures may result from increased pressure and from areas of inflammation in the brain tissue. Focal seizures (seizures that involve one limb or part of the body), persistent seizures, late-onset seizures and those that are difficult to control with medication indicate a poorer long-term outcome. Inflammation of the meninges may lead to abnormalities of the cranial nerves , a group of nerves arising from the brain stem that supply the head and neck area and which control, among other functions, eye movement, facial muscles, and hearing. Visual symptoms and hearing loss may persist after an episode of meningitis. Inflammation of the brain ( encephalitis ) or its blood vessels ( cerebral vasculitis ), as well as the formation of blood clots in the veins ( cerebral venous thrombosis ), may all lead to weakness, loss of sensation, or abnormal movement or function of the part of the body supplied by the affected area of the brain. In adults, the most common symptom of meningitis is a severe headache , occurring in almost 90% of cases of bacterial meningitis, followed by neck stiffness (the inability to flex the neck forward passively due to increased neck muscle tone and stiffness). The classic triad of diagnostic signs consists of neck stiffness, sudden high fever , and altered mental status ; however, all three features are present in only 44–46% of bacterial meningitis cases. If none of the three signs are present, acute meningitis is extremely unlikely. Other signs commonly associated with meningitis include photophobia (intolerance to bright light) and phonophobia (intolerance to loud noises). Small children often do not exhibit the aforementioned symptoms, and may only be irritable and look unwell. The fontanelle (the soft spot on the top of a baby's head) can bulge in infants aged up to 6 months. Other features that distinguish meningitis from less severe illnesses in young children are leg pain, cold extremities, and an abnormal skin color . Neck stiffness occurs in 70% of bacterial meningitis in adults. Other signs include the presence of positive Kernig's sign or Brudziński sign . Kernig's sign is assessed with the person lying supine , with the hip and knee flexed to 90 degrees. In a person with a positive Kernig's sign, pain limits passive extension of the knee. A positive Brudzinski's sign occurs when flexion of the neck causes involuntary flexion of the knee and hip. Although Kernig's sign and Brudzinski's sign are both commonly used to screen for meningitis, the sensitivity of these tests is limited. They do, however, have very good specificity for meningitis: the signs rarely occur in other diseases. Another test, known as the "jolt accentuation maneuver" helps determine whether meningitis is present in those reporting fever and headache. A person is asked to rapidly rotate the head horizontally; if this does not make the headache worse, meningitis is unlikely. Other problems can produce symptoms similar to those above, but from non-meningitic causes. This is called meningism or pseudomeningitis. Meningitis caused by the bacterium Neisseria meningitidis (known as "meningococcal meningitis") can be differentiated from meningitis with other causes by a rapidly spreading petechial rash , which may precede other symptoms. The rash consists of numerous small, irregular purple or red spots ("petechiae") on the trunk, lower extremities , mucous membranes, conjunctiva, and (occasionally) the palms of the hands or soles of the feet. The rash is typically non-blanching ; the redness does not disappear when pressed with a finger or a glass tumbler. Although this rash is not necessarily present in meningococcal meningitis, it is relatively specific for the disease; it does, however, occasionally occur in meningitis due to other bacteria. Other clues on the cause of meningitis may be the skin signs of hand, foot and mouth disease and genital herpes , both of which are associated with various forms of viral meningitis. Additional problems may occur in the early stage of the illness. These may require specific treatment, and sometimes indicate severe illness or worse prognosis. The infection may trigger sepsis , a systemic inflammatory response syndrome of falling blood pressure , fast heart rate , high or abnormally low temperature, and rapid breathing . Very low blood pressure may occur at an early stage, especially but not exclusively in meningococcal meningitis; this may lead to insufficient blood supply to other organs. Disseminated intravascular coagulation , the excessive activation of blood clotting , may obstruct blood flow to organs and paradoxically increase the bleeding risk. Gangrene of limbs can occur in meningococcal disease . Severe meningococcal and pneumococcal infections may result in hemorrhaging of the adrenal glands , leading to Waterhouse-Friderichsen syndrome , which is often fatal. The brain tissue may swell , pressure inside the skull may increase and the swollen brain may herniate through the skull base. This may be noticed by a decreasing level of consciousness , loss of the pupillary light reflex , and abnormal posturing . The inflammation of the brain tissue may also obstruct the normal flow of CSF around the brain ( hydrocephalus ). Seizures may occur for various reasons; in children, seizures are common in the early stages of meningitis (in 30% of cases) and do not necessarily indicate an underlying cause. Seizures may result from increased pressure and from areas of inflammation in the brain tissue. Focal seizures (seizures that involve one limb or part of the body), persistent seizures, late-onset seizures and those that are difficult to control with medication indicate a poorer long-term outcome. Inflammation of the meninges may lead to abnormalities of the cranial nerves , a group of nerves arising from the brain stem that supply the head and neck area and which control, among other functions, eye movement, facial muscles, and hearing. Visual symptoms and hearing loss may persist after an episode of meningitis. Inflammation of the brain ( encephalitis ) or its blood vessels ( cerebral vasculitis ), as well as the formation of blood clots in the veins ( cerebral venous thrombosis ), may all lead to weakness, loss of sensation, or abnormal movement or function of the part of the body supplied by the affected area of the brain. Meningitis is typically caused by an infection . Most infections are due to viruses , and others due to bacteria , fungi , and parasites . Mostly the parasites are parasitic worms , but can also rarely include parasitic amoebae . Meningitis may also result from various non-infectious causes. The term aseptic meningitis refers to cases of meningitis in which no bacterial infection can be demonstrated. This type of meningitis is usually caused by viruses, but it may be due to bacterial infection that has already been partially treated, when bacteria disappear from the meninges, or when pathogens infect a space adjacent to the meninges (such as sinusitis ). Endocarditis (an infection of the heart valves which spreads small clusters of bacteria through the bloodstream) may cause aseptic meningitis. Aseptic meningitis may also result from infection with spirochetes , a group of bacteria that includes Treponema pallidum (the cause of syphilis ) and Borrelia burgdorferi (known for causing Lyme disease ), and may also result from cerebral malaria (malaria infecting the brain). The types of bacteria that cause bacterial meningitis vary according to the infected individual's age group. A head injury potentially allows nasal cavity bacteria to enter the meningeal space. Similarly, devices in the brain and meninges, such as cerebral shunts , extraventricular drains or Ommaya reservoirs , carry an increased risk of meningitis. In these cases, people are more likely to be infected with Staphylococci , Pseudomonas , and other Gram-negative bacteria . These pathogens are also associated with meningitis in people with an impaired immune system . An infection in the head and neck area, such as otitis media or mastoiditis , can lead to meningitis in a small proportion of people. Recipients of cochlear implants for hearing loss are more at risk for pneumococcal meningitis. In rare cases, Enterococcus spp. can be responsible for meningitis, both community and hospital-acquired, usually as a secondary result of trauma or surgery, or due to intestinal diseases (e.g., strongyloidiasis). Tuberculous meningitis , which is meningitis caused by Mycobacterium tuberculosis , is more common in people from countries in which tuberculosis is endemic, but is also encountered in people with immune problems, such as AIDS . Recurrent bacterial meningitis may be caused by persisting anatomical defects, either congenital or acquired, or by disorders of the immune system . Anatomical defects allow continuity between the external environment and the nervous system . The most common cause of recurrent meningitis is a skull fracture , particularly fractures that affect the base of the skull or extend towards the sinuses and petrous pyramids . Approximately 59% of recurrent meningitis cases are due to such anatomical abnormalities, 36% are due to immune deficiencies (such as complement deficiency , which predisposes especially to recurrent meningococcal meningitis), and 5% are due to ongoing infections in areas adjacent to the meninges. Viruses that cause meningitis include enteroviruses , herpes simplex virus (generally type 2, which produces most genital sores; less commonly type 1), varicella zoster virus (known for causing chickenpox and shingles ), mumps virus , HIV , LCMV , Arboviruses (acquired from a mosquito or other insect), and the influenza virus . Mollaret's meningitis is a chronic recurrent form of herpes meningitis; it is thought to be caused by herpes simplex virus type 2 . There are a number of risk factors for fungal meningitis , including the use of immunosuppressants (such as after organ transplantation ), HIV/AIDS , and the loss of immunity associated with aging. It is uncommon in those with a normal immune system but has occurred with medication contamination . Symptom onset is typically more gradual, with headaches and fever being present for at least a couple of weeks before diagnosis. The most common fungal meningitis is cryptococcal meningitis due to Cryptococcus neoformans . In Africa, cryptococcal meningitis is now the most common cause of meningitis in multiple studies, and it accounts for 20–25% of AIDS-related deaths in Africa. Other less common pathogenic fungi which can cause meningitis include: Coccidioides immitis , Histoplasma capsulatum , Blastomyces dermatitidis , and Candida species. A parasitic worm is often assumed to be the cause of eosinophilic meningitis when there is a predominance of eosinophils (a type of white blood cell) found in the cerebrospinal fluid. The most common parasites implicated are Angiostrongylus cantonensis , Gnathostoma spinigerum , Schistosoma , as well as the conditions cysticercosis , toxocariasis , baylisascariasis , paragonimiasis , and a number of rarer infections and noninfective conditions. Rarely, free-living parasitic amoebae can cause naegleriasis , also called amebic meningitis , a type of meningoencephalitis where not only the meninges are affected but also the brain tissue . Meningitis may occur as the result of several non-infectious causes: spread of cancer to the meninges ( malignant or neoplastic meningitis ) and certain drugs (mainly non-steroidal anti-inflammatory drugs , antibiotics and intravenous immunoglobulins ). It may also be caused by several inflammatory conditions, such as sarcoidosis (which is then called neurosarcoidosis ), connective tissue disorders such as systemic lupus erythematosus , and certain forms of vasculitis (inflammatory conditions of the blood vessel wall), such as Behçet's disease . Epidermoid cysts and dermoid cysts may cause meningitis by releasing irritant matter into the subarachnoid space. Rarely, migraine may cause meningitis, but this diagnosis is usually only made when other causes have been eliminated. The types of bacteria that cause bacterial meningitis vary according to the infected individual's age group. A head injury potentially allows nasal cavity bacteria to enter the meningeal space. Similarly, devices in the brain and meninges, such as cerebral shunts , extraventricular drains or Ommaya reservoirs , carry an increased risk of meningitis. In these cases, people are more likely to be infected with Staphylococci , Pseudomonas , and other Gram-negative bacteria . These pathogens are also associated with meningitis in people with an impaired immune system . An infection in the head and neck area, such as otitis media or mastoiditis , can lead to meningitis in a small proportion of people. Recipients of cochlear implants for hearing loss are more at risk for pneumococcal meningitis. In rare cases, Enterococcus spp. can be responsible for meningitis, both community and hospital-acquired, usually as a secondary result of trauma or surgery, or due to intestinal diseases (e.g., strongyloidiasis). Tuberculous meningitis , which is meningitis caused by Mycobacterium tuberculosis , is more common in people from countries in which tuberculosis is endemic, but is also encountered in people with immune problems, such as AIDS . Recurrent bacterial meningitis may be caused by persisting anatomical defects, either congenital or acquired, or by disorders of the immune system . Anatomical defects allow continuity between the external environment and the nervous system . The most common cause of recurrent meningitis is a skull fracture , particularly fractures that affect the base of the skull or extend towards the sinuses and petrous pyramids . Approximately 59% of recurrent meningitis cases are due to such anatomical abnormalities, 36% are due to immune deficiencies (such as complement deficiency , which predisposes especially to recurrent meningococcal meningitis), and 5% are due to ongoing infections in areas adjacent to the meninges. Viruses that cause meningitis include enteroviruses , herpes simplex virus (generally type 2, which produces most genital sores; less commonly type 1), varicella zoster virus (known for causing chickenpox and shingles ), mumps virus , HIV , LCMV , Arboviruses (acquired from a mosquito or other insect), and the influenza virus . Mollaret's meningitis is a chronic recurrent form of herpes meningitis; it is thought to be caused by herpes simplex virus type 2 . There are a number of risk factors for fungal meningitis , including the use of immunosuppressants (such as after organ transplantation ), HIV/AIDS , and the loss of immunity associated with aging. It is uncommon in those with a normal immune system but has occurred with medication contamination . Symptom onset is typically more gradual, with headaches and fever being present for at least a couple of weeks before diagnosis. The most common fungal meningitis is cryptococcal meningitis due to Cryptococcus neoformans . In Africa, cryptococcal meningitis is now the most common cause of meningitis in multiple studies, and it accounts for 20–25% of AIDS-related deaths in Africa. Other less common pathogenic fungi which can cause meningitis include: Coccidioides immitis , Histoplasma capsulatum , Blastomyces dermatitidis , and Candida species. A parasitic worm is often assumed to be the cause of eosinophilic meningitis when there is a predominance of eosinophils (a type of white blood cell) found in the cerebrospinal fluid. The most common parasites implicated are Angiostrongylus cantonensis , Gnathostoma spinigerum , Schistosoma , as well as the conditions cysticercosis , toxocariasis , baylisascariasis , paragonimiasis , and a number of rarer infections and noninfective conditions. Rarely, free-living parasitic amoebae can cause naegleriasis , also called amebic meningitis , a type of meningoencephalitis where not only the meninges are affected but also the brain tissue .Meningitis may occur as the result of several non-infectious causes: spread of cancer to the meninges ( malignant or neoplastic meningitis ) and certain drugs (mainly non-steroidal anti-inflammatory drugs , antibiotics and intravenous immunoglobulins ). It may also be caused by several inflammatory conditions, such as sarcoidosis (which is then called neurosarcoidosis ), connective tissue disorders such as systemic lupus erythematosus , and certain forms of vasculitis (inflammatory conditions of the blood vessel wall), such as Behçet's disease . Epidermoid cysts and dermoid cysts may cause meningitis by releasing irritant matter into the subarachnoid space. Rarely, migraine may cause meningitis, but this diagnosis is usually only made when other causes have been eliminated. The meninges comprise three membranes that, together with the cerebrospinal fluid , enclose and protect the brain and spinal cord (the central nervous system ). The pia mater is a delicate impermeable membrane that firmly adheres to the surface of the brain, following all the minor contours. The arachnoid mater (so named because of its spider-web-like appearance) is a loosely fitting sac on top of the pia mater. The subarachnoid space separates the arachnoid and pia mater membranes and is filled with cerebrospinal fluid. The outermost membrane, the dura mater , is a thick durable membrane, which is attached to both the arachnoid membrane and the skull. In bacterial meningitis, bacteria reach the meninges by one of two main routes: through the bloodstream (hematogenous spread) or through direct contact between the meninges and either the nasal cavity or the skin. In most cases, meningitis follows invasion of the bloodstream by organisms that live on mucosal surfaces such as the nasal cavity . This is often in turn preceded by viral infections, which break down the normal barrier provided by the mucosal surfaces. Once bacteria have entered the bloodstream, they enter the subarachnoid space in places where the blood–brain barrier is vulnerable – such as the choroid plexus . Meningitis occurs in 25% of newborns with bloodstream infections due to group B streptococci ; this phenomenon is much less common in adults. Direct contamination of the cerebrospinal fluid may arise from indwelling devices, skull fractures, or infections of the nasopharynx or the nasal sinuses that have formed a tract with the subarachnoid space (see above); occasionally, congenital defects of the dura mater can be identified. The large-scale inflammation that occurs in the subarachnoid space during meningitis is not a direct result of bacterial infection but can rather largely be attributed to the response of the immune system to the entry of bacteria into the central nervous system . When components of the bacterial cell membrane are identified by the immune cells of the brain ( astrocytes and microglia ), they respond by releasing large amounts of cytokines , hormone-like mediators that recruit other immune cells and stimulate other tissues to participate in an immune response. The blood–brain barrier becomes more permeable, leading to "vasogenic" cerebral edema (swelling of the brain due to fluid leakage from blood vessels). Large numbers of white blood cells enter the CSF, causing inflammation of the meninges and leading to "interstitial" edema (swelling due to fluid between the cells). In addition, the walls of the blood vessels themselves become inflamed (cerebral vasculitis), which leads to decreased blood flow and a third type of edema, "cytotoxic" edema . The three forms of cerebral edema all lead to increased intracranial pressure ; together with the lowered blood pressure often encountered in sepsis , this means that it is harder for blood to enter the brain; consequently brain cells are deprived of oxygen and undergo apoptosis ( programmed cell death ). Administration of antibiotics may initially worsen the process outlined above, by increasing the amount of bacterial cell membrane products released through the destruction of bacteria. Particular treatments, such as the use of corticosteroids , are aimed at dampening the immune system's response to this phenomenon. Diagnosing meningitis as promptly as possible can improve outcomes. There are no specific signs or symptoms that can indicate meningitis, and a lumbar puncture (spinal tap) to examine the cerebrospinal fluid is recommended for diagnosis. Lumbar puncture is contraindicated if there is a mass in the brain (tumor or abscess) or the intracranial pressure (ICP) is elevated, as it may lead to brain herniation . If someone is at risk for either a mass or raised ICP (recent head injury, a known immune system problem, localizing neurological signs, or evidence on examination of a raised ICP), a CT or MRI scan is recommended prior to the lumbar puncture. This applies in 45% of all adult cases. There are no physical tests that can rule out or determine if a person has meningitis. The jolt accentuation test is not specific or sensitive enough to completely rule out meningitis. If someone is suspected of having meningitis, blood tests are performed for markers of inflammation (e.g. C-reactive protein , complete blood count ), as well as blood cultures . If a CT or MRI is required before LP, or if LP proves difficult, professional guidelines suggest that antibiotics should be administered first to prevent delay in treatment, especially if this may be longer than 30 minutes. Often, CT or MRI scans are performed at a later stage to assess for complications of meningitis. In severe forms of meningitis, monitoring of blood electrolytes may be important; for example, hyponatremia is common in bacterial meningitis. The cause of hyponatremia, however, is controversial and may include dehydration, the inappropriate secretion of the antidiuretic hormone (SIADH), or overly aggressive intravenous fluid administration . A lumbar puncture is done by positioning the person, usually lying on the side, applying local anesthetic , and inserting a needle into the dural sac (a sac around the spinal cord) to collect cerebrospinal fluid (CSF). When this has been achieved, the "opening pressure" of the CSF is measured using a manometer . The pressure is normally between 6 and 18 cm water (cmH 2 O); in bacterial meningitis the pressure is usually elevated. In cryptococcal meningitis , intracranial pressure is markedly elevated. The initial appearance of the fluid may prove an indication of the nature of the infection: cloudy CSF indicates higher levels of protein, white and red blood cells and/or bacteria, and therefore may suggest bacterial meningitis. The CSF sample is examined for presence and types of white blood cells , red blood cells , protein content and glucose level. Gram staining of the sample may demonstrate bacteria in bacterial meningitis, but absence of bacteria does not exclude bacterial meningitis as they are only seen in 60% of cases; this figure is reduced by a further 20% if antibiotics were administered before the sample was taken. Gram staining is also less reliable in particular infections such as listeriosis . Microbiological culture of the sample is more sensitive (it identifies the organism in 70–85% of cases) but results can take up to 48 hours to become available. The type of white blood cell predominantly present (see table) indicates whether meningitis is bacterial (usually neutrophil-predominant) or viral (usually lymphocyte-predominant), although at the beginning of the disease this is not always a reliable indicator. Less commonly, eosinophils predominate, suggesting parasitic or fungal etiology, among others. The concentration of glucose in CSF is normally above 40% of that in blood. In bacterial meningitis it is typically lower; the CSF glucose level is therefore divided by the blood glucose (CSF glucose to serum glucose ratio). A ratio ≤0.4 is indicative of bacterial meningitis; in the newborn, glucose levels in CSF are normally higher, and a ratio below 0.6 (60%) is therefore considered abnormal. High levels of lactate in CSF indicate a higher likelihood of bacterial meningitis, as does a higher white blood cell count. If lactate levels are less than 35 mg/dl and the person has not previously received antibiotics then this may rule out bacterial meningitis. Various other specialized tests may be used to distinguish between different types of meningitis. A latex agglutination test may be positive in meningitis caused by Streptococcus pneumoniae , Neisseria meningitidis , Haemophilus influenzae , Escherichia coli and group B streptococci ; its routine use is not encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic. Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is of limited use unless other tests have been unhelpful. Polymerase chain reaction (PCR) is a technique used to amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA in cerebrospinal fluid; it is a highly sensitive and specific test since only trace amounts of the infecting agent's DNA is required. It may identify bacteria in bacterial meningitis and may assist in distinguishing the various causes of viral meningitis ( enterovirus , herpes simplex virus 2 and mumps in those not vaccinated for this). Serology (identification of antibodies to viruses) may be useful in viral meningitis. If tuberculous meningitis is suspected, the sample is processed for Ziehl–Neelsen stain , which has a low sensitivity, and tuberculosis culture, which takes a long time to process; PCR is being used increasingly. Diagnosis of cryptococcal meningitis can be made at low cost using an India ink stain of the CSF; however, testing for cryptococcal antigen in blood or CSF is more sensitive. A diagnostic and therapeutic difficulty is "partially treated meningitis", where there are meningitis symptoms after receiving antibiotics (such as for presumptive sinusitis ). When this happens, CSF findings may resemble those of viral meningitis, but antibiotic treatment may need to be continued until there is definitive positive evidence of a viral cause (e.g. a positive enterovirus PCR). Meningitis can be diagnosed after death has occurred. The findings from a post mortem are usually a widespread inflammation of the pia mater and arachnoid layers of the meninges. Neutrophil granulocytes tend to have migrated to the cerebrospinal fluid and the base of the brain, along with cranial nerves and the spinal cord , may be surrounded with pus – as may the meningeal vessels. A lumbar puncture is done by positioning the person, usually lying on the side, applying local anesthetic , and inserting a needle into the dural sac (a sac around the spinal cord) to collect cerebrospinal fluid (CSF). When this has been achieved, the "opening pressure" of the CSF is measured using a manometer . The pressure is normally between 6 and 18 cm water (cmH 2 O); in bacterial meningitis the pressure is usually elevated. In cryptococcal meningitis , intracranial pressure is markedly elevated. The initial appearance of the fluid may prove an indication of the nature of the infection: cloudy CSF indicates higher levels of protein, white and red blood cells and/or bacteria, and therefore may suggest bacterial meningitis. The CSF sample is examined for presence and types of white blood cells , red blood cells , protein content and glucose level. Gram staining of the sample may demonstrate bacteria in bacterial meningitis, but absence of bacteria does not exclude bacterial meningitis as they are only seen in 60% of cases; this figure is reduced by a further 20% if antibiotics were administered before the sample was taken. Gram staining is also less reliable in particular infections such as listeriosis . Microbiological culture of the sample is more sensitive (it identifies the organism in 70–85% of cases) but results can take up to 48 hours to become available. The type of white blood cell predominantly present (see table) indicates whether meningitis is bacterial (usually neutrophil-predominant) or viral (usually lymphocyte-predominant), although at the beginning of the disease this is not always a reliable indicator. Less commonly, eosinophils predominate, suggesting parasitic or fungal etiology, among others. The concentration of glucose in CSF is normally above 40% of that in blood. In bacterial meningitis it is typically lower; the CSF glucose level is therefore divided by the blood glucose (CSF glucose to serum glucose ratio). A ratio ≤0.4 is indicative of bacterial meningitis; in the newborn, glucose levels in CSF are normally higher, and a ratio below 0.6 (60%) is therefore considered abnormal. High levels of lactate in CSF indicate a higher likelihood of bacterial meningitis, as does a higher white blood cell count. If lactate levels are less than 35 mg/dl and the person has not previously received antibiotics then this may rule out bacterial meningitis. Various other specialized tests may be used to distinguish between different types of meningitis. A latex agglutination test may be positive in meningitis caused by Streptococcus pneumoniae , Neisseria meningitidis , Haemophilus influenzae , Escherichia coli and group B streptococci ; its routine use is not encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic. Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is of limited use unless other tests have been unhelpful. Polymerase chain reaction (PCR) is a technique used to amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA in cerebrospinal fluid; it is a highly sensitive and specific test since only trace amounts of the infecting agent's DNA is required. It may identify bacteria in bacterial meningitis and may assist in distinguishing the various causes of viral meningitis ( enterovirus , herpes simplex virus 2 and mumps in those not vaccinated for this). Serology (identification of antibodies to viruses) may be useful in viral meningitis. If tuberculous meningitis is suspected, the sample is processed for Ziehl–Neelsen stain , which has a low sensitivity, and tuberculosis culture, which takes a long time to process; PCR is being used increasingly. Diagnosis of cryptococcal meningitis can be made at low cost using an India ink stain of the CSF; however, testing for cryptococcal antigen in blood or CSF is more sensitive. A diagnostic and therapeutic difficulty is "partially treated meningitis", where there are meningitis symptoms after receiving antibiotics (such as for presumptive sinusitis ). When this happens, CSF findings may resemble those of viral meningitis, but antibiotic treatment may need to be continued until there is definitive positive evidence of a viral cause (e.g. a positive enterovirus PCR). Meningitis can be diagnosed after death has occurred. The findings from a post mortem are usually a widespread inflammation of the pia mater and arachnoid layers of the meninges. Neutrophil granulocytes tend to have migrated to the cerebrospinal fluid and the base of the brain, along with cranial nerves and the spinal cord , may be surrounded with pus – as may the meningeal vessels. For some causes of meningitis, protection can be provided in the long term through vaccination , or in the short term with antibiotics . Some behavioral measures may also be effective. Bacterial and viral meningitis are contagious, but neither is as contagious as the common cold or flu . Both can be transmitted through droplets of respiratory secretions during close contact such as kissing, sneezing or coughing on someone, but bacterial meningitis cannot be spread by only breathing the air where a person with meningitis has been. Viral meningitis is typically caused by enteroviruses , and is most commonly spread through fecal contamination. The risk of infection can be decreased by changing the behavior that led to transmission. Since the 1980s, many countries have included immunization against Haemophilus influenzae type B in their routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of meningitis in young children in those countries. In the countries in which the disease burden is highest, however, the vaccine is still too expensive. Similarly, immunization against mumps has led to a sharp fall in the number of cases of mumps meningitis, which prior to vaccination occurred in 15% of all cases of mumps. Meningococcus vaccines exist against groups A, B, C, W135 and Y. In countries where the vaccine for meningococcus group C was introduced, cases caused by this pathogen have decreased substantially. A quadrivalent vaccine now exists, which combines four vaccines with the exception of B; immunization with this ACW135Y vaccine is now a visa requirement for taking part in Hajj . Development of a vaccine against group B meningococci has proved much more difficult, as its surface proteins (which would normally be used to make a vaccine) only elicit a weak response from the immune system , or cross-react with normal human proteins. Still, some countries ( New Zealand , Cuba , Norway and Chile ) have developed vaccines against local strains of group B meningococci; some have shown good results and are used in local immunization schedules. Two new vaccines, both approved in 2014, are effective against a wider range of group B meningococci strains. In Africa, until recently, the approach for prevention and control of meningococcal epidemics was based on early detection of the disease and emergency reactive mass vaccination of the at-risk population with bivalent A/C or trivalent A/C/W135 polysaccharide vaccines, though the introduction of MenAfriVac (meningococcus group A vaccine) has demonstrated effectiveness in young people and has been described as a model for product development partnerships in resource-limited settings. Routine vaccination against Streptococcus pneumoniae with the pneumococcal conjugate vaccine (PCV), which is active against seven common serotypes of this pathogen, significantly reduces the incidence of pneumococcal meningitis. The pneumococcal polysaccharide vaccine , which covers 23 strains, is only administered to certain groups (e.g. those who have had a splenectomy , the surgical removal of the spleen); it does not elicit a significant immune response in all recipients, e.g. small children. Childhood vaccination with Bacillus Calmette-Guérin has been reported to significantly reduce the rate of tuberculous meningitis, but its waning effectiveness in adulthood has prompted a search for a better vaccine. Short-term antibiotic prophylaxis is another method of prevention, particularly of meningococcal meningitis. In cases of meningococcal meningitis, preventative treatment in close contacts with antibiotics (e.g. rifampicin , ciprofloxacin or ceftriaxone ) can reduce their risk of contracting the condition, but does not protect against future infections. Resistance to rifampicin has been noted to increase after use, which has caused some to recommend considering other agents. While antibiotics are frequently used in an attempt to prevent meningitis in those with a basilar skull fracture there is not enough evidence to determine whether this is beneficial or harmful. This applies to those with or without a CSF leak. Bacterial and viral meningitis are contagious, but neither is as contagious as the common cold or flu . Both can be transmitted through droplets of respiratory secretions during close contact such as kissing, sneezing or coughing on someone, but bacterial meningitis cannot be spread by only breathing the air where a person with meningitis has been. Viral meningitis is typically caused by enteroviruses , and is most commonly spread through fecal contamination. The risk of infection can be decreased by changing the behavior that led to transmission.Since the 1980s, many countries have included immunization against Haemophilus influenzae type B in their routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of meningitis in young children in those countries. In the countries in which the disease burden is highest, however, the vaccine is still too expensive. Similarly, immunization against mumps has led to a sharp fall in the number of cases of mumps meningitis, which prior to vaccination occurred in 15% of all cases of mumps. Meningococcus vaccines exist against groups A, B, C, W135 and Y. In countries where the vaccine for meningococcus group C was introduced, cases caused by this pathogen have decreased substantially. A quadrivalent vaccine now exists, which combines four vaccines with the exception of B; immunization with this ACW135Y vaccine is now a visa requirement for taking part in Hajj . Development of a vaccine against group B meningococci has proved much more difficult, as its surface proteins (which would normally be used to make a vaccine) only elicit a weak response from the immune system , or cross-react with normal human proteins. Still, some countries ( New Zealand , Cuba , Norway and Chile ) have developed vaccines against local strains of group B meningococci; some have shown good results and are used in local immunization schedules. Two new vaccines, both approved in 2014, are effective against a wider range of group B meningococci strains. In Africa, until recently, the approach for prevention and control of meningococcal epidemics was based on early detection of the disease and emergency reactive mass vaccination of the at-risk population with bivalent A/C or trivalent A/C/W135 polysaccharide vaccines, though the introduction of MenAfriVac (meningococcus group A vaccine) has demonstrated effectiveness in young people and has been described as a model for product development partnerships in resource-limited settings. Routine vaccination against Streptococcus pneumoniae with the pneumococcal conjugate vaccine (PCV), which is active against seven common serotypes of this pathogen, significantly reduces the incidence of pneumococcal meningitis. The pneumococcal polysaccharide vaccine , which covers 23 strains, is only administered to certain groups (e.g. those who have had a splenectomy , the surgical removal of the spleen); it does not elicit a significant immune response in all recipients, e.g. small children. Childhood vaccination with Bacillus Calmette-Guérin has been reported to significantly reduce the rate of tuberculous meningitis, but its waning effectiveness in adulthood has prompted a search for a better vaccine. Short-term antibiotic prophylaxis is another method of prevention, particularly of meningococcal meningitis. In cases of meningococcal meningitis, preventative treatment in close contacts with antibiotics (e.g. rifampicin , ciprofloxacin or ceftriaxone ) can reduce their risk of contracting the condition, but does not protect against future infections. Resistance to rifampicin has been noted to increase after use, which has caused some to recommend considering other agents. While antibiotics are frequently used in an attempt to prevent meningitis in those with a basilar skull fracture there is not enough evidence to determine whether this is beneficial or harmful. This applies to those with or without a CSF leak. Meningitis is potentially life-threatening and has a high mortality rate if untreated; delay in treatment has been associated with a poorer outcome. Thus, treatment with wide-spectrum antibiotics should not be delayed while confirmatory tests are being conducted. If meningococcal disease is suspected in primary care, guidelines recommend that benzylpenicillin be administered before transfer to hospital. Intravenous fluids should be administered if hypotension (low blood pressure) or shock are present. It is not clear whether intravenous fluid should be given routinely or whether this should be restricted. Given that meningitis can cause a number of early severe complications, regular medical review is recommended to identify these complications early and to admit the person to an intensive care unit if deemed necessary. Mechanical ventilation may be needed if the level of consciousness is very low, or if there is evidence of respiratory failure . If there are signs of raised intracranial pressure, measures to monitor the pressure may be taken; this would allow the optimization of the cerebral perfusion pressure and various treatments to decrease the intracranial pressure with medication (e.g. mannitol ). Seizures are treated with anticonvulsants . Hydrocephalus (obstructed flow of CSF) may require insertion of a temporary or long-term drainage device, such as a cerebral shunt . The osmotic therapy, glycerol , has an unclear effect on mortality but may decrease hearing problems. Empiric antibiotics (treatment without exact diagnosis) should be started immediately, even before the results of the lumbar puncture and CSF analysis are known. The choice of initial treatment depends largely on the kind of bacteria that cause meningitis in a particular place and population. For instance, in the United Kingdom, empirical treatment consists of a third-generation cefalosporin such as cefotaxime or ceftriaxone . In the US, where resistance to cefalosporins is increasingly found in streptococci, addition of vancomycin to the initial treatment is recommended. Chloramphenicol , either alone or in combination with ampicillin , however, appears to work equally well. Empirical therapy may be chosen on the basis of the person's age, whether the infection was preceded by a head injury , whether the person has undergone recent neurosurgery and whether or not a cerebral shunt is present. In young children and those over 50 years of age, as well as those who are immunocompromised, the addition of ampicillin is recommended to cover Listeria monocytogenes . Once the Gram stain results become available, and the broad type of bacterial cause is known, it may be possible to change the antibiotics to those likely to deal with the presumed group of pathogens. The results of the CSF culture generally take longer to become available (24–48 hours). Once they do, empiric therapy may be switched to specific antibiotic therapy targeted to the specific causative organism and its sensitivities to antibiotics. For an antibiotic to be effective in meningitis it must not only be active against the pathogenic bacterium but also reach the meninges in adequate quantities; some antibiotics have inadequate penetrance and therefore have little use in meningitis. Most of the antibiotics used in meningitis have not been tested directly on people with meningitis in clinical trials . Rather, the relevant knowledge has mostly derived from laboratory studies in rabbits . Tuberculous meningitis requires prolonged treatment with antibiotics. While tuberculosis of the lungs is typically treated for six months, those with tuberculous meningitis are typically treated for a year or longer. Fluid given intravenously are an essential part of treatment of bacterial meningitis. There is no difference in terms of mortality or acute severe neurological complications in children given a maintenance regimen over restricted-fluid regimen, but evidence is in favor of the maintenance regimen in terms of emergence of chronic severe neurological complications. Additional treatment with corticosteroids (usually dexamethasone ) has shown some benefits, such as a reduction of hearing loss , and better short term neurological outcomes in adolescents and adults from high-income countries with low rates of HIV. Some research has found reduced rates of death while other research has not. They also appear to be beneficial in those with tuberculosis meningitis, at least in those who are HIV negative. Professional guidelines therefore recommend the commencement of dexamethasone or a similar corticosteroid just before the first dose of antibiotics is given, and continued for four days. Given that most of the benefit of the treatment is confined to those with pneumococcal meningitis, some guidelines suggest that dexamethasone be discontinued if another cause for meningitis is identified. The likely mechanism is suppression of overactive inflammation. Additional treatment with corticosteroids have a different role in children than in adults. Though the benefit of corticosteroids has been demonstrated in adults as well as in children from high-income countries, their use in children from low-income countries is not supported by the evidence; the reason for this discrepancy is not clear. Even in high-income countries, the benefit of corticosteroids is only seen when they are given prior to the first dose of antibiotics, and is greatest in cases of H. influenzae meningitis, the incidence of which has decreased dramatically since the introduction of the Hib vaccine . Thus, corticosteroids are recommended in the treatment of pediatric meningitis if the cause is H. influenzae , and only if given prior to the first dose of antibiotics; other uses are controversial. In addition to the primary therapy of antibiotics and corticosteroids, other adjuvant therapies are under development or are sometimes used to try and improve survival from bacterial meningitis and reduce the risk of neurological problems. Examples of adjuvant therapies that have been trialed include acetaminophen , immunoglobulin therapy , heparin , pentoxifyline , and a mononucleotide mixture with succinic acid . It is not clear if any of these therapies are helpful or worsen outcomes in people with acute bacterial meningitis. Viral meningitis typically only requires supportive therapy; most viruses responsible for causing meningitis are not amenable to specific treatment. Viral meningitis tends to run a more benign course than bacterial meningitis. Herpes simplex virus and varicella zoster virus may respond to treatment with antiviral drugs such as aciclovir , but there are no clinical trials that have specifically addressed whether this treatment is effective. Mild cases of viral meningitis can be treated at home with conservative measures such as fluid, bedrest, and analgesics. Fungal meningitis, such as cryptococcal meningitis , is treated with long courses of high dose antifungals , such as amphotericin B and flucytosine . Raised intracranial pressure is common in fungal meningitis, and frequent (ideally daily) lumbar punctures to relieve the pressure are recommended, or alternatively a lumbar drain. Empiric antibiotics (treatment without exact diagnosis) should be started immediately, even before the results of the lumbar puncture and CSF analysis are known. The choice of initial treatment depends largely on the kind of bacteria that cause meningitis in a particular place and population. For instance, in the United Kingdom, empirical treatment consists of a third-generation cefalosporin such as cefotaxime or ceftriaxone . In the US, where resistance to cefalosporins is increasingly found in streptococci, addition of vancomycin to the initial treatment is recommended. Chloramphenicol , either alone or in combination with ampicillin , however, appears to work equally well. Empirical therapy may be chosen on the basis of the person's age, whether the infection was preceded by a head injury , whether the person has undergone recent neurosurgery and whether or not a cerebral shunt is present. In young children and those over 50 years of age, as well as those who are immunocompromised, the addition of ampicillin is recommended to cover Listeria monocytogenes . Once the Gram stain results become available, and the broad type of bacterial cause is known, it may be possible to change the antibiotics to those likely to deal with the presumed group of pathogens. The results of the CSF culture generally take longer to become available (24–48 hours). Once they do, empiric therapy may be switched to specific antibiotic therapy targeted to the specific causative organism and its sensitivities to antibiotics. For an antibiotic to be effective in meningitis it must not only be active against the pathogenic bacterium but also reach the meninges in adequate quantities; some antibiotics have inadequate penetrance and therefore have little use in meningitis. Most of the antibiotics used in meningitis have not been tested directly on people with meningitis in clinical trials . Rather, the relevant knowledge has mostly derived from laboratory studies in rabbits . Tuberculous meningitis requires prolonged treatment with antibiotics. While tuberculosis of the lungs is typically treated for six months, those with tuberculous meningitis are typically treated for a year or longer. Fluid given intravenously are an essential part of treatment of bacterial meningitis. There is no difference in terms of mortality or acute severe neurological complications in children given a maintenance regimen over restricted-fluid regimen, but evidence is in favor of the maintenance regimen in terms of emergence of chronic severe neurological complications. Additional treatment with corticosteroids (usually dexamethasone ) has shown some benefits, such as a reduction of hearing loss , and better short term neurological outcomes in adolescents and adults from high-income countries with low rates of HIV. Some research has found reduced rates of death while other research has not. They also appear to be beneficial in those with tuberculosis meningitis, at least in those who are HIV negative. Professional guidelines therefore recommend the commencement of dexamethasone or a similar corticosteroid just before the first dose of antibiotics is given, and continued for four days. Given that most of the benefit of the treatment is confined to those with pneumococcal meningitis, some guidelines suggest that dexamethasone be discontinued if another cause for meningitis is identified. The likely mechanism is suppression of overactive inflammation. Additional treatment with corticosteroids have a different role in children than in adults. Though the benefit of corticosteroids has been demonstrated in adults as well as in children from high-income countries, their use in children from low-income countries is not supported by the evidence; the reason for this discrepancy is not clear. Even in high-income countries, the benefit of corticosteroids is only seen when they are given prior to the first dose of antibiotics, and is greatest in cases of H. influenzae meningitis, the incidence of which has decreased dramatically since the introduction of the Hib vaccine . Thus, corticosteroids are recommended in the treatment of pediatric meningitis if the cause is H. influenzae , and only if given prior to the first dose of antibiotics; other uses are controversial. In addition to the primary therapy of antibiotics and corticosteroids, other adjuvant therapies are under development or are sometimes used to try and improve survival from bacterial meningitis and reduce the risk of neurological problems. Examples of adjuvant therapies that have been trialed include acetaminophen , immunoglobulin therapy , heparin , pentoxifyline , and a mononucleotide mixture with succinic acid . It is not clear if any of these therapies are helpful or worsen outcomes in people with acute bacterial meningitis. Empiric antibiotics (treatment without exact diagnosis) should be started immediately, even before the results of the lumbar puncture and CSF analysis are known. The choice of initial treatment depends largely on the kind of bacteria that cause meningitis in a particular place and population. For instance, in the United Kingdom, empirical treatment consists of a third-generation cefalosporin such as cefotaxime or ceftriaxone . In the US, where resistance to cefalosporins is increasingly found in streptococci, addition of vancomycin to the initial treatment is recommended. Chloramphenicol , either alone or in combination with ampicillin , however, appears to work equally well. Empirical therapy may be chosen on the basis of the person's age, whether the infection was preceded by a head injury , whether the person has undergone recent neurosurgery and whether or not a cerebral shunt is present. In young children and those over 50 years of age, as well as those who are immunocompromised, the addition of ampicillin is recommended to cover Listeria monocytogenes . Once the Gram stain results become available, and the broad type of bacterial cause is known, it may be possible to change the antibiotics to those likely to deal with the presumed group of pathogens. The results of the CSF culture generally take longer to become available (24–48 hours). Once they do, empiric therapy may be switched to specific antibiotic therapy targeted to the specific causative organism and its sensitivities to antibiotics. For an antibiotic to be effective in meningitis it must not only be active against the pathogenic bacterium but also reach the meninges in adequate quantities; some antibiotics have inadequate penetrance and therefore have little use in meningitis. Most of the antibiotics used in meningitis have not been tested directly on people with meningitis in clinical trials . Rather, the relevant knowledge has mostly derived from laboratory studies in rabbits . Tuberculous meningitis requires prolonged treatment with antibiotics. While tuberculosis of the lungs is typically treated for six months, those with tuberculous meningitis are typically treated for a year or longer. Fluid given intravenously are an essential part of treatment of bacterial meningitis. There is no difference in terms of mortality or acute severe neurological complications in children given a maintenance regimen over restricted-fluid regimen, but evidence is in favor of the maintenance regimen in terms of emergence of chronic severe neurological complications. Additional treatment with corticosteroids (usually dexamethasone ) has shown some benefits, such as a reduction of hearing loss , and better short term neurological outcomes in adolescents and adults from high-income countries with low rates of HIV. Some research has found reduced rates of death while other research has not. They also appear to be beneficial in those with tuberculosis meningitis, at least in those who are HIV negative. Professional guidelines therefore recommend the commencement of dexamethasone or a similar corticosteroid just before the first dose of antibiotics is given, and continued for four days. Given that most of the benefit of the treatment is confined to those with pneumococcal meningitis, some guidelines suggest that dexamethasone be discontinued if another cause for meningitis is identified. The likely mechanism is suppression of overactive inflammation. Additional treatment with corticosteroids have a different role in children than in adults. Though the benefit of corticosteroids has been demonstrated in adults as well as in children from high-income countries, their use in children from low-income countries is not supported by the evidence; the reason for this discrepancy is not clear. Even in high-income countries, the benefit of corticosteroids is only seen when they are given prior to the first dose of antibiotics, and is greatest in cases of H. influenzae meningitis, the incidence of which has decreased dramatically since the introduction of the Hib vaccine . Thus, corticosteroids are recommended in the treatment of pediatric meningitis if the cause is H. influenzae , and only if given prior to the first dose of antibiotics; other uses are controversial. In addition to the primary therapy of antibiotics and corticosteroids, other adjuvant therapies are under development or are sometimes used to try and improve survival from bacterial meningitis and reduce the risk of neurological problems. Examples of adjuvant therapies that have been trialed include acetaminophen , immunoglobulin therapy , heparin , pentoxifyline , and a mononucleotide mixture with succinic acid . It is not clear if any of these therapies are helpful or worsen outcomes in people with acute bacterial meningitis. Viral meningitis typically only requires supportive therapy; most viruses responsible for causing meningitis are not amenable to specific treatment. Viral meningitis tends to run a more benign course than bacterial meningitis. Herpes simplex virus and varicella zoster virus may respond to treatment with antiviral drugs such as aciclovir , but there are no clinical trials that have specifically addressed whether this treatment is effective. Mild cases of viral meningitis can be treated at home with conservative measures such as fluid, bedrest, and analgesics. Fungal meningitis, such as cryptococcal meningitis , is treated with long courses of high dose antifungals , such as amphotericin B and flucytosine . Raised intracranial pressure is common in fungal meningitis, and frequent (ideally daily) lumbar punctures to relieve the pressure are recommended, or alternatively a lumbar drain. no data 1000 Untreated, bacterial meningitis is almost always fatal. According to the WHO bacterial meningitis has an overall mortality rate of 16.7% (with treatment). Viral meningitis, in contrast, tends to resolve spontaneously and is rarely fatal. With treatment, mortality (risk of death) from bacterial meningitis depends on the age of the person and the underlying cause. Of newborns, 20–30% may die from an episode of bacterial meningitis. This risk is much lower in older children, whose mortality is about 2%, but rises again to about 19–37% in adults. Risk of death is predicted by various factors apart from age, such as the pathogen and the time it takes for the pathogen to be cleared from the cerebrospinal fluid, the severity of the generalized illness, a decreased level of consciousness or an abnormally low count of white blood cells in the CSF. Meningitis caused by H. influenzae and meningococci has a better prognosis than cases caused by group B streptococci, coliforms and S. pneumoniae . In adults, too, meningococcal meningitis has a lower mortality (3–7%) than pneumococcal disease. In children there are several potential disabilities which may result from damage to the nervous system, including sensorineural hearing loss , epilepsy , learning and behavioral difficulties, as well as decreased intelligence . These occur in about 15% of survivors. Some of the hearing loss may be reversible. In adults, 66% of all cases emerge without disability. The main problems are deafness (in 14%) and cognitive impairment (in 10%). Tuberculous meningitis in children continues to be associated with a significant risk of death even with treatment (19%), and a significant proportion of the surviving children have ongoing neurological problems. Just over a third of all cases survives with no problems. 0–2 3-3 4–6 7–9 10–20 21–31 32–61 62–153 154–308 309–734 Although meningitis is a notifiable disease in many countries, the exact incidence rate is unknown. In 2013 meningitis resulted in 303,000 deaths – down from 464,000 deaths in 1990. In 2010 it was estimated that meningitis resulted in 420,000 deaths, excluding cryptococcal meningitis . Bacterial meningitis occurs in about 3 people per 100,000 annually in Western countries . Population-wide studies have shown that viral meningitis is more common, at 10.9 per 100,000, and occurs more often in the summer. In Brazil, the rate of bacterial meningitis is higher, at 45.8 per 100,000 annually. Sub-Saharan Africa has been plagued by large epidemics of meningococcal meningitis for over a century, leading to it being labeled the "meningitis belt". Epidemics typically occur in the dry season (December to June), and an epidemic wave can last two to three years, dying out during the intervening rainy seasons. Attack rates of 100–800 cases per 100,000 are encountered in this area, which is poorly served by medical care . These cases are predominantly caused by meningococci. The largest epidemic ever recorded in history swept across the entire region in 1996–1997, causing over 250,000 cases and 25,000 deaths. Meningococcal disease occurs in epidemics in areas where many people live together for the first time, such as army barracks during mobilization, university and college campuses and the annual Hajj pilgrimage. Although the pattern of epidemic cycles in Africa is not well understood, several factors have been associated with the development of epidemics in the meningitis belt. They include: medical conditions (immunological susceptibility of the population), demographic conditions (travel and large population displacements), socioeconomic conditions (overcrowding and poor living conditions), climatic conditions (drought and dust storms), and concurrent infections (acute respiratory infections). There are significant differences in the local distribution of causes for bacterial meningitis. For instance, while N. meningitides groups B and C cause most disease episodes in Europe, group A is found in Asia and continues to predominate in Africa, where it causes most of the major epidemics in the meningitis belt, accounting for about 80% to 85% of documented meningococcal meningitis cases. Some suggest that Hippocrates may have realized the existence of meningitis, and it seems that meningism was known to pre-Renaissance physicians such as Avicenna . The description of tuberculous meningitis, then called " dropsy in the brain", is often attributed to Edinburgh physician Sir Robert Whytt in a posthumous report that appeared in 1768, although the link with tuberculosis and its pathogen was not made until the next century. It appears that epidemic meningitis is a relatively recent phenomenon. The first recorded major outbreak occurred in Geneva in 1805. Several other epidemics in Europe and the United States were described shortly afterward, and the first report of an epidemic in Africa appeared in 1840. African epidemics became much more common in the 20th century, starting with a major epidemic sweeping Nigeria and Ghana in 1905–1908. The first report of bacterial infection underlying meningitis was by the Austrian bacteriologist Anton Weichselbaum , who in 1887 described the meningococcus . Mortality from meningitis was very high (over 90%) in early reports. In 1906, antiserum was produced in horses; this was developed further by the American scientist Simon Flexner and markedly decreased mortality from meningococcal disease. In 1944, penicillin was first reported to be effective in meningitis. The introduction in the late 20th century of Haemophilus vaccines led to a marked fall in cases of meningitis associated with this pathogen, and in 2002, evidence emerged that treatment with steroids could improve the prognosis of bacterial meningitis.

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Acute hemorrhagic fever syndrome

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COVID-19

Coronavirus disease 2019 ( COVID-19 ) is a contagious disease caused by the coronavirus SARS-CoV-2 . The first known case was identified in Wuhan , China, in December 2019. The disease quickly spread worldwide, resulting in the COVID-19 pandemic . The symptoms of COVID‑19 are variable but often include fever, fatigue, cough, breathing difficulties , loss of smell , and loss of taste . Symptoms may begin one to fourteen days after exposure to the virus. At least a third of people who are infected do not develop noticeable symptoms . Of those who develop symptoms noticeable enough to be classified as patients, most (81%) develop mild to moderate symptoms (up to mild pneumonia ), while 14% develop severe symptoms ( dyspnea , hypoxia , or more than 50% lung involvement on imaging), and 5% develop critical symptoms ( respiratory failure , shock , or multiorgan dysfunction ). Older people are at a higher risk of developing severe symptoms. Some complications result in death. Some people continue to experience a range of effects ( long COVID ) for months or years after infection, and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease. COVID‑19 transmission occurs when infectious particles are breathed in or come into contact with the eyes, nose, or mouth. The risk is highest when people are in close proximity, but small airborne particles containing the virus can remain suspended in the air and travel over longer distances, particularly indoors. Transmission can also occur when people touch their eyes, nose or mouth after touching surfaces or objects that have been contaminated by the virus. People remain contagious for up to 20 days and can spread the virus even if they do not develop symptoms. Testing methods for COVID-19 to detect the virus's nucleic acid include real-time reverse transcription polymerase chain reaction (RT ‑ PCR), transcription-mediated amplification , and reverse transcription loop-mediated isothermal amplification (RT ‑ LAMP) from a nasopharyngeal swab . Several COVID-19 vaccines have been approved and distributed in various countries, many of which have initiated mass vaccination campaigns . Other preventive measures include physical or social distancing , quarantining , ventilation of indoor spaces, use of face masks or coverings in public, covering coughs and sneezes, hand washing , and keeping unwashed hands away from the face. While drugs have been developed to inhibit the virus, the primary treatment is still symptomatic , managing the disease through supportive care , isolation , and experimental measures .During the initial outbreak in Wuhan , the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus", with the disease sometimes called "Wuhan pneumonia". In the past, many diseases have been named after geographical locations, such as the Spanish flu , Middle East respiratory syndrome , and Zika virus . In January 2020, the World Health Organization (WHO) recommended 2019-nCoV and 2019-nCoV acute respiratory disease as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations or groups of people in disease and virus names to prevent social stigma . The official names COVID‑19 and SARS-CoV-2 were issued by the WHO on 11 February 2020 with COVID-19 being shorthand for "coronavirus disease 2019". The WHO additionally uses "the COVID‑19 virus" and "the virus responsible for COVID‑19" in public communications. The symptoms of COVID-19 are variable depending on the type of variant contracted, ranging from mild symptoms to a potentially fatal illness. Common symptoms include coughing , fever , loss of smell (anosmia) and taste (ageusia), with less common ones including headaches , nasal congestion and runny nose , muscle pain , sore throat , diarrhea , eye irritation , and toes swelling or turning purple, and in moderate to severe cases, breathing difficulties . People with the COVID-19 infection may have different symptoms, and their symptoms may change over time. Three common clusters of symptoms have been identified: one respiratory symptom cluster with cough, sputum , shortness of breath , and fever; a musculoskeletal symptom cluster with muscle and joint pain, headache, and fatigue; and a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea. In people without prior ear, nose, or throat disorders, loss of taste combined with loss of smell is associated with COVID-19 and is reported in as many as 88% of symptomatic cases. Published data on the neuropathological changes related with COVID-19 have been limited and contentious, with neuropathological descriptions ranging from moderate to severe hemorrhagic and hypoxia phenotypes , thrombotic consequences, changes in acute disseminated encephalomyelitis (ADEM-type), encephalitis and meningitis . Many COVID-19 patients with co-morbidities have hypoxia and have been in intensive care for varying lengths of time, confounding interpretation of the data. Of people who show symptoms, 81% develop only mild to moderate symptoms (up to mild pneumonia ), while 14% develop severe symptoms ( dyspnea , hypoxia , or more than 50% lung involvement on imaging) that require hospitalization, and 5% of patients develop critical symptoms ( respiratory failure , septic shock , or multiorgan dysfunction ) requiring ICU admission. [ needs update ] At least a third of the people who are infected with the virus do not develop noticeable symptoms at any point in time. These asymptomatic carriers tend not to get tested and can still spread the disease. Other infected people will develop symptoms later (called "pre-symptomatic") or have very mild symptoms and can also spread the virus. As is common with infections, there is a delay between the moment a person first becomes infected and the appearance of the first symptoms. The median delay for COVID-19 is four to five days possibly being infectious on 1-4 of those days. Most symptomatic people experience symptoms within two to seven days after exposure, and almost all will experience at least one symptom within 12 days. Most people recover from the acute phase of the disease. However, some people continue to experience a range of effects, such as fatigue , for months, even after recovery. This is the result of a condition called long COVID , which can be described as a range of persistent symptoms that continue for weeks or months at a time. Long-term damage to organs has also been observed after the onset of COVID-19. Multi-year studies are underway to further investigate the potential long-term effects of the disease. Complications may include pneumonia , acute respiratory distress syndrome (ARDS), multi-organ failure , septic shock , and death. Cardiovascular complications may include heart failure, arrhythmias (including atrial fibrillation ), heart inflammation , and thrombosis , particularly venous thromboembolism . Approximately 20–30% of people who present with COVID‑19 have elevated liver enzymes , reflecting liver injury. Neurologic manifestations include seizure , stroke, encephalitis , and Guillain–Barré syndrome (which includes loss of motor functions ). Following the infection, children may develop paediatric multisystem inflammatory syndrome , which has symptoms similar to Kawasaki disease , which can be fatal. In very rare cases, acute encephalopathy can occur, and it can be considered in those who have been diagnosed with COVID‑19 and have an altered mental status. According to the US Centers for Disease Control and Prevention , pregnant women are at increased risk of becoming seriously ill from COVID‑19. This is because pregnant women with COVID‑19 appear to be more likely to develop respiratory and obstetric complications that can lead to miscarriage , premature delivery and intrauterine growth restriction . Fungal infections such as aspergillosis , candidiasis , cryptococcosis and mucormycosis have been recorded in patients recovering from COVID‑19. Complications may include pneumonia , acute respiratory distress syndrome (ARDS), multi-organ failure , septic shock , and death. Cardiovascular complications may include heart failure, arrhythmias (including atrial fibrillation ), heart inflammation , and thrombosis , particularly venous thromboembolism . Approximately 20–30% of people who present with COVID‑19 have elevated liver enzymes , reflecting liver injury. Neurologic manifestations include seizure , stroke, encephalitis , and Guillain–Barré syndrome (which includes loss of motor functions ). Following the infection, children may develop paediatric multisystem inflammatory syndrome , which has symptoms similar to Kawasaki disease , which can be fatal. In very rare cases, acute encephalopathy can occur, and it can be considered in those who have been diagnosed with COVID‑19 and have an altered mental status. According to the US Centers for Disease Control and Prevention , pregnant women are at increased risk of becoming seriously ill from COVID‑19. This is because pregnant women with COVID‑19 appear to be more likely to develop respiratory and obstetric complications that can lead to miscarriage , premature delivery and intrauterine growth restriction . Fungal infections such as aspergillosis , candidiasis , cryptococcosis and mucormycosis have been recorded in patients recovering from COVID‑19. COVID‑19 is caused by infection with a strain of coronavirus known as "severe acute respiratory syndrome coronavirus 2" ( SARS-CoV-2 ). COVID-19 is mainly transmitted when people breathe in air contaminated by droplets / aerosols and small airborne particles containing the virus. Infected people exhale those particles as they breathe, talk, cough, sneeze, or sing. Transmission is more likely the closer people are. However, infection can occur over longer distances, particularly indoors. The transmission of the virus is carried out through virus-laden fluid particles, or droplets, which are created in the respiratory tract, and they are expelled by the mouth and the nose. There are three types of transmission: "droplet" and "contact", which are associated with large droplets, and "airborne", which is associated with small droplets. If the droplets are above a certain critical size, they settle faster than they evaporate , and therefore they contaminate surfaces surrounding them. Droplets that are below a certain critical size, evaporate faster than they settle; due to that fact, they form nuclei that remain airborne for a long period of time over extensive distances. Infectivity can begin four to five days before the onset of symptoms. Infected people can spread the disease even if they are pre-symptomatic or asymptomatic . Most commonly, the peak viral load in upper respiratory tract samples occurs close to the time of symptom onset and declines after the first week after symptoms begin. Current evidence suggests a duration of viral shedding and the period of infectiousness of up to ten days following symptom onset for people with mild to moderate COVID-19, and up to 20 days for persons with severe COVID-19, including immunocompromised people. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. It was first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan. All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature, particularly in Rhinolophus sinicus aka Chinese horseshoe bats. Outside the human body, the virus is destroyed by household soap which bursts its protective bubble . Hospital disinfectants, alcohols, heat, povidone-iodine , and ultraviolet-C (UV-C) irradiation are also effective disinfection methods for surfaces. SARS-CoV-2 is closely related to the original SARS-CoV . It is thought to have an animal ( zoonotic ) origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus , in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13 ). The structural proteins of SARS-CoV-2 include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). The M protein of SARS-CoV-2 is about 98% similar to the M protein of bat SARS-CoV, maintains around 98% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only around 38% with the M protein of MERS-CoV. The many thousands of SARS-CoV-2 variants are grouped into either clades or lineages . The WHO, in collaboration with partners, expert networks, national authorities, institutions and researchers, have established nomenclature systems for naming and tracking SARS-CoV-2 genetic lineages by GISAID , Nextstrain and Pango . The expert group convened by the WHO recommended the labelling of variants using letters of the Greek alphabet , for example, Alpha , Beta , Delta , and Gamma , giving the justification that they "will be easier and more practical to discussed by non-scientific audiences". 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). The Pango tool groups variants into lineages , with many circulating lineages being classed under the B.1 lineage. Several notable variants of SARS-CoV-2 emerged throughout 2020. Cluster 5 emerged among minks and mink farmers in Denmark . After strict quarantines and a mink euthanasia campaign, the cluster was assessed to no longer be circulating among humans in Denmark as of 1 February 2021. As of December 2021 [ update ] , there are five dominant variants of SARS-CoV-2 spreading among global populations: the Alpha variant (B.1.1.7, formerly called the UK variant), first found in London and Kent, the Beta variant (B.1.351, formerly called the South Africa variant), the Gamma variant (P.1, formerly called the Brazil variant), the Delta variant (B.1.617.2, formerly called the India variant), and the Omicron variant (B.1.1.529), which had spread to 57 countries as of 7 December. On December 19, 2023, the WHO declared that another distinctive variant, JN.1, had emerged as a "variant of interest". Though the WHO expected an increase in cases globally, particularly for countries entering winter, the overall global health risk was considered low. COVID-19 is mainly transmitted when people breathe in air contaminated by droplets / aerosols and small airborne particles containing the virus. Infected people exhale those particles as they breathe, talk, cough, sneeze, or sing. Transmission is more likely the closer people are. However, infection can occur over longer distances, particularly indoors. The transmission of the virus is carried out through virus-laden fluid particles, or droplets, which are created in the respiratory tract, and they are expelled by the mouth and the nose. There are three types of transmission: "droplet" and "contact", which are associated with large droplets, and "airborne", which is associated with small droplets. If the droplets are above a certain critical size, they settle faster than they evaporate , and therefore they contaminate surfaces surrounding them. Droplets that are below a certain critical size, evaporate faster than they settle; due to that fact, they form nuclei that remain airborne for a long period of time over extensive distances. Infectivity can begin four to five days before the onset of symptoms. Infected people can spread the disease even if they are pre-symptomatic or asymptomatic . Most commonly, the peak viral load in upper respiratory tract samples occurs close to the time of symptom onset and declines after the first week after symptoms begin. Current evidence suggests a duration of viral shedding and the period of infectiousness of up to ten days following symptom onset for people with mild to moderate COVID-19, and up to 20 days for persons with severe COVID-19, including immunocompromised people. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. It was first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan. All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature, particularly in Rhinolophus sinicus aka Chinese horseshoe bats. Outside the human body, the virus is destroyed by household soap which bursts its protective bubble . Hospital disinfectants, alcohols, heat, povidone-iodine , and ultraviolet-C (UV-C) irradiation are also effective disinfection methods for surfaces. SARS-CoV-2 is closely related to the original SARS-CoV . It is thought to have an animal ( zoonotic ) origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus , in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13 ). The structural proteins of SARS-CoV-2 include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). The M protein of SARS-CoV-2 is about 98% similar to the M protein of bat SARS-CoV, maintains around 98% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only around 38% with the M protein of MERS-CoV. The many thousands of SARS-CoV-2 variants are grouped into either clades or lineages . The WHO, in collaboration with partners, expert networks, national authorities, institutions and researchers, have established nomenclature systems for naming and tracking SARS-CoV-2 genetic lineages by GISAID , Nextstrain and Pango . The expert group convened by the WHO recommended the labelling of variants using letters of the Greek alphabet , for example, Alpha , Beta , Delta , and Gamma , giving the justification that they "will be easier and more practical to discussed by non-scientific audiences". 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). The Pango tool groups variants into lineages , with many circulating lineages being classed under the B.1 lineage. Several notable variants of SARS-CoV-2 emerged throughout 2020. Cluster 5 emerged among minks and mink farmers in Denmark . After strict quarantines and a mink euthanasia campaign, the cluster was assessed to no longer be circulating among humans in Denmark as of 1 February 2021. As of December 2021 [ update ] , there are five dominant variants of SARS-CoV-2 spreading among global populations: the Alpha variant (B.1.1.7, formerly called the UK variant), first found in London and Kent, the Beta variant (B.1.351, formerly called the South Africa variant), the Gamma variant (P.1, formerly called the Brazil variant), the Delta variant (B.1.617.2, formerly called the India variant), and the Omicron variant (B.1.1.529), which had spread to 57 countries as of 7 December. On December 19, 2023, the WHO declared that another distinctive variant, JN.1, had emerged as a "variant of interest". Though the WHO expected an increase in cases globally, particularly for countries entering winter, the overall global health risk was considered low. The SARS-CoV-2 virus can infect a wide range of cells and systems of the body. COVID‑19 is most known for affecting the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs). The lungs are the organs most affected by COVID‑19 because the virus accesses host cells via the receptor for the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant on the surface of type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a " spike " to connect to the ACE2 receptor and enter the host cell. Following viral entry, COVID‑19 infects the ciliated epithelium of the nasopharynx and upper airways. Autopsies of people who died of COVID‑19 have found diffuse alveolar damage , and lymphocyte-containing inflammatory infiltrates within the lung. One common symptom, loss of smell, results from infection of the support cells of the olfactory epithelium , with subsequent damage to the olfactory neurons . The involvement of both the central and peripheral nervous system in COVID‑19 has been reported in many medical publications. It is clear that many people with COVID-19 exhibit neurological or mental health issues . The virus is not detected in the central nervous system (CNS) of the majority of COVID-19 patients with neurological issues . However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID‑19, but these results need to be confirmed. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the blood–brain barrier to gain access to the CNS, possibly within an infected white blood cell. Research conducted when Alpha was the dominant variant has suggested COVID-19 may cause brain damage. Later research showed that all variants studied (including Omicron) killed brain cells, but the exact cells killed varied by variant. It is unknown if such damage is temporary or permanent. Observed individuals infected with COVID-19 (most with mild cases) experienced an additional 0.2% to 2% of brain tissue lost in regions of the brain connected to the sense of smell compared with uninfected individuals, and the overall effect on the brain was equivalent on average to at least one extra year of normal ageing; infected individuals also scored lower on several cognitive tests. All effects were more pronounced among older ages. The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric , duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine . The virus can cause acute myocardial injury and chronic damage to the cardiovascular system . An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis and venous thromboembolism occurs in people transferred to intensive care units with COVID‑19 infections, and may be related to poor prognosis. Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) may have a significant role in mortality, incidents of clots leading to pulmonary embolisms , and ischaemic events (strokes) within the brain found as complications leading to death in people infected with COVID‑19. Infection may initiate a chain of vasoconstrictive responses within the body, including pulmonary vasoconstriction – a possible mechanism in which oxygenation decreases during pneumonia. Furthermore, damage of arterioles and capillaries was found in brain tissue samples of people who died from COVID‑19. COVID ‑ 19 may also cause substantial structural changes to blood cells , sometimes persisting for months after hospital discharge. A low level of blood lymphocytes may result from the virus acting through ACE2-related entry into lymphocytes. Another common cause of death is complications related to the kidneys . Early reports show that up to 30% of hospitalised patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems. Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID‑19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL ‑ 2 , IL ‑ 7 , IL ‑ 6 , granulocyte-macrophage colony-stimulating factor (GM ‑ CSF), interferon gamma-induced protein 10 (IP ‑ 10), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1 ‑ alpha (MIP ‑ 1 ‑ alpha), and tumour necrosis factor (TNF ‑ α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology. Interferon alpha plays a complex, Janus-faced role in the pathogenesis of COVID-19. Although it promotes the elimination of virus-infected cells, it also upregulates the expression of ACE-2, thereby facilitating the SARS-Cov2 virus to enter cells and to replicate. A competition of negative feedback loops (via protective effects of interferon alpha) and positive feedback loops (via upregulation of ACE-2) is assumed to determine the fate of patients suffering from COVID-19. Additionally, people with COVID‑19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer , and ferritin . Systemic inflammation results in vasodilation , allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID‑19. Lymphocytic infiltrates have also been reported at autopsy. Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus-host range and cellular tropism via the receptor-binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID‑19 vaccines. The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response. Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-CoV-2 virus targets causing COVID‑19. Theoretically, the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID‑19, though animal data suggest some potential protective effect of ARB; however no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain. The effect of the virus on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome . Among healthy adults not exposed to SARS-CoV-2, about 35% have CD4 + T cells that recognise the SARS-CoV-2 S protein (particularly the S2 subunit) and about 50% react to other proteins of the virus, suggesting cross-reactivity from previous common colds caused by other coronaviruses. It is unknown whether different persons use similar antibody genes in response to COVID‑19. The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm . Levels of interleukin 1B , interferon-gamma , interferon-inducible protein 10, and monocyte chemoattractant protein 1 were all associated with COVID‑19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of morbidity and mortality in COVID‑19 disease. A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID‑19, it is related to worse prognosis and increased fatality. The storm causes acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, encephalitis , acute kidney injury , and vasculitis . The production of IL-1 , IL-2 , IL-6 , TNF-alpha , and interferon-gamma , all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the central nervous system , the microglia , neurons , and astrocytes , are also involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon. There are many unknowns for pregnant women during the COVID-19 pandemic. Given that they are prone to have complications and severe disease infection with other types of coronaviruses, they have been identified as a vulnerable group and advised to take supplementary preventive measures. Physiological responses to pregnancy can include: However, from the evidence base, it is difficult to conclude whether pregnant women are at increased risk of grave consequences of this virus. In addition to the above, other clinical studies have proved that SARS-CoV-2 can affect the period of pregnancy in different ways. On the one hand, there is little evidence of its impact up to 12 weeks gestation. On the other hand, COVID-19 infection may cause increased rates of unfavourable outcomes in the course of the pregnancy. Some examples of these could be foetal growth restriction, preterm birth, and perinatal mortality, which refers to the foetal death past 22 or 28 completed weeks of pregnancy as well as the death among live-born children up to seven completed days of life. For preterm birth, a 2023 review indicates that there appears to be a correlation with COVID-19. Unvaccinated women in later stages of pregnancy with COVID-19 are more likely than other patients to need very intensive care. Babies born to mothers with COVID-19 are more likely to have breathing problems. Pregnant women are strongly encouraged to get vaccinated . Following viral entry, COVID‑19 infects the ciliated epithelium of the nasopharynx and upper airways. Autopsies of people who died of COVID‑19 have found diffuse alveolar damage , and lymphocyte-containing inflammatory infiltrates within the lung. One common symptom, loss of smell, results from infection of the support cells of the olfactory epithelium , with subsequent damage to the olfactory neurons . The involvement of both the central and peripheral nervous system in COVID‑19 has been reported in many medical publications. It is clear that many people with COVID-19 exhibit neurological or mental health issues . The virus is not detected in the central nervous system (CNS) of the majority of COVID-19 patients with neurological issues . However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID‑19, but these results need to be confirmed. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the blood–brain barrier to gain access to the CNS, possibly within an infected white blood cell. Research conducted when Alpha was the dominant variant has suggested COVID-19 may cause brain damage. Later research showed that all variants studied (including Omicron) killed brain cells, but the exact cells killed varied by variant. It is unknown if such damage is temporary or permanent. Observed individuals infected with COVID-19 (most with mild cases) experienced an additional 0.2% to 2% of brain tissue lost in regions of the brain connected to the sense of smell compared with uninfected individuals, and the overall effect on the brain was equivalent on average to at least one extra year of normal ageing; infected individuals also scored lower on several cognitive tests. All effects were more pronounced among older ages. The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric , duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine . The virus can cause acute myocardial injury and chronic damage to the cardiovascular system . An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis and venous thromboembolism occurs in people transferred to intensive care units with COVID‑19 infections, and may be related to poor prognosis. Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) may have a significant role in mortality, incidents of clots leading to pulmonary embolisms , and ischaemic events (strokes) within the brain found as complications leading to death in people infected with COVID‑19. Infection may initiate a chain of vasoconstrictive responses within the body, including pulmonary vasoconstriction – a possible mechanism in which oxygenation decreases during pneumonia. Furthermore, damage of arterioles and capillaries was found in brain tissue samples of people who died from COVID‑19. COVID ‑ 19 may also cause substantial structural changes to blood cells , sometimes persisting for months after hospital discharge. A low level of blood lymphocytes may result from the virus acting through ACE2-related entry into lymphocytes. Another common cause of death is complications related to the kidneys . Early reports show that up to 30% of hospitalised patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems. Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID‑19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL ‑ 2 , IL ‑ 7 , IL ‑ 6 , granulocyte-macrophage colony-stimulating factor (GM ‑ CSF), interferon gamma-induced protein 10 (IP ‑ 10), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1 ‑ alpha (MIP ‑ 1 ‑ alpha), and tumour necrosis factor (TNF ‑ α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology. Interferon alpha plays a complex, Janus-faced role in the pathogenesis of COVID-19. Although it promotes the elimination of virus-infected cells, it also upregulates the expression of ACE-2, thereby facilitating the SARS-Cov2 virus to enter cells and to replicate. A competition of negative feedback loops (via protective effects of interferon alpha) and positive feedback loops (via upregulation of ACE-2) is assumed to determine the fate of patients suffering from COVID-19. Additionally, people with COVID‑19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer , and ferritin . Systemic inflammation results in vasodilation , allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID‑19. Lymphocytic infiltrates have also been reported at autopsy. Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus-host range and cellular tropism via the receptor-binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID‑19 vaccines. The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response. Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-CoV-2 virus targets causing COVID‑19. Theoretically, the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID‑19, though animal data suggest some potential protective effect of ARB; however no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain. The effect of the virus on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome . Among healthy adults not exposed to SARS-CoV-2, about 35% have CD4 + T cells that recognise the SARS-CoV-2 S protein (particularly the S2 subunit) and about 50% react to other proteins of the virus, suggesting cross-reactivity from previous common colds caused by other coronaviruses. It is unknown whether different persons use similar antibody genes in response to COVID‑19. Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus-host range and cellular tropism via the receptor-binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID‑19 vaccines. The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response. Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-CoV-2 virus targets causing COVID‑19. Theoretically, the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID‑19, though animal data suggest some potential protective effect of ARB; however no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain. The effect of the virus on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome . Among healthy adults not exposed to SARS-CoV-2, about 35% have CD4 + T cells that recognise the SARS-CoV-2 S protein (particularly the S2 subunit) and about 50% react to other proteins of the virus, suggesting cross-reactivity from previous common colds caused by other coronaviruses. It is unknown whether different persons use similar antibody genes in response to COVID‑19. The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm . Levels of interleukin 1B , interferon-gamma , interferon-inducible protein 10, and monocyte chemoattractant protein 1 were all associated with COVID‑19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of morbidity and mortality in COVID‑19 disease. A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID‑19, it is related to worse prognosis and increased fatality. The storm causes acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, encephalitis , acute kidney injury , and vasculitis . The production of IL-1 , IL-2 , IL-6 , TNF-alpha , and interferon-gamma , all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the central nervous system , the microglia , neurons , and astrocytes , are also involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon. There are many unknowns for pregnant women during the COVID-19 pandemic. Given that they are prone to have complications and severe disease infection with other types of coronaviruses, they have been identified as a vulnerable group and advised to take supplementary preventive measures. Physiological responses to pregnancy can include: However, from the evidence base, it is difficult to conclude whether pregnant women are at increased risk of grave consequences of this virus. In addition to the above, other clinical studies have proved that SARS-CoV-2 can affect the period of pregnancy in different ways. On the one hand, there is little evidence of its impact up to 12 weeks gestation. On the other hand, COVID-19 infection may cause increased rates of unfavourable outcomes in the course of the pregnancy. Some examples of these could be foetal growth restriction, preterm birth, and perinatal mortality, which refers to the foetal death past 22 or 28 completed weeks of pregnancy as well as the death among live-born children up to seven completed days of life. For preterm birth, a 2023 review indicates that there appears to be a correlation with COVID-19. Unvaccinated women in later stages of pregnancy with COVID-19 are more likely than other patients to need very intensive care. Babies born to mothers with COVID-19 are more likely to have breathing problems. Pregnant women are strongly encouraged to get vaccinated . COVID‑19 can provisionally be diagnosed on the basis of symptoms and confirmed using reverse transcription polymerase chain reaction (RT-PCR) or other nucleic acid testing of infected secretions. Along with laboratory testing, chest CT scans may be helpful to diagnose COVID‑19 in individuals with a high clinical suspicion of infection. Detection of a past infection is possible with serological tests , which detect antibodies produced by the body in response to the infection. The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests , which detects the presence of viral RNA fragments. As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited". The test is typically done on respiratory samples obtained by a nasopharyngeal swab ; however, a nasal swab or sputum sample may also be used. Results are generally available within hours. The WHO has published several testing protocols for the disease. Several laboratories and companies have developed serological tests, which detect antibodies produced by the body in response to infection. Several have been evaluated by Public Health England and approved for use in the UK. The University of Oxford 's CEBM has pointed to mounting evidence that "a good proportion of 'new' mild cases and people re-testing positives after quarantine or discharge from hospital are not infectious, but are simply clearing harmless virus particles which their immune system has efficiently dealt with" and have called for "an international effort to standardize and periodically calibrate testing" In September 2020, the UK government issued "guidance for procedures to be implemented in laboratories to provide assurance of positive SARS-CoV-2 RNA results during periods of low prevalence, when there is a reduction in the predictive value of positive test results". Chest CT scans may be helpful to diagnose COVID‑19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses. Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions . Many groups have created COVID‑19 datasets that include imagery such as the Italian Radiological Society which has compiled an international online database of imaging findings for confirmed cases. Due to overlap with other infections such as adenovirus , imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID‑19. A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive . In late 2019, the WHO assigned emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID‑19 without lab-confirmed SARS-CoV-2 infection. The main pathological findings at autopsy are:The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests , which detects the presence of viral RNA fragments. As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited". The test is typically done on respiratory samples obtained by a nasopharyngeal swab ; however, a nasal swab or sputum sample may also be used. Results are generally available within hours. The WHO has published several testing protocols for the disease. Several laboratories and companies have developed serological tests, which detect antibodies produced by the body in response to infection. Several have been evaluated by Public Health England and approved for use in the UK. The University of Oxford 's CEBM has pointed to mounting evidence that "a good proportion of 'new' mild cases and people re-testing positives after quarantine or discharge from hospital are not infectious, but are simply clearing harmless virus particles which their immune system has efficiently dealt with" and have called for "an international effort to standardize and periodically calibrate testing" In September 2020, the UK government issued "guidance for procedures to be implemented in laboratories to provide assurance of positive SARS-CoV-2 RNA results during periods of low prevalence, when there is a reduction in the predictive value of positive test results". Chest CT scans may be helpful to diagnose COVID‑19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses. Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions . Many groups have created COVID‑19 datasets that include imagery such as the Italian Radiological Society which has compiled an international online database of imaging findings for confirmed cases. Due to overlap with other infections such as adenovirus , imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID‑19. A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive . In late 2019, the WHO assigned emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID‑19 without lab-confirmed SARS-CoV-2 infection. The main pathological findings at autopsy are:Preventive measures to reduce the chances of infection include getting vaccinated, staying at home, wearing a mask in public, avoiding crowded places, keeping distance from others, ventilating indoor spaces, managing potential exposure durations, washing hands with soap and water often and for at least twenty seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands. Those diagnosed with COVID‑19 or who believe they may be infected are advised by the CDC to stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask before entering the healthcare provider's office and when in any room or vehicle with another person, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items. The first COVID‑19 vaccine was granted regulatory approval on 2 December 2020 by the UK medicines regulator MHRA . It was evaluated for emergency use authorisation (EUA) status by the US FDA , and in several other countries. Initially, the US National Institutes of Health guidelines do not recommend any medication for prevention of COVID‑19, before or after exposure to the SARS-CoV-2 virus, outside the setting of a clinical trial. Without a vaccine, other prophylactic measures, or effective treatments, a key part of managing COVID‑19 is trying to decrease and delay the epidemic peak, known as "flattening the curve ". This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of active cases, and delaying additional cases until effective treatments or a vaccine become available. Prior to the COVID‑19 pandemic , an established body of knowledge existed about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome ( SARS ) and Middle East respiratory syndrome ( MERS ). This knowledge accelerated the development of various vaccine platforms in early 2020. The initial focus of SARS-CoV-2 vaccines was on preventing symptomatic, often severe, illness. In 2020, the first COVID ‑ 19 vaccines were developed and made available to the public through emergency authorizations and conditional approvals. Initially, most COVID ‑ 19 vaccines were two-dose vaccines, with the sole exception being the single-dose Janssen COVID‑19 vaccine . However, immunity from the vaccines has been found to wane over time, requiring people to get booster doses of the vaccine to maintain protection against COVID ‑ 19. The COVID ‑ 19 vaccines are widely credited for their role in reducing the spread of COVID ‑ 19 and reducing the severity and death caused by COVID ‑ 19. According to a June 2022 study, COVID ‑ 19 vaccines prevented an additional 14.4 to 19.8 million deaths in 185 countries and territories from 8 December 2020 to 8 December 2021. Many countries implemented phased distribution plans that prioritized those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. Common side effects of COVID ‑ 19 vaccines include soreness, redness, rash, inflammation at the injection site, fatigue, headache, myalgia (muscle pain), and arthralgia (joint pain), which resolve without medical treatment within a few days. COVID ‑ 19 vaccination is safe for people who are pregnant or are breastfeeding. In community and healthcare settings, the use of face masks is intended as source control to limit transmission of the virus and for personal protection to prevent infection. Properly worn masks both limit the respiratory droplets and aerosols spread by infected individuals and help protect healthy individuals from infection. Reviews of various kinds of scientific studies have concluded that masking is effective in protecting the individual against COVID-19. Various case-control and population-based studies have also shown that increased levels of masking in a community reduces the spread of SARS-CoV-2, though there is a paucity of evidence from randomized controlled trials (RCTs). Masks vary in how well they work, with N95 and surgical masks outperforming cloth masks, but even cloth masks, with their variability in fabric type and mask fit, provide wearers with substantial protection from particles carrying COVID-19. The CDC states that avoiding crowded indoor spaces reduces the risk of COVID-19 infection. When indoors, increasing the rate of air change, decreasing recirculation of air and increasing the use of outdoor air can reduce transmission. The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols. Exhaled respiratory particles can build-up within enclosed spaces with inadequate ventilation . The risk of COVID‑19 infection increases especially in spaces where people engage in physical exertion or raise their voice (e.g., exercising, shouting, singing) as this increases exhalation of respiratory droplets. Prolonged exposure to these conditions, typically more than 15 minutes, leads to higher risk of infection. Displacement ventilation with large natural inlets can move stale air directly to the exhaust in laminar flow while significantly reducing the concentration of droplets and particles. Passive ventilation reduces energy consumption and maintenance costs but may lack controllability and heat recovery . Displacement ventilation can also be achieved mechanically with higher energy and maintenance costs. The use of large ducts and openings helps to prevent mixing in closed environments. Recirculation and mixing should be avoided because recirculation prevents dilution of harmful particles and redistributes possibly contaminated air, and mixing increases the concentration and range of infectious particles and keeps larger particles in the air. Thorough hand hygiene after any cough or sneeze is required. The WHO also recommends that individuals wash hands often with soap and water for at least twenty seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose. When soap and water are not available, the CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol. For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol . Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis ". Glycerol is added as a humectant . Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of the disease by minimising close contact between individuals. Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres. Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others. In 2020, outbreaks occurred in prisons due to crowding and an inability to enforce adequate social distancing. In the United States, the prisoner population is ageing and many of them are at high risk for poor outcomes from COVID‑19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare. After being expelled from the body, coronaviruses can survive on surfaces for hours to days. If a person touches the dirty surface, they may deposit the virus at the eyes, nose, or mouth where it can enter the body and cause infection. Evidence indicates that contact with infected surfaces is not the main driver of COVID‑19, leading to recommendations for optimised disinfection procedures to avoid issues such as the increase of antimicrobial resistance through the use of inappropriate cleaning products and processes. Deep cleaning and other surface sanitation has been criticised as hygiene theatre , giving a false sense of security against something primarily spread through the air. The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity. Coronaviruses die very quickly when exposed to the UV light in sunlight . Like other enveloped viruses, SARS-CoV-2 survives longest when the temperature is at room temperature or lower, and when the relative humidity is low (<50%). On many surfaces, including glass, some types of plastic, stainless steel, and skin, the virus can remain infective for several days indoors at room temperature, or even about a week under ideal conditions. On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours. The virus dies faster on porous surfaces than on non-porous surfaces due to capillary action within pores and faster aerosol droplet evaporation. However, of the many surfaces tested, two with the longest survival times are N95 respirator masks and surgical masks, both of which are considered porous surfaces. The CDC says that in most situations, cleaning surfaces with soap or detergent, not disinfecting, is enough to reduce risk of transmission. The CDC recommends that if a COVID‑19 case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATMs used by the ill persons should be disinfected. Surfaces may be decontaminated with 62–71 per cent ethanol , 50–100 per cent isopropanol, 0.1 per cent sodium hypochlorite , 0.5 per cent hydrogen peroxide, 0.2–7.5 per cent povidone-iodine , or 50–200 ppm hypochlorous acid . Other solutions, such as benzalkonium chloride and chlorhexidine gluconate , are less effective. Ultraviolet germicidal irradiation may also be used, although popular devices require 5–10 min exposure and may deteriorate some materials over time. A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inoculum volumes) can be seen in the supplementary material of. Self-isolation at home has been recommended for those diagnosed with COVID‑19 and those who suspect they have been infected. Health agencies have issued detailed instructions for proper self-isolation. Many governments have mandated or recommended self-quarantine for entire populations. The strongest self-quarantine instructions have been issued to those in high-risk groups. Those who may have been exposed to someone with COVID‑19 and those who have recently travelled to a country or region with the widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure. A 2021 Cochrane rapid review found that based upon low-certainty evidence, international travel-related control measures such as restricting cross-border travel may help to contain the spread of COVID‑19. Additionally, symptom/exposure-based screening measures at borders may miss many positive cases. While test-based border screening measures may be more effective, it could also miss many positive cases if only conducted upon arrival without follow-up. The review concluded that a minimum 10-day quarantine may be beneficial in preventing the spread of COVID‑19 and may be more effective if combined with an additional control measure like border screening. Prior to the COVID‑19 pandemic , an established body of knowledge existed about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome ( SARS ) and Middle East respiratory syndrome ( MERS ). This knowledge accelerated the development of various vaccine platforms in early 2020. The initial focus of SARS-CoV-2 vaccines was on preventing symptomatic, often severe, illness. In 2020, the first COVID ‑ 19 vaccines were developed and made available to the public through emergency authorizations and conditional approvals. Initially, most COVID ‑ 19 vaccines were two-dose vaccines, with the sole exception being the single-dose Janssen COVID‑19 vaccine . However, immunity from the vaccines has been found to wane over time, requiring people to get booster doses of the vaccine to maintain protection against COVID ‑ 19. The COVID ‑ 19 vaccines are widely credited for their role in reducing the spread of COVID ‑ 19 and reducing the severity and death caused by COVID ‑ 19. According to a June 2022 study, COVID ‑ 19 vaccines prevented an additional 14.4 to 19.8 million deaths in 185 countries and territories from 8 December 2020 to 8 December 2021. Many countries implemented phased distribution plans that prioritized those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. Common side effects of COVID ‑ 19 vaccines include soreness, redness, rash, inflammation at the injection site, fatigue, headache, myalgia (muscle pain), and arthralgia (joint pain), which resolve without medical treatment within a few days. COVID ‑ 19 vaccination is safe for people who are pregnant or are breastfeeding. In community and healthcare settings, the use of face masks is intended as source control to limit transmission of the virus and for personal protection to prevent infection. Properly worn masks both limit the respiratory droplets and aerosols spread by infected individuals and help protect healthy individuals from infection. Reviews of various kinds of scientific studies have concluded that masking is effective in protecting the individual against COVID-19. Various case-control and population-based studies have also shown that increased levels of masking in a community reduces the spread of SARS-CoV-2, though there is a paucity of evidence from randomized controlled trials (RCTs). Masks vary in how well they work, with N95 and surgical masks outperforming cloth masks, but even cloth masks, with their variability in fabric type and mask fit, provide wearers with substantial protection from particles carrying COVID-19. The CDC states that avoiding crowded indoor spaces reduces the risk of COVID-19 infection. When indoors, increasing the rate of air change, decreasing recirculation of air and increasing the use of outdoor air can reduce transmission. The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols. Exhaled respiratory particles can build-up within enclosed spaces with inadequate ventilation . The risk of COVID‑19 infection increases especially in spaces where people engage in physical exertion or raise their voice (e.g., exercising, shouting, singing) as this increases exhalation of respiratory droplets. Prolonged exposure to these conditions, typically more than 15 minutes, leads to higher risk of infection. Displacement ventilation with large natural inlets can move stale air directly to the exhaust in laminar flow while significantly reducing the concentration of droplets and particles. Passive ventilation reduces energy consumption and maintenance costs but may lack controllability and heat recovery . Displacement ventilation can also be achieved mechanically with higher energy and maintenance costs. The use of large ducts and openings helps to prevent mixing in closed environments. Recirculation and mixing should be avoided because recirculation prevents dilution of harmful particles and redistributes possibly contaminated air, and mixing increases the concentration and range of infectious particles and keeps larger particles in the air. Thorough hand hygiene after any cough or sneeze is required. The WHO also recommends that individuals wash hands often with soap and water for at least twenty seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose. When soap and water are not available, the CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol. For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol . Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis ". Glycerol is added as a humectant . Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of the disease by minimising close contact between individuals. Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres. Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others. In 2020, outbreaks occurred in prisons due to crowding and an inability to enforce adequate social distancing. In the United States, the prisoner population is ageing and many of them are at high risk for poor outcomes from COVID‑19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare. After being expelled from the body, coronaviruses can survive on surfaces for hours to days. If a person touches the dirty surface, they may deposit the virus at the eyes, nose, or mouth where it can enter the body and cause infection. Evidence indicates that contact with infected surfaces is not the main driver of COVID‑19, leading to recommendations for optimised disinfection procedures to avoid issues such as the increase of antimicrobial resistance through the use of inappropriate cleaning products and processes. Deep cleaning and other surface sanitation has been criticised as hygiene theatre , giving a false sense of security against something primarily spread through the air. The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity. Coronaviruses die very quickly when exposed to the UV light in sunlight . Like other enveloped viruses, SARS-CoV-2 survives longest when the temperature is at room temperature or lower, and when the relative humidity is low (<50%). On many surfaces, including glass, some types of plastic, stainless steel, and skin, the virus can remain infective for several days indoors at room temperature, or even about a week under ideal conditions. On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours. The virus dies faster on porous surfaces than on non-porous surfaces due to capillary action within pores and faster aerosol droplet evaporation. However, of the many surfaces tested, two with the longest survival times are N95 respirator masks and surgical masks, both of which are considered porous surfaces. The CDC says that in most situations, cleaning surfaces with soap or detergent, not disinfecting, is enough to reduce risk of transmission. The CDC recommends that if a COVID‑19 case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATMs used by the ill persons should be disinfected. Surfaces may be decontaminated with 62–71 per cent ethanol , 50–100 per cent isopropanol, 0.1 per cent sodium hypochlorite , 0.5 per cent hydrogen peroxide, 0.2–7.5 per cent povidone-iodine , or 50–200 ppm hypochlorous acid . Other solutions, such as benzalkonium chloride and chlorhexidine gluconate , are less effective. Ultraviolet germicidal irradiation may also be used, although popular devices require 5–10 min exposure and may deteriorate some materials over time. A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inoculum volumes) can be seen in the supplementary material of. Self-isolation at home has been recommended for those diagnosed with COVID‑19 and those who suspect they have been infected. Health agencies have issued detailed instructions for proper self-isolation. Many governments have mandated or recommended self-quarantine for entire populations. The strongest self-quarantine instructions have been issued to those in high-risk groups. Those who may have been exposed to someone with COVID‑19 and those who have recently travelled to a country or region with the widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure. A 2021 Cochrane rapid review found that based upon low-certainty evidence, international travel-related control measures such as restricting cross-border travel may help to contain the spread of COVID‑19. Additionally, symptom/exposure-based screening measures at borders may miss many positive cases. While test-based border screening measures may be more effective, it could also miss many positive cases if only conducted upon arrival without follow-up. The review concluded that a minimum 10-day quarantine may be beneficial in preventing the spread of COVID‑19 and may be more effective if combined with an additional control measure like border screening. The treatment and management of COVID-19 combines both supportive care , which includes treatment to relieve symptoms , fluid therapy , oxygen support as needed, and a growing list of approved medications. Highly effective vaccines have reduced mortality related to SARS-CoV-2; however, for those awaiting vaccination, as well as for the estimated millions of immunocompromised persons who are unlikely to respond robustly to vaccination, treatment remains important. Some people may experience persistent symptoms or disability after recovery from the infection, known as long COVID , but there is still limited information on the best management and rehabilitation for this condition. Most cases of COVID-19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing . Good personal hygiene and a healthy diet are also recommended. As of April 2020 the U.S. Centers for Disease Control and Prevention (CDC) recommended that those who suspect they are carrying the virus isolate themselves at home and wear a face mask. As of November 2020 use of the glucocorticoid dexamethasone had been strongly recommended in those severe cases treated in hospital with low oxygen levels, to reduce the risk of death. Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing. Extracorporeal membrane oxygenation (ECMO) has been used to address respiratory failure, but its benefits are still under consideration. Some of the cases of severe disease course are caused by systemic hyper-inflammation, the so-called cytokine storm . Although several medications have been approved in different countries as of April 2022, not all countries have these medications. Patients with mild to moderate symptoms who are in the risk groups can take nirmatrelvir/ritonavir (marketed as Paxlovid) or remdesivir , either of which reduces the risk of serious illness or hospitalization. In the US, the Biden Administration COVID-19 action plan includes the Test to Treat initiative, where people can go to a pharmacy, take a COVID test, and immediately receive free Paxlovid if they test positive. The severity of COVID‑19 varies. The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold . In 3–4% of cases (7.4% for those over age 65) symptoms are severe enough to cause hospitalisation. Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks. The Italian Istituto Superiore di Sanità reported that the median time between the onset of symptoms and death was twelve days, with seven being hospitalised. However, people transferred to an ICU had a median time of ten days between hospitalisation and death. Abnormal sodium levels during hospitalisation with COVID-19 are associated with poor prognoses: high sodium with a greater risk of death, and low sodium with an increased chance of needing ventilator support. Prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital are associated with severe course of COVID‑19 and with a transfer to ICU. Some early studies suggest 10% to 20% of people with COVID‑19 will experience symptoms lasting longer than a month . A majority of those who were admitted to hospital with severe disease report long-term problems including fatigue and shortness of breath. On 30 October 2020, WHO chief Tedros Adhanom warned that "to a significant number of people, the COVID virus poses a range of serious long-term effects". He has described the vast spectrum of COVID‑19 symptoms that fluctuate over time as "really concerning". They range from fatigue, a cough and shortness of breath, to inflammation and injury of major organs – including the lungs and heart, and also neurological and psychologic effects. Symptoms often overlap and can affect any system in the body. Infected people have reported cyclical bouts of fatigue, headaches, months of complete exhaustion, mood swings, and other symptoms. Tedros therefore concluded that a strategy of achieving herd immunity by infection, rather than vaccination, is "morally unconscionable and unfeasible". In terms of hospital readmissions about 9% of 106,000 individuals had to return for hospital treatment within two months of discharge. The average to readmit was eight days since first hospital visit. There are several risk factors that have been identified as being a cause of multiple admissions to a hospital facility. Among these are advanced age (above 65 years of age) and presence of a chronic condition such as diabetes, COPD, heart failure or chronic kidney disease. According to scientific reviews smokers are more likely to require intensive care or die compared to non-smokers. Acting on the same ACE2 pulmonary receptors affected by smoking, air pollution has been correlated with the disease. Short-term and chronic exposure to air pollution seems to enhance morbidity and mortality from COVID‑19. Pre-existing heart and lung diseases and also obesity , especially in conjunction with fatty liver disease , contributes to an increased health risk of COVID‑19. It is also assumed that those that are immunocompromised are at higher risk of getting severely sick from SARS-CoV-2. One research study that looked into the COVID‑19 infections in hospitalised kidney transplant recipients found a mortality rate of 11%. Men with untreated hypogonadism were 2.4 times more likely than men with eugonadism to be hospitalised if they contracted COVID-19; Hypogonad men treated with testosterone were less likely to be hospitalised for COVID-19 than men who were not treated for hypogonadism. Genetics plays an important role in the ability to fight off Covid. For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID‑19. Genetic screening is able to detect interferon effector genes. Some genetic variants are risk factors in specific populations. For instance, an allele of the DOCK2 gene (dedicator of cytokinesis 2 gene) is a common risk factor in Asian populations but much less common in Europe. The mutation leads to lower expression of DOCK2 especially in younger patients with severe Covid. In fact, many other genes and genetic variants have been found that determine the outcome of SARS-CoV-2 infections. While very young children have experienced lower rates of infection, older children have a rate of infection that is similar to the population as a whole. Children are likely to have milder symptoms and are at lower risk of severe disease than adults. The CDC reports that in the US roughly a third of hospitalised children were admitted to the ICU, while a European multinational study of hospitalised children from June 2020, found that about 8% of children admitted to a hospital needed intensive care. Four of the 582 children (0.7%) in the European study died, but the actual mortality rate may be "substantially lower" since milder cases that did not seek medical help were not included in the study. Around 10% to 30% of non-hospitalised people with COVID-19 go on to develop long COVID . For those that do need hospitalisation, the incidence of long-term effects is over 50%. Long COVID is an often severe multisystem disease with a large set of symptoms. There are likely various, possibly coinciding, causes. Organ damage from the acute infection can explain a part of the symptoms, but long COVID is also observed in people where organ damage seems to be absent. By a variety of mechanisms, the lungs are the organs most affected in COVID ‑ 19. In people requiring hospital admission, up to 98% of CT scans performed show lung abnormalities after 28 days of illness even if they had clinically improved. People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long-lasting effects, including pulmonary fibrosis. Overall, approximately one-third of those investigated after four weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO , even in asymptomatic people, but with the suggestion of continuing improvement with the passing of more time. After severe disease, lung function can take anywhere from three months to a year or more to return to previous levels. The risks of cognitive deficit , dementia , psychotic disorders, and epilepsy or seizures persists at an increased level two years after infection. The immune response by humans to SARS-CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production, just as with most other infections. B cells interact with T cells and begin dividing before selection into the plasma cell, partly on the basis of their affinity for antigen. Since SARS-CoV-2 has been in the human population only since December 2019, it remains unknown if the immunity is long-lasting in people who recover from the disease. The presence of neutralising antibodies in blood strongly correlates with protection from infection, but the level of neutralising antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralising antibody two months after infection. In another study, the level of neutralising antibodies fell four-fold one to four months after the onset of symptoms. However, the lack of antibodies in the blood does not mean antibodies will not be rapidly produced upon reexposure to SARS-CoV-2. Memory B cells specific for the spike and nucleocapsid proteins of SARS-CoV-2 last for at least six months after the appearance of symptoms. As of August 2021, reinfection with COVID‑19 was possible but uncommon. The first case of reinfection was documented in August 2020. A systematic review found 17 cases of confirmed reinfection in medical literature as of May 2021. With the Omicron variant , as of 2022, reinfections have become common, albeit it is unclear how common. COVID-19 reinfections are thought to likely be less severe than primary infections, especially if one was previously infected by the same variant. [ additional citation(s) needed ]Genetics plays an important role in the ability to fight off Covid. For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID‑19. Genetic screening is able to detect interferon effector genes. Some genetic variants are risk factors in specific populations. For instance, an allele of the DOCK2 gene (dedicator of cytokinesis 2 gene) is a common risk factor in Asian populations but much less common in Europe. The mutation leads to lower expression of DOCK2 especially in younger patients with severe Covid. In fact, many other genes and genetic variants have been found that determine the outcome of SARS-CoV-2 infections. While very young children have experienced lower rates of infection, older children have a rate of infection that is similar to the population as a whole. Children are likely to have milder symptoms and are at lower risk of severe disease than adults. The CDC reports that in the US roughly a third of hospitalised children were admitted to the ICU, while a European multinational study of hospitalised children from June 2020, found that about 8% of children admitted to a hospital needed intensive care. Four of the 582 children (0.7%) in the European study died, but the actual mortality rate may be "substantially lower" since milder cases that did not seek medical help were not included in the study. Around 10% to 30% of non-hospitalised people with COVID-19 go on to develop long COVID . For those that do need hospitalisation, the incidence of long-term effects is over 50%. Long COVID is an often severe multisystem disease with a large set of symptoms. There are likely various, possibly coinciding, causes. Organ damage from the acute infection can explain a part of the symptoms, but long COVID is also observed in people where organ damage seems to be absent. By a variety of mechanisms, the lungs are the organs most affected in COVID ‑ 19. In people requiring hospital admission, up to 98% of CT scans performed show lung abnormalities after 28 days of illness even if they had clinically improved. People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long-lasting effects, including pulmonary fibrosis. Overall, approximately one-third of those investigated after four weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO , even in asymptomatic people, but with the suggestion of continuing improvement with the passing of more time. After severe disease, lung function can take anywhere from three months to a year or more to return to previous levels. The risks of cognitive deficit , dementia , psychotic disorders, and epilepsy or seizures persists at an increased level two years after infection. The immune response by humans to SARS-CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production, just as with most other infections. B cells interact with T cells and begin dividing before selection into the plasma cell, partly on the basis of their affinity for antigen. Since SARS-CoV-2 has been in the human population only since December 2019, it remains unknown if the immunity is long-lasting in people who recover from the disease. The presence of neutralising antibodies in blood strongly correlates with protection from infection, but the level of neutralising antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralising antibody two months after infection. In another study, the level of neutralising antibodies fell four-fold one to four months after the onset of symptoms. However, the lack of antibodies in the blood does not mean antibodies will not be rapidly produced upon reexposure to SARS-CoV-2. Memory B cells specific for the spike and nucleocapsid proteins of SARS-CoV-2 last for at least six months after the appearance of symptoms. As of August 2021, reinfection with COVID‑19 was possible but uncommon. The first case of reinfection was documented in August 2020. A systematic review found 17 cases of confirmed reinfection in medical literature as of May 2021. With the Omicron variant , as of 2022, reinfections have become common, albeit it is unclear how common. COVID-19 reinfections are thought to likely be less severe than primary infections, especially if one was previously infected by the same variant. [ additional citation(s) needed ]Several measures are commonly used to quantify mortality. These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since the initial outbreak, and population characteristics such as age, sex, and overall health. The mortality rate reflects the number of deaths within a specific demographic group divided by the population of that demographic group. Consequently, the mortality rate reflects the prevalence as well as the severity of the disease within a given population. Mortality rates are highly correlated to age, with relatively low rates for young people and relatively high rates among the elderly. In fact, one relevant factor of mortality rates is the age structure of the countries' populations. For example, the case fatality rate for COVID‑19 is lower in India than in the US since India's younger population represents a larger percentage than in the US. The case fatality rate (CFR) reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 1.02% ( 6,881,955 / 676,609,955 ) as of 10 March 2023 . The number varies by region. A key metric in gauging the severity of COVID‑19 is the infection fatality rate (IFR), also referred to as the infection fatality ratio or infection fatality risk . This metric is calculated by dividing the total number of deaths from the disease by the total number of infected individuals; hence, in contrast to the CFR , the IFR incorporates asymptomatic and undiagnosed infections as well as reported cases. A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO. An analysis of those IFR rates indicates that COVID ‑ 19 is hazardous not only for the elderly but also for middle-aged adults, for whom the infection fatality rate of COVID-19 is two orders of magnitude greater than the annualised risk of a fatal automobile accident and far more dangerous than seasonal influenza . At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%. On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. (After sufficient time however, people can get reinfected). As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID‑19 (0.3% of the population). Antibody testing in New York City suggested an IFR of ≈0.9%, and ≈1.4%. In Bergamo province , 0.6% of the population has died. In September 2020, the U.S. Centers for Disease Control and Prevention (CDC) reported preliminary estimates of age-specific IFRs for public health planning purposes. COVID‑19 case fatality rates are higher among men than women in most countries. However, in a few countries like India, Nepal, Vietnam, and Slovenia the fatality cases are higher in women than men. Globally, men are more likely to be admitted to the ICU and more likely to die. One meta-analysis found that globally, men were more likely to get COVID‑19 than women; there were approximately 55 men and 45 women per 100 infections ( CI : 51.43–56.58). The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women. Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders. One review acknowledges the different mortality rates in Chinese men, suggesting that it may be attributable to lifestyle choices such as smoking and drinking alcohol rather than genetic factors. Smoking, which in some countries like China is mainly a male activity, is a habit that contributes to increasing significantly the case fatality rates among men. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe as of February 2020, 57% of the infected people were men and 72% of those died with COVID‑19 were men. As of April 2020, the US government is not tracking sex-related data of COVID‑19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently. In the US, a greater proportion of deaths due to COVID‑19 have occurred among African Americans and other minority groups. Structural factors that prevent them from practising social distancing include their concentration in crowded substandard housing and in "essential" occupations such as retail grocery workers, public transit employees, health-care workers and custodial staff. Greater prevalence of lacking health insurance and care of underlying conditions such as diabetes , hypertension, and heart disease also increase their risk of death. Similar issues affect Native American and Latino communities. On the one hand, in the Dominican Republic there is a clear example of both gender and ethnic inequality. In this Latin American territory, there is great inequality and precariousness that especially affects Dominican women, with greater emphasis on those of Haitian descent. According to a US health policy non-profit, 34% of American Indian and Alaska Native People (AIAN) non-elderly adults are at risk of serious illness compared to 21% of white non-elderly adults. The source attributes it to disproportionately high rates of many health conditions that may put them at higher risk as well as living conditions like lack of access to clean water. Leaders have called for efforts to research and address the disparities. In the UK, a greater proportion of deaths due to COVID‑19 have occurred in those of a Black , Asian , and other ethnic minority background. More severe impacts upon patients including the relative incidence of the necessity of hospitalisation requirements, and vulnerability to the disease has been associated via DNA analysis to be expressed in genetic variants at chromosomal region 3, features that are associated with European Neanderthal heritage. That structure imposes greater risks that those affected will develop a more severe form of the disease. The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet . This admixture of modern human and Neanderthal genes is estimated to have occurred roughly between 50,000 and 60,000 years ago in Southern Europe. Biological factors (immune response) and the general behaviour (habits) can strongly determine the consequences of COVID‑19. Most of those who die of COVID‑19 have pre-existing (underlying) conditions , including hypertension, diabetes mellitus , and cardiovascular disease . According to March data from the United States, 89% of those hospitalised had preexisting conditions. The Italian Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 96.1% of people had at least one comorbidity with the average person having 3.4 diseases. According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), ischaemic heart disease (27.6% of deaths), atrial fibrillation (23.1% of deaths) and chronic renal failure (20.2% of deaths). Most critical respiratory comorbidities according to the US Centers for Disease Control and Prevention (CDC), are: moderate or severe asthma , pre-existing COPD , pulmonary fibrosis , cystic fibrosis . Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes. When someone with existing respiratory problems is infected with COVID‑19, they might be at greater risk for severe symptoms. COVID‑19 also poses a greater risk to people who misuse opioids and amphetamines , insofar as their drug use may have caused lung damage. In August 2020, the CDC issued a caution that tuberculosis (TB) infections could increase the risk of severe illness or death. The WHO recommended that people with respiratory symptoms be screened for both diseases, as testing positive for COVID‑19 could not rule out co-infections. Some projections have estimated that reduced TB detection due to the pandemic could result in 6.3 million additional TB cases and 1.4 million TB-related deaths by 2025. The case fatality rate (CFR) reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 1.02% ( 6,881,955 / 676,609,955 ) as of 10 March 2023 . The number varies by region. A key metric in gauging the severity of COVID‑19 is the infection fatality rate (IFR), also referred to as the infection fatality ratio or infection fatality risk . This metric is calculated by dividing the total number of deaths from the disease by the total number of infected individuals; hence, in contrast to the CFR , the IFR incorporates asymptomatic and undiagnosed infections as well as reported cases. A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO. An analysis of those IFR rates indicates that COVID ‑ 19 is hazardous not only for the elderly but also for middle-aged adults, for whom the infection fatality rate of COVID-19 is two orders of magnitude greater than the annualised risk of a fatal automobile accident and far more dangerous than seasonal influenza . At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%. On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. (After sufficient time however, people can get reinfected). As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID‑19 (0.3% of the population). Antibody testing in New York City suggested an IFR of ≈0.9%, and ≈1.4%. In Bergamo province , 0.6% of the population has died. In September 2020, the U.S. Centers for Disease Control and Prevention (CDC) reported preliminary estimates of age-specific IFRs for public health planning purposes. A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO. An analysis of those IFR rates indicates that COVID ‑ 19 is hazardous not only for the elderly but also for middle-aged adults, for whom the infection fatality rate of COVID-19 is two orders of magnitude greater than the annualised risk of a fatal automobile accident and far more dangerous than seasonal influenza . At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%. On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. (After sufficient time however, people can get reinfected). As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID‑19 (0.3% of the population). Antibody testing in New York City suggested an IFR of ≈0.9%, and ≈1.4%. In Bergamo province , 0.6% of the population has died. In September 2020, the U.S. Centers for Disease Control and Prevention (CDC) reported preliminary estimates of age-specific IFRs for public health planning purposes. COVID‑19 case fatality rates are higher among men than women in most countries. However, in a few countries like India, Nepal, Vietnam, and Slovenia the fatality cases are higher in women than men. Globally, men are more likely to be admitted to the ICU and more likely to die. One meta-analysis found that globally, men were more likely to get COVID‑19 than women; there were approximately 55 men and 45 women per 100 infections ( CI : 51.43–56.58). The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women. Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders. One review acknowledges the different mortality rates in Chinese men, suggesting that it may be attributable to lifestyle choices such as smoking and drinking alcohol rather than genetic factors. Smoking, which in some countries like China is mainly a male activity, is a habit that contributes to increasing significantly the case fatality rates among men. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe as of February 2020, 57% of the infected people were men and 72% of those died with COVID‑19 were men. As of April 2020, the US government is not tracking sex-related data of COVID‑19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently. In the US, a greater proportion of deaths due to COVID‑19 have occurred among African Americans and other minority groups. Structural factors that prevent them from practising social distancing include their concentration in crowded substandard housing and in "essential" occupations such as retail grocery workers, public transit employees, health-care workers and custodial staff. Greater prevalence of lacking health insurance and care of underlying conditions such as diabetes , hypertension, and heart disease also increase their risk of death. Similar issues affect Native American and Latino communities. On the one hand, in the Dominican Republic there is a clear example of both gender and ethnic inequality. In this Latin American territory, there is great inequality and precariousness that especially affects Dominican women, with greater emphasis on those of Haitian descent. According to a US health policy non-profit, 34% of American Indian and Alaska Native People (AIAN) non-elderly adults are at risk of serious illness compared to 21% of white non-elderly adults. The source attributes it to disproportionately high rates of many health conditions that may put them at higher risk as well as living conditions like lack of access to clean water. Leaders have called for efforts to research and address the disparities. In the UK, a greater proportion of deaths due to COVID‑19 have occurred in those of a Black , Asian , and other ethnic minority background. More severe impacts upon patients including the relative incidence of the necessity of hospitalisation requirements, and vulnerability to the disease has been associated via DNA analysis to be expressed in genetic variants at chromosomal region 3, features that are associated with European Neanderthal heritage. That structure imposes greater risks that those affected will develop a more severe form of the disease. The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet . This admixture of modern human and Neanderthal genes is estimated to have occurred roughly between 50,000 and 60,000 years ago in Southern Europe. Biological factors (immune response) and the general behaviour (habits) can strongly determine the consequences of COVID‑19. Most of those who die of COVID‑19 have pre-existing (underlying) conditions , including hypertension, diabetes mellitus , and cardiovascular disease . According to March data from the United States, 89% of those hospitalised had preexisting conditions. The Italian Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 96.1% of people had at least one comorbidity with the average person having 3.4 diseases. According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), ischaemic heart disease (27.6% of deaths), atrial fibrillation (23.1% of deaths) and chronic renal failure (20.2% of deaths). Most critical respiratory comorbidities according to the US Centers for Disease Control and Prevention (CDC), are: moderate or severe asthma , pre-existing COPD , pulmonary fibrosis , cystic fibrosis . Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes. When someone with existing respiratory problems is infected with COVID‑19, they might be at greater risk for severe symptoms. COVID‑19 also poses a greater risk to people who misuse opioids and amphetamines , insofar as their drug use may have caused lung damage. In August 2020, the CDC issued a caution that tuberculosis (TB) infections could increase the risk of severe illness or death. The WHO recommended that people with respiratory symptoms be screened for both diseases, as testing positive for COVID‑19 could not rule out co-infections. Some projections have estimated that reduced TB detection due to the pandemic could result in 6.3 million additional TB cases and 1.4 million TB-related deaths by 2025. The virus is thought to be of natural animal origin, most likely through spillover infection . A joint-study conducted in early 2021 by the People's Republic of China and the World Health Organization indicated that the virus descended from a coronavirus that infects wild bats, and likely spread to humans through an intermediary wildlife host. There are several theories about where the index case originated and investigations into the origin of the pandemic are ongoing. According to articles published in July 2022 in Science , virus transmission into humans occurred through two spillover events in November 2019 and was likely due to live wildlife trade on the Huanan wet market in the city of Wuhan (Hubei, China). Doubts about the conclusions have mostly centered on the precise site of spillover. Earlier phylogenetics estimated that SARS-CoV-2 arose in October or November 2019. A phylogenetic algorithm analysis suggested that the virus may have been circulating in Guangdong before Wuhan. Most scientists believe the virus spilled into human populations through natural zoonosis , similar to the SARS-CoV-1 and MERS-CoV outbreaks, and consistent with other pandemics in human history. According to the Intergovernmental Panel on Climate Change several social and environmental factors including climate change , natural ecosystem destruction and wildlife trade increased the likelihood of such zoonotic spillover . One study made with the support of the European Union found climate change increased the likelihood of the pandemic by influencing distribution of bat species. Available evidence suggests that the SARS-CoV-2 virus was originally harboured by bats, and spread to humans multiple times from infected wild animals at the Huanan Seafood Market in Wuhan in December 2019. A minority of scientists and some members of the U.S intelligence community believe the virus may have been unintentionally leaked from a laboratory such as the Wuhan Institute of Virology . The US intelligence community has mixed views on the issue, but overall agrees with the scientific consensus that the virus was not developed as a biological weapon and is unlikely to have been genetically engineered . There is no evidence SARS-CoV-2 existed in any laboratory prior to the pandemic. The first confirmed human infections were in Wuhan. A study of the first 41 cases of confirmed COVID‑19, published in January 2020 in The Lancet , reported the earliest date of onset of symptoms as 1 December 2019. Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019. Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020. According to official Chinese sources, these were mostly linked to the Huanan Seafood Wholesale Market , which also sold live animals. In May 2020, George Gao , the director of the CDC, said animal samples collected from the seafood market had tested negative for the virus, indicating that the market was the site of an early superspreading event , but that it was not the site of the initial outbreak. Traces of the virus have been found in wastewater samples that were collected in Milan and Turin , Italy, on 18 December 2019. By December 2019, the spread of infection was almost entirely driven by human-to-human transmission. The number of COVID-19 cases in Hubei gradually increased, reaching sixty by 20 December, and at least 266 by 31 December. On 24 December, Wuhan Central Hospital sent a bronchoalveolar lavage fluid (BAL) sample from an unresolved clinical case to sequencing company Vision Medicals. On 27 and 28 December, Vision Medicals informed the Wuhan Central Hospital and the Chinese CDC of the results of the test, showing a new coronavirus. A pneumonia cluster of unknown cause was observed on 26 December and treated by the doctor Zhang Jixian in Hubei Provincial Hospital, who informed the Wuhan Jianghan CDC on 27 December. On 30 December, a test report addressed to Wuhan Central Hospital, from company CapitalBio Medlab, stated an erroneous positive result for SARS , causing a group of doctors at Wuhan Central Hospital to alert their colleagues and relevant hospital authorities of the result. The Wuhan Municipal Health Commission issued a notice to various medical institutions on "the treatment of pneumonia of unknown cause" that same evening. Eight of these doctors, including Li Wenliang (punished on 3 January), were later admonished by the police for spreading false rumours and another, Ai Fen , was reprimanded by her superiors for raising the alarm. The Wuhan Municipal Health Commission made the first public announcement of a pneumonia outbreak of unknown cause on 31 December, confirming 27 cases – enough to trigger an investigation. During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days. In early and mid-January 2020, the virus spread to other Chinese provinces , helped by the Chinese New Year migration and Wuhan being a transport hub and major rail interchange. On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen . Later official data shows 6,174 people had already developed symptoms by then, and more may have been infected. A report in The Lancet on 24 January indicated human transmission, strongly recommended personal protective equipment for health workers, and said testing for the virus was essential due to its "pandemic potential". On 30 January, the WHO declared COVID-19 a Public Health Emergency of International Concern . By this time, the outbreak spread by a factor of 100 to 200 times. Italy had its first confirmed cases on 31 January 2020, two tourists from China. Italy overtook China as the country with the most deaths on 19 March 2020. By 26 March the United States had overtaken China and Italy with the highest number of confirmed cases in the world. Research on coronavirus genomes indicates the majority of COVID-19 cases in New York came from European travellers, rather than directly from China or any other Asian country. Retesting of prior samples found a person in France who had the virus on 27 December 2019, and a person in the United States who died from the disease on 6 February 2020. RT-PCR testing of untreated wastewater samples from Brazil and Italy have suggested detection of SARS-CoV-2 as early as November and December 2019, respectively, but the methods of such sewage studies have not been optimised, many have not been peer-reviewed, details are often missing, and there is a risk of false positives due to contamination or if only one gene target is detected. A September 2020 review journal article said, "The possibility that the COVID‑19 infection had already spread to Europe at the end of last year is now indicated by abundant, even if partially circumstantial, evidence", including pneumonia case numbers and radiology in France and Italy in November and December. As of 1 October 2021 [ update ] , Reuters reported that it had estimated the worldwide total number of deaths due to COVID‑19 to have exceeded five million. The Public Health Emergency of International Concern for COVID-19 ended on May 5, 2023. By this time, everyday life in most countries had returned to how it was before the pandemic. After the initial outbreak of COVID ‑ 19, misinformation and disinformation regarding the origin, scale, prevention, treatment, and other aspects of the disease rapidly spread online. In September 2020, the US Centers for Disease Control and Prevention (CDC) published preliminary estimates of the risk of death by age groups in the United States, but those estimates were widely misreported and misunderstood. Humans appear to be capable of spreading the virus to some other animals, a type of disease transmission referred to as zooanthroponosis . Some pets, especially cats and ferrets , can catch this virus from infected humans. Symptoms in cats include respiratory (such as a cough) and digestive symptoms. Cats can spread the virus to other cats, and may be able to spread the virus to humans, but cat-to-human transmission of SARS-CoV-2 has not been proven. Compared to cats, dogs are less susceptible to this infection. Behaviours which increase the risk of transmission include kissing, licking, and petting the animal. The virus does not appear to be able to infect pigs , ducks , or chickens at all. Mice , rats, and rabbits, if they can be infected at all, are unlikely to be involved in spreading the virus. Tigers and lions in zoos have become infected as a result of contact with infected humans. As expected, monkeys and great ape species such as orangutans can also be infected with the COVID‑19 virus. Minks , which are in the same family as ferrets, have been infected. Minks may be asymptomatic, and can also spread the virus to humans. Multiple countries have identified infected animals in mink farms . Denmark , a major producer of mink pelts, ordered the slaughter of all minks over fears of viral mutations, following an outbreak referred to as Cluster 5 . A vaccine for mink and other animals is being researched. International research on vaccines and medicines in COVID ‑ 19 is underway by government organisations, academic groups, and industry researchers. The CDC has classified it to require a BSL3 grade laboratory. There has been a great deal of COVID‑19 research, involving accelerated research processes and publishing shortcuts to meet the global demand. As of December 2020 [ update ] , hundreds of clinical trials have been undertaken, with research happening on every continent except Antarctica . As of November 2020 [ update ] , more than 200 possible treatments have been studied in humans. Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission, diagnosis and prognosis of infection, estimation of the impact of interventions, or allocation of resources. Modelling studies are mostly based on compartmental models in epidemiology , estimating the number of infected people over time under given conditions. Several other types of models have been developed and used during the COVID ‑ 19 pandemic including computational fluid dynamics models to study the flow physics of COVID ‑ 19, retrofits of crowd movement models to study occupant exposure, mobility-data based models to investigate transmission, or the use of macroeconomic models to assess the economic impact of the pandemic. Repurposed antiviral drugs make up most of the research into COVID‑19 treatments. Other candidates in trials include vasodilators , corticosteroids , immune therapies, lipoic acid , bevacizumab , and recombinant angiotensin-converting enzyme 2. In March 2020, the World Health Organization (WHO) initiated the Solidarity trial to assess the treatment effects of some promising drugs: an experimental drug called remdesivir; anti-malarial drugs chloroquine and hydroxychloroquine; two anti-HIV drugs , lopinavir/ritonavir ; and interferon-beta . More than 300 active clinical trials are underway as of April 2020. Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best, and that they may reduce the antiviral activity of remdesivir. By May 2020 [ update ] , France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID‑19 treatment. In June, initial results from the randomised RECOVERY Trial in the United Kingdom showed that dexamethasone reduced mortality by one third for people who are critically ill on ventilators and one fifth for those receiving supplemental oxygen. Because this is a well-tested and widely available treatment, it was welcomed by the WHO, which is in the process of updating treatment guidelines to include dexamethasone and other steroids. Based on those preliminary results, dexamethasone treatment has been recommended by the NIH for patients with COVID‑19 who are mechanically ventilated or who require supplemental oxygen but not in patients with COVID‑19 who do not require supplemental oxygen. In September 2020, the WHO released updated guidance on using corticosteroids for COVID‑19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID‑19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID‑19 (conditional recommendation, based on low certainty evidence). The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID‑19 patients. In September 2020, the European Medicines Agency (EMA) endorsed the use of dexamethasone in adults and adolescents from twelve years of age and weighing at least 40 kilograms (88 lb) who require supplemental oxygen therapy. Dexamethasone can be taken by mouth or given as an injection or infusion (drip) into a vein . In November 2020, the US Food and Drug Administration (FDA) issued an emergency use authorisation for the investigational monoclonal antibody therapy bamlanivimab for the treatment of mild-to-moderate COVID‑19. Bamlanivimab is authorised for people with positive results of direct SARS-CoV-2 viral testing who are twelve years of age and older weighing at least 40 kilograms (88 lb) , and who are at high risk for progressing to severe COVID‑19 or hospitalisation. This includes those who are 65 years of age or older, or who have chronic medical conditions. In February 2021, the FDA issued an emergency use authorisation (EUA) for bamlanivimab and etesevimab administered together for the treatment of mild to moderate COVID‑19 in people twelve years of age or older weighing at least 40 kilograms (88 lb) who test positive for SARS‑CoV‑2 and who are at high risk for progressing to severe COVID‑19. The authorised use includes treatment for those who are 65 years of age or older or who have certain chronic medical conditions. In April 2021, the FDA revoked the emergency use authorisation (EUA) that allowed for the investigational monoclonal antibody therapy bamlanivimab, when administered alone, to be used for the treatment of mild-to-moderate COVID‑19 in adults and certain paediatric patients. A cytokine storm can be a complication in the later stages of severe COVID‑19. A cytokine storm is a potentially deadly immune reaction where a large amount of pro-inflammatory cytokines and chemokines are released too quickly. A cytokine storm can lead to ARDS and multiple organ failure. Data collected from Jin Yin-tan Hospital in Wuhan, China indicates that patients who had more severe responses to COVID‑19 had greater amounts of pro-inflammatory cytokines and chemokines in their system than patients who had milder responses. These high levels of pro-inflammatory cytokines and chemokines indicate presence of a cytokine storm. Tocilizumab has been included in treatment guidelines by China's National Health Commission after a small study was completed. It is undergoing a Phase II non-randomised trial at the national level in Italy after showing positive results in people with severe disease. Combined with a serum ferritin blood test to identify a cytokine storm (also called cytokine storm syndrome, not to be confused with cytokine release syndrome), it is meant to counter such developments, which are thought to be the cause of death in some affected people. The interleukin-6 receptor (IL-6R) antagonist was approved by the FDA to undergo a Phase III clinical trial assessing its effectiveness on COVID‑19 based on retrospective case studies for the treatment of steroid-refractory cytokine release syndrome induced by a different cause, CAR T cell therapy , in 2017. There is no randomised, controlled evidence that tocilizumab is an efficacious treatment for CRS. Prophylactic tocilizumab has been shown to increase serum IL-6 levels by saturating the IL-6R, driving IL-6 across the blood–brain barrier , and exacerbating neurotoxicity while having no effect on the incidence of CRS. Lenzilumab , an anti-GM-CSF monoclonal antibody , is protective in murine models for CAR T cell-induced CRS and neurotoxicity and is a viable therapeutic option due to the observed increase of pathogenic GM-CSF secreting T cells in hospitalised patients with COVID‑19. Transferring purified and concentrated antibodies produced by the immune systems of those who have recovered from COVID‑19 to people who need them is being investigated as a non-vaccine method of passive immunisation . Viral neutralisation is the anticipated mechanism of action by which passive antibody therapy can mediate defence against SARS-CoV-2. The spike protein of SARS-CoV-2 is the primary target for neutralising antibodies. As of 8 August 2020, eight neutralising antibodies targeting the spike protein of SARS-CoV-2 have entered clinical studies. It has been proposed that selection of broad-neutralising antibodies against SARS-CoV-2 and SARS-CoV might be useful for treating not only COVID‑19 but also future SARS-related CoV infections. Other mechanisms, however, such as antibody-dependant cellular cytotoxicity or phagocytosis , may be possible. Other forms of passive antibody therapy, for example, using manufactured monoclonal antibodies, are in development. The use of passive antibodies to treat people with active COVID ‑ 19 is also being studied. This involves the production of convalescent serum , which consists of the liquid portion of the blood from people who recovered from the infection and contains antibodies specific to this virus, which is then administered to active patients. This strategy was tried for SARS with inconclusive results. An updated Cochrane review in May 2023 found high certainty evidence that, for the treatment of people with moderate to severe COVID‑19, convalescent plasma did not reduce mortality or bring about symptom improvement. There continues to be uncertainty about the safety of convalescent plasma administration to people with COVID‑19 and differing outcomes measured in different studies limits their use in determining efficacy. Since the outbreak of the COVID‑19 pandemic, scholars have explored the bioethics , normative economics , and political theories of healthcare policies related to the public health crisis. Academics have pointed to the moral distress of healthcare workers, ethics of distributing scarce healthcare resources such as ventilators, and the global justice of vaccine diplomacies. [ citation needed ] The socio-economic inequalities between genders, races, groups with disabilities, communities, regions, countries, and continents have also drawn attention in academia and the general public.Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission, diagnosis and prognosis of infection, estimation of the impact of interventions, or allocation of resources. Modelling studies are mostly based on compartmental models in epidemiology , estimating the number of infected people over time under given conditions. Several other types of models have been developed and used during the COVID ‑ 19 pandemic including computational fluid dynamics models to study the flow physics of COVID ‑ 19, retrofits of crowd movement models to study occupant exposure, mobility-data based models to investigate transmission, or the use of macroeconomic models to assess the economic impact of the pandemic. Repurposed antiviral drugs make up most of the research into COVID‑19 treatments. Other candidates in trials include vasodilators , corticosteroids , immune therapies, lipoic acid , bevacizumab , and recombinant angiotensin-converting enzyme 2. In March 2020, the World Health Organization (WHO) initiated the Solidarity trial to assess the treatment effects of some promising drugs: an experimental drug called remdesivir; anti-malarial drugs chloroquine and hydroxychloroquine; two anti-HIV drugs , lopinavir/ritonavir ; and interferon-beta . More than 300 active clinical trials are underway as of April 2020. Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best, and that they may reduce the antiviral activity of remdesivir. By May 2020 [ update ] , France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID‑19 treatment. In June, initial results from the randomised RECOVERY Trial in the United Kingdom showed that dexamethasone reduced mortality by one third for people who are critically ill on ventilators and one fifth for those receiving supplemental oxygen. Because this is a well-tested and widely available treatment, it was welcomed by the WHO, which is in the process of updating treatment guidelines to include dexamethasone and other steroids. Based on those preliminary results, dexamethasone treatment has been recommended by the NIH for patients with COVID‑19 who are mechanically ventilated or who require supplemental oxygen but not in patients with COVID‑19 who do not require supplemental oxygen. In September 2020, the WHO released updated guidance on using corticosteroids for COVID‑19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID‑19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID‑19 (conditional recommendation, based on low certainty evidence). The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID‑19 patients. In September 2020, the European Medicines Agency (EMA) endorsed the use of dexamethasone in adults and adolescents from twelve years of age and weighing at least 40 kilograms (88 lb) who require supplemental oxygen therapy. Dexamethasone can be taken by mouth or given as an injection or infusion (drip) into a vein . In November 2020, the US Food and Drug Administration (FDA) issued an emergency use authorisation for the investigational monoclonal antibody therapy bamlanivimab for the treatment of mild-to-moderate COVID‑19. Bamlanivimab is authorised for people with positive results of direct SARS-CoV-2 viral testing who are twelve years of age and older weighing at least 40 kilograms (88 lb) , and who are at high risk for progressing to severe COVID‑19 or hospitalisation. This includes those who are 65 years of age or older, or who have chronic medical conditions. In February 2021, the FDA issued an emergency use authorisation (EUA) for bamlanivimab and etesevimab administered together for the treatment of mild to moderate COVID‑19 in people twelve years of age or older weighing at least 40 kilograms (88 lb) who test positive for SARS‑CoV‑2 and who are at high risk for progressing to severe COVID‑19. The authorised use includes treatment for those who are 65 years of age or older or who have certain chronic medical conditions. In April 2021, the FDA revoked the emergency use authorisation (EUA) that allowed for the investigational monoclonal antibody therapy bamlanivimab, when administered alone, to be used for the treatment of mild-to-moderate COVID‑19 in adults and certain paediatric patients. A cytokine storm can be a complication in the later stages of severe COVID‑19. A cytokine storm is a potentially deadly immune reaction where a large amount of pro-inflammatory cytokines and chemokines are released too quickly. A cytokine storm can lead to ARDS and multiple organ failure. Data collected from Jin Yin-tan Hospital in Wuhan, China indicates that patients who had more severe responses to COVID‑19 had greater amounts of pro-inflammatory cytokines and chemokines in their system than patients who had milder responses. These high levels of pro-inflammatory cytokines and chemokines indicate presence of a cytokine storm. Tocilizumab has been included in treatment guidelines by China's National Health Commission after a small study was completed. It is undergoing a Phase II non-randomised trial at the national level in Italy after showing positive results in people with severe disease. Combined with a serum ferritin blood test to identify a cytokine storm (also called cytokine storm syndrome, not to be confused with cytokine release syndrome), it is meant to counter such developments, which are thought to be the cause of death in some affected people. The interleukin-6 receptor (IL-6R) antagonist was approved by the FDA to undergo a Phase III clinical trial assessing its effectiveness on COVID‑19 based on retrospective case studies for the treatment of steroid-refractory cytokine release syndrome induced by a different cause, CAR T cell therapy , in 2017. There is no randomised, controlled evidence that tocilizumab is an efficacious treatment for CRS. Prophylactic tocilizumab has been shown to increase serum IL-6 levels by saturating the IL-6R, driving IL-6 across the blood–brain barrier , and exacerbating neurotoxicity while having no effect on the incidence of CRS. Lenzilumab , an anti-GM-CSF monoclonal antibody , is protective in murine models for CAR T cell-induced CRS and neurotoxicity and is a viable therapeutic option due to the observed increase of pathogenic GM-CSF secreting T cells in hospitalised patients with COVID‑19. Transferring purified and concentrated antibodies produced by the immune systems of those who have recovered from COVID‑19 to people who need them is being investigated as a non-vaccine method of passive immunisation . Viral neutralisation is the anticipated mechanism of action by which passive antibody therapy can mediate defence against SARS-CoV-2. The spike protein of SARS-CoV-2 is the primary target for neutralising antibodies. As of 8 August 2020, eight neutralising antibodies targeting the spike protein of SARS-CoV-2 have entered clinical studies. It has been proposed that selection of broad-neutralising antibodies against SARS-CoV-2 and SARS-CoV might be useful for treating not only COVID‑19 but also future SARS-related CoV infections. Other mechanisms, however, such as antibody-dependant cellular cytotoxicity or phagocytosis , may be possible. Other forms of passive antibody therapy, for example, using manufactured monoclonal antibodies, are in development. The use of passive antibodies to treat people with active COVID ‑ 19 is also being studied. This involves the production of convalescent serum , which consists of the liquid portion of the blood from people who recovered from the infection and contains antibodies specific to this virus, which is then administered to active patients. This strategy was tried for SARS with inconclusive results. An updated Cochrane review in May 2023 found high certainty evidence that, for the treatment of people with moderate to severe COVID‑19, convalescent plasma did not reduce mortality or bring about symptom improvement. There continues to be uncertainty about the safety of convalescent plasma administration to people with COVID‑19 and differing outcomes measured in different studies limits their use in determining efficacy. A cytokine storm can be a complication in the later stages of severe COVID‑19. A cytokine storm is a potentially deadly immune reaction where a large amount of pro-inflammatory cytokines and chemokines are released too quickly. A cytokine storm can lead to ARDS and multiple organ failure. Data collected from Jin Yin-tan Hospital in Wuhan, China indicates that patients who had more severe responses to COVID‑19 had greater amounts of pro-inflammatory cytokines and chemokines in their system than patients who had milder responses. These high levels of pro-inflammatory cytokines and chemokines indicate presence of a cytokine storm. Tocilizumab has been included in treatment guidelines by China's National Health Commission after a small study was completed. It is undergoing a Phase II non-randomised trial at the national level in Italy after showing positive results in people with severe disease. Combined with a serum ferritin blood test to identify a cytokine storm (also called cytokine storm syndrome, not to be confused with cytokine release syndrome), it is meant to counter such developments, which are thought to be the cause of death in some affected people. The interleukin-6 receptor (IL-6R) antagonist was approved by the FDA to undergo a Phase III clinical trial assessing its effectiveness on COVID‑19 based on retrospective case studies for the treatment of steroid-refractory cytokine release syndrome induced by a different cause, CAR T cell therapy , in 2017. There is no randomised, controlled evidence that tocilizumab is an efficacious treatment for CRS. Prophylactic tocilizumab has been shown to increase serum IL-6 levels by saturating the IL-6R, driving IL-6 across the blood–brain barrier , and exacerbating neurotoxicity while having no effect on the incidence of CRS. Lenzilumab , an anti-GM-CSF monoclonal antibody , is protective in murine models for CAR T cell-induced CRS and neurotoxicity and is a viable therapeutic option due to the observed increase of pathogenic GM-CSF secreting T cells in hospitalised patients with COVID‑19. Transferring purified and concentrated antibodies produced by the immune systems of those who have recovered from COVID‑19 to people who need them is being investigated as a non-vaccine method of passive immunisation . Viral neutralisation is the anticipated mechanism of action by which passive antibody therapy can mediate defence against SARS-CoV-2. The spike protein of SARS-CoV-2 is the primary target for neutralising antibodies. As of 8 August 2020, eight neutralising antibodies targeting the spike protein of SARS-CoV-2 have entered clinical studies. It has been proposed that selection of broad-neutralising antibodies against SARS-CoV-2 and SARS-CoV might be useful for treating not only COVID‑19 but also future SARS-related CoV infections. Other mechanisms, however, such as antibody-dependant cellular cytotoxicity or phagocytosis , may be possible. Other forms of passive antibody therapy, for example, using manufactured monoclonal antibodies, are in development. The use of passive antibodies to treat people with active COVID ‑ 19 is also being studied. This involves the production of convalescent serum , which consists of the liquid portion of the blood from people who recovered from the infection and contains antibodies specific to this virus, which is then administered to active patients. This strategy was tried for SARS with inconclusive results. An updated Cochrane review in May 2023 found high certainty evidence that, for the treatment of people with moderate to severe COVID‑19, convalescent plasma did not reduce mortality or bring about symptom improvement. There continues to be uncertainty about the safety of convalescent plasma administration to people with COVID‑19 and differing outcomes measured in different studies limits their use in determining efficacy. Since the outbreak of the COVID‑19 pandemic, scholars have explored the bioethics , normative economics , and political theories of healthcare policies related to the public health crisis. Academics have pointed to the moral distress of healthcare workers, ethics of distributing scarce healthcare resources such as ventilators, and the global justice of vaccine diplomacies. [ citation needed ] The socio-economic inequalities between genders, races, groups with disabilities, communities, regions, countries, and continents have also drawn attention in academia and the general public.

Wiki

Acute hemorrhagic fever syndrome

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

Hematocrit

The hematocrit ( / h ɪ ˈ m æ t ə k r ɪ t / ) ( Ht or HCT ), also known by several other names , is the volume percentage (vol%) of red blood cells (RBCs) in blood , measured as part of a blood test . The measurement depends on the number and size of red blood cells. It is normally 40.7–50.3% for males and 36.1–44.3% for females. It is a part of a person's complete blood count results, along with hemoglobin concentration, white blood cell count and platelet count. Because the purpose of red blood cells is to transfer oxygen from the lungs to body tissues, a blood sample's hematocrit—the red blood cell volume percentage—can become a point of reference of its capability of delivering oxygen. Hematocrit levels that are too high or too low can indicate a blood disorder, dehydration , or other medical conditions. An abnormally low hematocrit may suggest anemia , a decrease in the total amount of red blood cells, while an abnormally high hematocrit is called polycythemia . Both are potentially life-threatening disorders.There are other names for the hematocrit, such as packed cell volume (PCV), volume of packed red cells (VPRC), or erythrocyte volume fraction (EVF). The term hematocrit (or haematocrit in British English ) comes from the Ancient Greek words haima ( αἷμα , "blood") and kritēs ( κριτής , "judge"), and hematocrit means "to separate blood". It was coined in 1891 by Swedish physiologist Magnus Blix as haematokrit , modeled after lactokrit .With modern lab equipment, the hematocrit can be calculated by an automated analyzer or directly measured, depending on the analyzer manufacturer. Calculated hematocrit is determined by multiplying the red cell count by the mean cell volume . The hematocrit is slightly more accurate, as the PCV includes small amounts of blood plasma trapped between the red cells. An estimated hematocrit as a percentage may be derived by tripling the hemoglobin concentration in g / dL and dropping the units. The packed cell volume (PCV) can be determined by centrifuging EDTA -treated or heparinized blood in a capillary tube (also known as a microhematocrit tube) at 10,000 RPM for five minutes. This separates the blood into layers. The volume of packed red blood cells divided by the total volume of the blood sample gives the PCV. Since a tube is used, this can be calculated by measuring the lengths of the layers. Another way of measuring hematocrit levels is by optical methods such as spectrophotometry . Through differential spectrophotometry, the differences in optical densities of a blood sample flowing through small-bore glass tubes at isosbestic wavelengths for deoxyhemoglobin and oxyhemoglobin and the product of the luminal diameter and hematocrit create a linear relationship that is used to measure hematocrit levels. Other than potential bruising at the puncture site, and/or dizziness, there are no complications associated with this test. While known hematocrit levels are used in detecting conditions, it may fail at times due to hematocrit being the measure of concentration of red blood cells through volume in a blood sample. It does not account for the mass of the red blood cells, and thus the changes in mass can alter a hematocrit level or go undetected while affecting a subject's condition. Additionally, there have been cases in which the blood for testing was inadvertently drawn proximal to an intravenous line that was infusing packed red cells or fluids. In these situations, the hemoglobin level in the blood sample will not be the true level for the patient because the sample will contain a large amount of the infused material rather than what is diluted into the circulating whole blood. That is, if packed red cells are being supplied, the sample will contain a large amount of those cells and the hematocrit will be artificially very high.Hematocrit can vary from the determining factors of the number of red blood cells. These factors can be from the age and sex of the subject. [ clarification needed ] Typically, a higher hematocrit level signifies the blood sample's ability to transport oxygen, which has led to reports that an "optimal hematocrit level" may exist. Optimal hematocrit levels have been studied through combinations of assays on blood sample's hematocrit itself, viscosity, and hemoglobin level. Hematocrit levels also serve as an indicator of health conditions. Thus, tests on hematocrit levels are often carried out in the process of diagnosis of such conditions, and may be conducted prior to surgery. Additionally, the health conditions associated with certain hematocrit levels are the same as ones associated with certain hemoglobin levels. As blood flows from the arterioles into the capillaries, a change in pressure occurs. In order to maintain pressure, the capillaries branch off to a web of vessels that carry blood into the venules. Through this process blood undergoes micro-circulation. In micro-circulation, the Fåhræus effect will take place, resulting in a large change in hematocrit. As blood flows through the arterioles, red cells will act a feed hematocrit (Hf), while in the capillaries, a tube hematocrit (Ht) occurs. In tube hematocrit, plasma fills most of the vessel while the red cells travel through in somewhat of a single file line. From this stage, blood will enter the venules increasing in hematocrit, in other words the discharge hematocrit (Hd).In large vessels with low hematocrit, viscosity dramatically drops and red cells take in a lot of energy. While in smaller vessels at the micro-circulation scale, viscosity is very high. With the increase in shear stress at the wall, a lot of energy is used to move cells. [ citation needed ]Relationships between hematocrit, viscosity, and shear rate are important factors to put into consideration. Since blood is non-Newtonian, the viscosity of the blood is in relation to the hematocrit, and as a function of shear rate. This is important when it comes to determining shear force, since a lower hematocrit level indicates that there is a need for more force to push the red blood cells through the system. This is because shear rate is defined as the rate to which adjacent layers of fluid move in respect to each other. Plasma is a more viscous material than typically red blood cells, [ citation needed ] since they are able to adjust their size to the radius of a tube; the shear rate is purely dependent on the amount of red blood cells being forced in a vessel. Generally at both sea levels and high altitudes, hematocrit levels rise as children mature. These health-related causes and impacts of elevated hematocrit levels have been reported: Hematocrit levels were also reported to be correlated with social factors that influence subjects. In the 1966–80 Health Examination Survey, there was a small rise in mean hematocrit levels in female and male adolescents that reflected a rise in annual family income. Additionally, a higher education in a parent has been put into account for a rise in mean hematocrit levels of the child. Lowered hematocrit levels also pose health impacts. These causes and impacts have been reported:Generally at both sea levels and high altitudes, hematocrit levels rise as children mature. These health-related causes and impacts of elevated hematocrit levels have been reported: Hematocrit levels were also reported to be correlated with social factors that influence subjects. In the 1966–80 Health Examination Survey, there was a small rise in mean hematocrit levels in female and male adolescents that reflected a rise in annual family income. Additionally, a higher education in a parent has been put into account for a rise in mean hematocrit levels of the child. Lowered hematocrit levels also pose health impacts. These causes and impacts have been reported:

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Acute hemorrhagic fever syndrome

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Abdominal pain

Abdominal pain , also known as a stomach ache , is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given that, approaching the examination of a person and planning of a differential diagnosis is extremely important. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome . About 15% of people have a more serious underlying condition such as appendicitis , leaking or ruptured abdominal aortic aneurysm , diverticulitis , or ectopic pregnancy . In a third of cases, the exact cause is unclear. The onset of abdominal pain can be abrupt, quick, or gradual. Sudden onset pain happens in a split second. Rapidly onset pain starts mild and gets worse over the next few minutes. Pain that gradually intensifies only after several hours or even days has passed is referred to as gradual onset pain. One can describe abdominal pain as either continuous or sporadic and as cramping , dull, or aching. The characteristic of cramping abdominal pain is that it comes in brief waves, builds to a peak, and then abruptly stops for a period during which there is no more pain. The pain flares up and off periodically. The most common cause of persistent dull or aching abdominal pain is edema or distention of the wall of a hollow viscus. A dull or aching pain may also be felt due to a stretch in the liver and spleen capsules. The most frequent reasons for abdominal pain are gastroenteritis (13%), irritable bowel syndrome (8%), urinary tract problems (5%), inflammation of the stomach (5%) and constipation (5%). In about 30% of cases, the cause is not determined. About 10% of cases have a more serious cause including gallbladder ( gallstones or biliary dyskinesia ) or pancreas problems (4%), diverticulitis (3%), appendicitis (2%) and cancer (1%). More common in those who are older, ischemic colitis , mesenteric ischemia , and abdominal aortic aneurysms are other serious causes. Acute abdomen is a condition where there is a sudden onset of severe abdominal pain requiring immediate recognition and management of the underlying cause. The underlying cause may involve infection, inflammation , vascular occlusion or bowel obstruction. The pain may elicit nausea and vomiting , abdominal distention , fever and signs of shock . A common condition associated with acute abdominal pain is appendicitis . Here is a list of acute abdomen causes: Source: Source: Viscero-visceral referral: happens when one organ with afferent nerves close to another organ is sensitized or inflamed (in this case any of the abdominal viscera) Viscero-somatic referral: any pain in the viscera that causes pain in the muscle, bone, and skin (of the abdomen in case of abdominal pain) Somatic-visceral referral: pain in the skin, muscles, and bone that causes referred pain in the viscera (of the abdomen such as the stomach, kidneys, bladder, etc.) Source: Acute pancreatitis . Sickle cell anemia . Diabetic ketoacidosis (DKA). Adrenal crisis . Pyelonephritis . Lead poisoning . Familial Mediterranean fever (FMF). Source: Pelvic inflammatory disease (PID) and abscess. Ectopic pregnancy . Hemorrhagic ovarian cyst . Adnexal or ovarian torsion . A more extensive list includes the following: [ citation needed ] The location of abdominal pain can provide information about what may be causing the pain. The abdomen can be divided into four regions called quadrants. Locations and associated conditions include: Spleen Kidney: kidney stone (nephrolithiasis), complicated urinary tract infectionAcute abdomen is a condition where there is a sudden onset of severe abdominal pain requiring immediate recognition and management of the underlying cause. The underlying cause may involve infection, inflammation , vascular occlusion or bowel obstruction. The pain may elicit nausea and vomiting , abdominal distention , fever and signs of shock . A common condition associated with acute abdominal pain is appendicitis . Here is a list of acute abdomen causes: Source: Source: Viscero-visceral referral: happens when one organ with afferent nerves close to another organ is sensitized or inflamed (in this case any of the abdominal viscera) Viscero-somatic referral: any pain in the viscera that causes pain in the muscle, bone, and skin (of the abdomen in case of abdominal pain) Somatic-visceral referral: pain in the skin, muscles, and bone that causes referred pain in the viscera (of the abdomen such as the stomach, kidneys, bladder, etc.) Source: Acute pancreatitis . Sickle cell anemia . Diabetic ketoacidosis (DKA). Adrenal crisis . Pyelonephritis . Lead poisoning . Familial Mediterranean fever (FMF). Source: Pelvic inflammatory disease (PID) and abscess. Ectopic pregnancy . Hemorrhagic ovarian cyst . Adnexal or ovarian torsion .Source: Viscero-visceral referral: happens when one organ with afferent nerves close to another organ is sensitized or inflamed (in this case any of the abdominal viscera) Viscero-somatic referral: any pain in the viscera that causes pain in the muscle, bone, and skin (of the abdomen in case of abdominal pain) Somatic-visceral referral: pain in the skin, muscles, and bone that causes referred pain in the viscera (of the abdomen such as the stomach, kidneys, bladder, etc.)A more extensive list includes the following: [ citation needed ]The location of abdominal pain can provide information about what may be causing the pain. The abdomen can be divided into four regions called quadrants. Locations and associated conditions include: Spleen Kidney: kidney stone (nephrolithiasis), complicated urinary tract infectionEsophagus Lower respiratory tract Stomach Proximal duodenum Liver Biliary tract Gallbladder Pancreas Cecum Appendix Ascending colon Proximal transverse colon Descending colon Sigmoid colon Rectum Fever Superior anal canal Abdominal pain can be referred to as visceral pain or peritoneal pain. The contents of the abdomen can be divided into the foregut , midgut , and hindgut . The foregut contains the pharynx , lower respiratory tract , portions of the esophagus , stomach , portions of the duodenum (proximal), liver , biliary tract (including the gallbladder and bile ducts ), and the pancreas . The midgut contains portions of the duodenum (distal), cecum , appendix , ascending colon , and first half of the transverse colon . The hindgut contains the distal half of the transverse colon, descending colon , sigmoid colon , rectum , and superior anal canal . Each subsection of the gut has an associated visceral afferent nerve that transmits sensory information from the viscera to the spinal cord, traveling with the autonomic sympathetic nerves. The visceral sensory information from the gut traveling to the spinal cord, termed the visceral afferent, is non-specific and overlaps with the somatic afferent nerves, which are very specific. Therefore, visceral afferent information traveling to the spinal cord can present in the distribution of the somatic afferent nerve; this is why appendicitis initially presents with T10 periumbilical pain when it first begins and becomes T12 pain as the abdominal wall peritoneum (which is rich with somatic afferent nerves) is involved. A thorough patient history and physical examination is used to better understand the underlying cause of abdominal pain. The process of gathering a history may include: After gathering a thorough history, one should perform a physical exam in order to identify important physical signs that might clarify the diagnosis, including a cardiovascular exam , lung exam, thorough abdominal exam, and for females, a genitourinary exam. Additional investigations that can aid diagnosis include: If diagnosis remains unclear after history, examination, and basic investigations as above, then more advanced investigations may reveal a diagnosis. Such tests include: The management of abdominal pain depends on many factors, including the etiology of the pain. Some dietary changes that some may participate in are: resting after a meal, chewing food completely and slowly, and avoiding stressful and high excitement situations after a meal. Some at home strategies like these can avoid future abdominal issues, resulting in the need of professional assistance. In the emergency department, a person presenting with abdominal pain may initially require IV fluids due to decreased intake secondary to abdominal pain and possible emesis or vomiting. Treatment for abdominal pain includes analgesia, such as non-opioid (ketorolac) and opioid medications ( morphine , fentanyl ). Choice of analgesia is dependent on the cause of the pain, as ketorolac can worsen some intra-abdominal processes. Patients presenting to the emergency department with abdominal pain may receive a "GI cocktail" that includes an antacid (examples include omeprazole , ranitidine , magnesium hydroxide , and calcium chloride ) and lidocaine . After addressing pain, there may be a role for antimicrobial treatment in some cases of abdominal pain. Butylscopolamine (Buscopan) is used to treat cramping abdominal pain with some success. Surgical management for causes of abdominal pain includes but is not limited to cholecystectomy , appendectomy , and exploratory laparotomy . [ citation needed ] Below is a brief overview of abdominal pain emergencies. Periumbilical pain, migrates to RLQ Abdominal CT IV fluids as needed General surgery consultation, possible appendectomy Antibiotics Pain control Imaging (RUQ ultrasound) Labs ( leukocytosis , transamintis , hyperbilirubinemia ) IV fluids as needed General surgery consultation, possible cholecystectomy Antibiotics Pain, nausea control Labs (elevated lipase ) Imaging (abdominal CT, ultrasound) IV fluids as needed Pain, nausea control Possibly consultation of general surgery or interventional radiology Imaging (abdominal X-ray, abdominal CT) IV fluids as needed Nasogastric tube placement General surgery consultation Pain control Labs ( complete blood count , coagulation profile, transaminases , stool guaiac ) Blood transfusion as needed Medications: proton pump inhibitor , octreotide Stable patient: observation Unstable patient: consultation ( general surgery , gastroenterology , interventional radiology ) Labs ( complete blood count , coagulation profile, transaminases , stool guaiac ) Blood transfusion as needed Medications: proton pump inhibitor Stable patient: observation Unstable patient: consultation ( general surgery , gastroenterology , interventional radiology ) Imaging (abdominal X-ray or CT showing free air) Labs ( complete blood count ) General surgery consultation Antibiotics Cecal volvulus: Abdominal pain (acute onset), nausea, vomiting Imaging (abdominal X-ray or CT) Cecal: General surgery consultation ( right hemicolectomy ) If ruptured ectopic pregnancy, the patient may present with peritoneal irritation and hypovolemic shock Labs: complete blood count , urine pregnancy test followed with quantitative blood beta-hCG Imaging: transvaginal ultrasound If patient is stable: continue diagnostic workup, establish OBGYN follow-up Imaging: Ultrasound, CT angiography , MRA/ magnetic resonance angiography If patient is stable: admit for observation Imaging: Chest X-ray (showing widened mediastinum ), CT angiography , MRA , transthoracic echocardiogram /TTE, transesophageal echocardiogram /TEE Blood transfusion as needed (obtain type and cross ) Medications: reduce blood pressure ( sodium nitroprusside plus beta blocker or calcium channel blocker ) Surgery consultation Imaging: FAST examination, CT of abdomen and pelvis Diagnostic peritoneal aspiration and lavage If patient is unstable: general or trauma surgery consultation with subsequent exploratory laparotomy Imaging: FAST examination, CT of abdomen and pelvis Diagnostic peritoneal aspiration and lavage If patient is unstable: general or trauma surgery consultation with subsequent exploratory laparotomy and possible splenectomy If patient is stable: medical management, consultation of interventional radiology for possible arterial embolizationBelow is a brief overview of abdominal pain emergencies. Periumbilical pain, migrates to RLQ Abdominal CT IV fluids as needed General surgery consultation, possible appendectomy Antibiotics Pain control Imaging (RUQ ultrasound) Labs ( leukocytosis , transamintis , hyperbilirubinemia ) IV fluids as needed General surgery consultation, possible cholecystectomy Antibiotics Pain, nausea control Labs (elevated lipase ) Imaging (abdominal CT, ultrasound) IV fluids as needed Pain, nausea control Possibly consultation of general surgery or interventional radiology Imaging (abdominal X-ray, abdominal CT) IV fluids as needed Nasogastric tube placement General surgery consultation Pain control Labs ( complete blood count , coagulation profile, transaminases , stool guaiac ) Blood transfusion as needed Medications: proton pump inhibitor , octreotide Stable patient: observation Unstable patient: consultation ( general surgery , gastroenterology , interventional radiology ) Labs ( complete blood count , coagulation profile, transaminases , stool guaiac ) Blood transfusion as needed Medications: proton pump inhibitor Stable patient: observation Unstable patient: consultation ( general surgery , gastroenterology , interventional radiology ) Imaging (abdominal X-ray or CT showing free air) Labs ( complete blood count ) General surgery consultation Antibiotics Cecal volvulus: Abdominal pain (acute onset), nausea, vomiting Imaging (abdominal X-ray or CT) Cecal: General surgery consultation ( right hemicolectomy ) If ruptured ectopic pregnancy, the patient may present with peritoneal irritation and hypovolemic shock Labs: complete blood count , urine pregnancy test followed with quantitative blood beta-hCG Imaging: transvaginal ultrasound If patient is stable: continue diagnostic workup, establish OBGYN follow-up Imaging: Ultrasound, CT angiography , MRA/ magnetic resonance angiography If patient is stable: admit for observation Imaging: Chest X-ray (showing widened mediastinum ), CT angiography , MRA , transthoracic echocardiogram /TTE, transesophageal echocardiogram /TEE Blood transfusion as needed (obtain type and cross ) Medications: reduce blood pressure ( sodium nitroprusside plus beta blocker or calcium channel blocker ) Surgery consultation Imaging: FAST examination, CT of abdomen and pelvis Diagnostic peritoneal aspiration and lavage If patient is unstable: general or trauma surgery consultation with subsequent exploratory laparotomy Imaging: FAST examination, CT of abdomen and pelvis Diagnostic peritoneal aspiration and lavage If patient is unstable: general or trauma surgery consultation with subsequent exploratory laparotomy and possible splenectomy If patient is stable: medical management, consultation of interventional radiology for possible arterial embolizationOne well-known aspect of primary health care is its low prevalence of potentially dangerous abdominal pain causes. Patients with abdominal pain have a higher percentage of unexplained complaints (category "no diagnosis") than patients with other symptoms (such as dyspnea or chest pain ). Most people who suffer from stomach pain have a benign issue, like dyspepsia . In general, it is discovered that 20% to 25% of patients with abdominal pain have a serious condition that necessitates admission to an acute care hospital. Abdominal pain is the reason about 3% of adults see their family physician. Rates of emergency department (ED) visits in the United States for abdominal pain increased 18% from 2006 through to 2011. This was the largest increase out of 20 common conditions seen in the ED. The rate of ED use for nausea and vomiting also increased 18%. More time and resources are used on older patients with abdominal pain than on any other patient presentation in the emergency department (ED). Compared to younger patients with the same complaint, their length of stay is 20% longer, they need to be admitted almost half the time, and they need surgery 1/3 of the time. Age does not reduce the total number of T cells , but it does reduce their functionality. The elderly person's ability to fight infection is weakened as a result. Additionally, they have changed the strength and integrity of their skin and mucous membranes , which are physical barriers to infection. It is well known that older patients experience altered pain perception. The challenge of obtaining a sufficient history from an elderly patient can be attributed to multiple factors. Reduced memory or hearing could make the issue worse. It is common to encounter stoicism combined with a fear of losing one's independence if a serious condition is discovered. Changes in mental status, whether acute or chronic, are common. Unique clinical challenges arise when pregnant women experience abdominal pain. First off, there are many possible causes of abdominal pain during pregnancy. These include intraabdominal diseases that arise incidentally during pregnancy as well as obstetric or gynecologic disorders associated with pregnancy. Secondly, pregnancy modifies the natural history and clinical manifestation of numerous abdominal disorders. Third, pregnancy modifies and limits the diagnostic assessment. For instance, concerns about fetal safety during pregnancy are raised by invasive exams and radiologic testing. Fourth, while receiving therapy during pregnancy, the mother's and the fetus' interests need to be taken into account. More time and resources are used on older patients with abdominal pain than on any other patient presentation in the emergency department (ED). Compared to younger patients with the same complaint, their length of stay is 20% longer, they need to be admitted almost half the time, and they need surgery 1/3 of the time. Age does not reduce the total number of T cells , but it does reduce their functionality. The elderly person's ability to fight infection is weakened as a result. Additionally, they have changed the strength and integrity of their skin and mucous membranes , which are physical barriers to infection. It is well known that older patients experience altered pain perception. The challenge of obtaining a sufficient history from an elderly patient can be attributed to multiple factors. Reduced memory or hearing could make the issue worse. It is common to encounter stoicism combined with a fear of losing one's independence if a serious condition is discovered. Changes in mental status, whether acute or chronic, are common. Unique clinical challenges arise when pregnant women experience abdominal pain. First off, there are many possible causes of abdominal pain during pregnancy. These include intraabdominal diseases that arise incidentally during pregnancy as well as obstetric or gynecologic disorders associated with pregnancy. Secondly, pregnancy modifies the natural history and clinical manifestation of numerous abdominal disorders. Third, pregnancy modifies and limits the diagnostic assessment. For instance, concerns about fetal safety during pregnancy are raised by invasive exams and radiologic testing. Fourth, while receiving therapy during pregnancy, the mother's and the fetus' interests need to be taken into account.

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Acute hemorrhagic fever syndrome

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

Toxic megacolon

Toxic megacolon is an acute form of colonic distension. It is characterized by a very dilated colon ( megacolon ), accompanied by abdominal distension ( bloating ), and sometimes fever , abdominal pain , or shock . Toxic megacolon is usually a complication of inflammatory bowel disease , such as ulcerative colitis and, more rarely, Crohn's disease , and of some infections of the colon, including Clostridium difficile infections, which have led to pseudomembranous colitis . Other forms of megacolon exist and can be congenital (present since birth, such as Hirschsprung's disease ). It can also be caused by Entamoeba histolytica and Shigella . It may also be caused by the use of loperamide .There may be signs of septic shock . A physical examination reveals abdominal tenderness and possible loss of bowel sounds. An abdominal radiography shows colonic dilation. White blood cell count is usually elevated. Severe sepsis may present with hypothermia or leukopenia . [ citation needed ] Perforation of the colon Sepsis Shock Emergency action may be required if severe abdominal pain develops, particularly if it is accompanied by fever, rapid heart rate, tenderness when the abdomen is pressed, bloody diarrhea , frequent diarrhea, or painful bowel movements. Colonoscopy is contraindicated, as it may rupture the dilated colon resulting in peritonitis and septic shock.Perforation of the colon Sepsis Shock Emergency action may be required if severe abdominal pain develops, particularly if it is accompanied by fever, rapid heart rate, tenderness when the abdomen is pressed, bloody diarrhea , frequent diarrhea, or painful bowel movements. Colonoscopy is contraindicated, as it may rupture the dilated colon resulting in peritonitis and septic shock.The pathological process involves inflammation and damage to the colonic wall with unknown toxins breaking down the protective mucosal barrier and exposing the muscularis propria . There is relative destruction of the ganglion cells and swelling of the nerve fibers in the myenteric plexus, with concomitant damage to the colonic musculature. This results in almost complete paralysis of the diseased segment of the colon with loss of smooth muscle substance, tone and motility. This can lead to further complications as pressure builds up in the colon due to relative fecal stasis including sepsis, intestinal hemorrhage or free perforation and spontaneous decompression. Massively dilated colon with air-fluid level can be seen on abdominal radiograph or CT scan. The objective of treatment is to decompress the bowel and to prevent swallowed air from further distending the bowel. If decompression is not achieved or the patient does not improve with medical management, surgery is indicated. When surgery is required the recommended procedure is a colectomy (surgical removal of all or part of the colon) with end ileostomy . Fluid and electrolyte replacement help to prevent dehydration and shock. Use of corticosteroids may be indicated to suppress the inflammatory reaction in the colon if megacolon has resulted from active inflammatory bowel disease. Antibiotics may be given to prevent sepsis . If the condition does not improve, the risk of death is significant. In case of poor response to conservative therapy, a colectomy is usually required.

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Acute hemorrhagic fever syndrome

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Lonomia obliqua

Lonomia obliqua , the giant silkworm moth (a name also used for a wide range of other saturniid moths), is a species of saturniid moth from South America . It is famous for its larval form, rather than the adult moth, primarily because of the caterpillar's defense mechanism, urticating bristles that inject a potentially deadly venom. The caterpillar has been responsible for many human deaths, especially in southern Brazil . Its venom has been the subject of numerous medical studies. The species was first described by Francis Walker in 1855. Guinness World Records classified the Lonomia obliqua as the most venomous caterpillar in the world. These caterpillars are about 4.5 to 5.5 centimeters (about 2 in) long, with background colors ranging from green to brown. Well camouflaged, they have rows of tubercles crowned with whorls of easily detachable spines of different sizes. Caterpillars of many species can cause irritation by their hollow body hairs that envenom or detach easily, or can be poisonous if ingested; . Prior to investigations into Lonomia caterpillars, it was not known that caterpillars could produce toxins in sufficient quantities to kill a human. Lonomia obliqua is found in the south of Brazil in the states of Rio Grande do Sul , Santa Catarina , and Paraná . The species appears to be spreading to the southeast of Brazil, and recent accidents with the species were reported in the states of São Paulo , Rio de Janeiro , and Minas Gerais . L. obliqua is also found in Uruguay, Paraguay, and Argentina. The species became internationally known when an epidemic occurred in an agrarian community in Rio Grande do Sul. Hematoma and gangrene -like symptoms manifested, spreading throughout the body, eventually causing massive blood leakage into the brain and, in several cases, death. At first the cause could not be determined, although each victim stated they had "just handled a bunch of leafy branches to break the trail or gather vegetation." Exploring the area, the only creature commonly found within all the incidents was the L. obliqua caterpillar. Its hair growth covers its body, and each clump of spines is able to easily puncture the skin and release toxins into the victim. Lonomia obliqua has a toxic venom which causes disseminated intravascular coagulation and a consumptive coagulopathy, which can lead to a hemorrhagic syndrome. The toxins are stored in sacs at the base of each spine. As the spines penetrate the victim, venom flows through the hollow bristles and into the puncture wound. It was discovered that the toxin in the caterpillar's skin held potent anti-clotting agents. This anti-clotting agent would attach to another protein of the body's cells and cause them to leak as blood is unable to clot. This internal bleeding would fill the surrounding tissue with "bruised blood". This internal bleeding spreads through the internal organs and eventually leads to compression and brain death. This accounts for the minimum of 500 deaths resulting from contact with L. obliqua caterpillars. The poison only takes effect in fairly large amounts; in order to experience the extreme effects caused by the toxins, a human victim would probably need to be stung at least 20 to 100 times because each sting only injects a minute amount of venom. [ citation needed ] Of the 26 species of the genus Lonomia found on the American continent, only Lonomia obliqua and Lonomia achelous have caused severe reactions, leading to hemorrhagic syndrome. Since 1989 the number of human accidents caused by these caterpillars has been increasing in the southern region of Brazil. Most victims were male (63%), many were between 0 and 19 years old (45%), and lesions are especially common on the hands (38%). The reported death rate is 2.5%. During the venom extraction, after removal of all spicules, each caterpillar produces approximately 2.4 mg of venom, the total amount of venom injected in an individual weighing 70kg can reach up to 1.4 - 1.7 mg/kg. Disseminated intravascular coagulation occurs as the toxin interacts with the victim's body. One serious effect on envenomed victims is hemorrhage syndrome. "First described by Arocha-Pinango and Layrisse in Venezuela in 1967, the hemorrhagic diathesis caused in humans by touching the Lonomia species begins with inflammatory changes at the site of envenoming, followed by systemic symptoms such as headache, fever, vomiting, and malaise. After 24 hours, a severe bleeding disorder ensues, leading to ecchymosis , hematuria , pulmonary , and intracranial hemorrhages , and acute kidney injury ." Although few cases are recorded, a case study of a fatal encounter was published in Arquivos de Neuro-Psiquiatria : "A 70-year-old, previously healthy woman developed a sudden coma. Four days before, she had started to present hematuria. Shortly after admission, her coma was rated as Glasgow 3 . Physical examination revealed several skin hemorrhages, and gross hematuria was present. Based on information in a note left by the patient, two small hyperemic lesions were identified on the tip of her left toe. Along with the note was the green caterpillar which was hidden inside of her slipper. CT-scan imaging revealed multiple intracerebral hemorrhages. She died seven days after being envenomed." In another case, internal bleeding spread throughout the lower body. While this victim did not die, prompt medical attention was necessary. [ citation needed ]While there are many reported cases of serious injuries and fatalities, there are not many records of proper treatment should an individual be stung. According to Dr. Robert Norris, stings and abrasions caused by Lonomia obliqua should be treated with antifibrinolytics . If blood products are required, they must be given cautiously to avoid fueling the constant consumptive coagulopathy . An antiserum is produced by the Butantan Institute in São Paulo, Brazil. It effectively reverses the coagulation disorders induced by Lonomia obliqua venom, and patients treated with this antiserum recover rapidly. L. obliqua caterpillar toxin has been the subject of numerous studies to determine its medical value. In particular the component called "Lopap" ( L. obliqua prothrombin activator protease) has exhibited anticoagulant and anti- apoptotic qualities.

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Acute hemorrhagic fever syndrome

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List of systemic diseases with ocular manifestations

An ocular manifestation of a systemic disease is an eye condition that directly or indirectly results from a disease process in another part of the body. There are many diseases known to cause ocular or visual changes. Diabetes , for example, is the leading cause of new cases of blindness in those aged 20–74, with ocular manifestations such as diabetic retinopathy and macular edema affecting up to 80% of those who have had the disease for 15 years or more. [ citation needed ] Other diseases such as acquired immunodeficiency syndrome (AIDS) and hypertension are commonly found to have associated ocular symptoms.

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Acute hemorrhagic fever syndrome

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

Heart failure

Heart failure ( HF ), also known as congestive heart failure ( CHF ), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF typically presents with shortness of breath , excessive fatigue , and bilateral leg swelling . The severity of the heart failure is mainly decided based on ejection fraction and also measured by the severity of symptoms. Other conditions that have symptoms similar to heart failure include obesity , kidney failure , liver disease, anemia , and thyroid disease . Common causes of heart failure include coronary artery disease , heart attack , high blood pressure , atrial fibrillation , valvular heart disease , excessive alcohol consumption , infection , and cardiomyopathy . These cause heart failure by altering the structure or the function of the heart or in some cases both. There are different types of heart failure: right-sided heart failure , which affects the right heart , left-sided heart failure , which affects the left heart , and biventricular heart failure, which affects both sides of the heart. Left-sided heart failure may be present with a reduced ejection fraction or with a preserved ejection fraction . Heart failure is not the same as cardiac arrest , in which blood flow stops completely due to the failure of the heart to pump. Diagnosis is based on symptoms, physical findings, and echocardiography . Blood tests , and a chest x-ray may be useful to determine the underlying cause. Treatment depends on severity and case. For people with chronic, stable, mild heart failure, treatment usually consists of lifestyle changes, such as not smoking , physical exercise , and dietary changes, as well as medications. In heart failure due to left ventricular dysfunction, angiotensin-converting-enzyme inhibitors , angiotensin receptor blockers , or angiotensin receptor-neprilysin inhibitors , along with beta blockers , mineralocorticoid receptor antagonists and SGLT2 inhibitors are recommended. Diuretics may also be prescribed to prevent fluid retention and the resulting shortness of breath. Depending on the case, an implanted device such as a pacemaker or implantable cardiac defibrillator may sometimes be recommended. In some moderate or more severe cases, cardiac resynchronization therapy (CRT) or cardiac contractility modulation may be beneficial. In severe disease that persists despite all other measures, a cardiac assist device ventricular assist device , or, occasionally, heart transplantation may be recommended. Heart failure is a common, costly, and potentially fatal condition, and is the leading cause of hospitalization and readmission in older adults. Heart failure often leads to more drastic health impairments than failure of other, similarly complex organs such as the kidneys or liver. In 2015, it affected about 40 million people worldwide. Overall, heart failure affects about 2% of adults, and more than 10% of those over the age of 70. Rates are predicted to increase. The risk of death in the first year after diagnosis is about 35%, while the risk of death in the second year is less than 10% in those still alive. The risk of death is comparable to that of some cancers. In the United Kingdom, the disease is the reason for 5% of emergency hospital admissions. Heart failure has been known since ancient times; it is mentioned in the Ebers Papyrus around 1550 BCE. Heart failure is not a disease but a syndrome – a combination of signs and symptoms – caused by the failure of the heart to pump blood to support the circulatory system at rest or during activity. : 3612 It develops when the heart fails to properly fill with blood during diastole , resulting in a decrease in intracardiac pressures or in ejection during systole , reducing cardiac output to the rest of the body. : 3612 : e272 The filling failure and high intracardiac pressure can lead to fluid accumulation in the veins and tissue. This manifests as water retention and swelling due to fluid accumulation ( edema ) called congestion . Impaired ejection can lead to inadequate blood flow to the body tissues, resulting in ischemia . Congestive heart failure is a pathophysiological condition in which the heart's output is insufficient to meet the needs of the body and lungs. The term "congestive heart failure" is often used because one of the most common symptoms is congestion or fluid accumulation in the tissues and veins of the lungs or other parts of a person's body. Congestion manifests itself particularly in the form of fluid accumulation and swelling (edema) , in the form of peripheral edema (causing swollen limbs and feet) and pulmonary edema (causing difficulty breathing) and ascites (swollen abdomen). Pulse pressure , which is the difference between the systolic ("top number") and diastolic ("bottom number") blood pressures, is often low/narrow (i.e. 25% or less of the level of the systolic) in people with heart failure, and this can be an early warning sign. Symptoms of heart failure are traditionally divided into left-sided and right-sided because the left and right ventricles supply different parts of the circulation. In biventricular heart failure, both sides of the heart are affected. Left-sided heart failure is the more common. The left side of the heart takes oxygen-rich blood from the lungs and pumps it to the rest of the circulatory system in the body (except for the pulmonary circulation ). Failure of the left side of the heart causes blood to back up into the lungs, causing breathing difficulties and fatigue due to an insufficient supply of oxygenated blood. Common respiratory signs include increased respiratory rate and labored breathing (nonspecific signs of shortness of breath). Rales or crackles heard initially in the lung bases and when severe in all lung fields indicate the development of pulmonary edema (fluid in the alveoli ). Cyanosis , indicates deficiency of oxygen in the blood , is a late sign of extremely severe pulmonary edema. Other signs of left ventricular failure include a laterally displaced apex beat (which occurs when the heart is enlarged) and a gallop rhythm (additional heart sounds), which may be heard as a sign of increased blood flow or increased intracardiac pressure. Heart murmurs may indicate the presence of valvular heart disease, either as a cause (e.g., aortic stenosis ) or as a consequence (e.g., mitral regurgitation ) of heart failure. Reverse insufficiency of the left ventricle causes congestion in the blood vessels of the lungs, so that symptoms are predominantly respiratory. Reverse insufficiency can be divided into the failure of the left atrium, the left ventricle, or both within the left circuit. Patients will experience shortness of breath (dyspnea) on exertion and, in severe cases, dyspnea at rest. Increasing breathlessness while lying down, called orthopnea , also occurs. It can be measured by the number of pillows required to lie comfortably, with extreme cases of orthopnea forcing the patient to sleep sitting up. Another symptom of heart failure is paroxysmal nocturnal dyspnea : a sudden nocturnal attack of severe shortness of breath, usually occurring several hours after falling asleep. There may be " cardiac asthma " or wheezing . Impaired left ventricular forward function can lead to symptoms of poor systemic perfusion such as dizziness , confusion , and cool extremities at rest. Loss of consciousness may also occur due to loss of blood supply to the brain. Right-sided heart failure is often caused by pulmonary heart disease (cor pulmonale), which is typically caused by issues with pulmonary circulation such as pulmonary hypertension or pulmonic stenosis . Physical examination may reveal pitting peripheral edema, ascites, liver enlargement , and spleen enlargement . Jugular venous pressure is frequently assessed as a marker of fluid status, which can be accentuated by testing hepatojugular reflux . If the right ventricular pressure is increased, a parasternal heave which causes the compensatory increase in contraction strength may be present. Backward failure of the right ventricle leads to congestion of systemic capillaries. This generates excess fluid accumulation in the body. This causes swelling under the skin ( peripheral edema or anasarca ) and usually affects the dependent parts of the body first, causing foot and ankle swelling in people who are standing up and sacral edema in people who are predominantly lying down. Nocturia (frequent night-time urination) may occur when fluid from the legs is returned to the bloodstream while lying down at night. In progressively severe cases, ascites (fluid accumulation in the abdominal cavity causing swelling) and liver enlargement may develop. Significant liver congestion may result in impaired liver function ( congestive hepatopathy ), jaundice, and coagulopathy (problems of decreased or increased blood clotting). Dullness of the lung fields when percussed and reduced breath sounds at the base of the lungs may suggest the development of a pleural effusion (fluid collection between the lung and the chest wall ). Though it can occur in isolated left- or right-sided heart failure, it is more common in biventricular failure because pleural veins drain into both the systemic and pulmonary venous systems. When unilateral, effusions are often right-sided. If a person with a failure of one ventricle lives long enough, it will tend to progress to failure of both ventricles. For example, left ventricular failure allows pulmonary edema and pulmonary hypertension to occur, which increase stress on the right ventricle. Though still harmful, right ventricular failure is not as deleterious to the left side. The left side of the heart takes oxygen-rich blood from the lungs and pumps it to the rest of the circulatory system in the body (except for the pulmonary circulation ). Failure of the left side of the heart causes blood to back up into the lungs, causing breathing difficulties and fatigue due to an insufficient supply of oxygenated blood. Common respiratory signs include increased respiratory rate and labored breathing (nonspecific signs of shortness of breath). Rales or crackles heard initially in the lung bases and when severe in all lung fields indicate the development of pulmonary edema (fluid in the alveoli ). Cyanosis , indicates deficiency of oxygen in the blood , is a late sign of extremely severe pulmonary edema. Other signs of left ventricular failure include a laterally displaced apex beat (which occurs when the heart is enlarged) and a gallop rhythm (additional heart sounds), which may be heard as a sign of increased blood flow or increased intracardiac pressure. Heart murmurs may indicate the presence of valvular heart disease, either as a cause (e.g., aortic stenosis ) or as a consequence (e.g., mitral regurgitation ) of heart failure. Reverse insufficiency of the left ventricle causes congestion in the blood vessels of the lungs, so that symptoms are predominantly respiratory. Reverse insufficiency can be divided into the failure of the left atrium, the left ventricle, or both within the left circuit. Patients will experience shortness of breath (dyspnea) on exertion and, in severe cases, dyspnea at rest. Increasing breathlessness while lying down, called orthopnea , also occurs. It can be measured by the number of pillows required to lie comfortably, with extreme cases of orthopnea forcing the patient to sleep sitting up. Another symptom of heart failure is paroxysmal nocturnal dyspnea : a sudden nocturnal attack of severe shortness of breath, usually occurring several hours after falling asleep. There may be " cardiac asthma " or wheezing . Impaired left ventricular forward function can lead to symptoms of poor systemic perfusion such as dizziness , confusion , and cool extremities at rest. Loss of consciousness may also occur due to loss of blood supply to the brain. Right-sided heart failure is often caused by pulmonary heart disease (cor pulmonale), which is typically caused by issues with pulmonary circulation such as pulmonary hypertension or pulmonic stenosis . Physical examination may reveal pitting peripheral edema, ascites, liver enlargement , and spleen enlargement . Jugular venous pressure is frequently assessed as a marker of fluid status, which can be accentuated by testing hepatojugular reflux . If the right ventricular pressure is increased, a parasternal heave which causes the compensatory increase in contraction strength may be present. Backward failure of the right ventricle leads to congestion of systemic capillaries. This generates excess fluid accumulation in the body. This causes swelling under the skin ( peripheral edema or anasarca ) and usually affects the dependent parts of the body first, causing foot and ankle swelling in people who are standing up and sacral edema in people who are predominantly lying down. Nocturia (frequent night-time urination) may occur when fluid from the legs is returned to the bloodstream while lying down at night. In progressively severe cases, ascites (fluid accumulation in the abdominal cavity causing swelling) and liver enlargement may develop. Significant liver congestion may result in impaired liver function ( congestive hepatopathy ), jaundice, and coagulopathy (problems of decreased or increased blood clotting). Dullness of the lung fields when percussed and reduced breath sounds at the base of the lungs may suggest the development of a pleural effusion (fluid collection between the lung and the chest wall ). Though it can occur in isolated left- or right-sided heart failure, it is more common in biventricular failure because pleural veins drain into both the systemic and pulmonary venous systems. When unilateral, effusions are often right-sided. If a person with a failure of one ventricle lives long enough, it will tend to progress to failure of both ventricles. For example, left ventricular failure allows pulmonary edema and pulmonary hypertension to occur, which increase stress on the right ventricle. Though still harmful, right ventricular failure is not as deleterious to the left side. Since heart failure is a syndrome and not a disease, establishing the underlying cause is vital to diagnosis and treatment. In heart failure, the structure or the function of the heart or in some cases both are altered. : 3612 Heart failure is the potential end stage of all heart diseases. Common causes of heart failure include coronary artery disease , including a previous myocardial infarction (heart attack), high blood pressure , atrial fibrillation , valvular heart disease , excess alcohol use , infection , and cardiomyopathy of an unknown cause. : e279 : Table 5 In addition, viral infection and subsequent inflammation of the heart's myocardial tissue (termed myocarditis ) can similarly contribute to the development of heart failure. Genetic predisposition plays an important role. If more than one cause is present, progression is more likely and prognosis is worse. Heart damage can predispose a person to develop heart failure later in life and has many causes including systemic viral infections (e.g., HIV ), chemotherapeutic agents such as daunorubicin , cyclophosphamide , trastuzumab and substance use disorders of substances such as alcohol , cocaine , and methamphetamine . An uncommon cause is exposure to certain toxins such as lead and cobalt . Additionally, infiltrative disorders such as amyloidosis and connective tissue diseases such as systemic lupus erythematosus have similar consequences. Obstructive sleep apnea (a condition of sleep wherein disordered breathing overlaps with obesity, hypertension, and/or diabetes) is regarded as an independent cause of heart failure. Recent reports from clinical trials have also linked variation in blood pressure to heart failure and cardiac changes that may give rise to heart failure. High-output heart failure happens when the amount of blood pumped out is more than typical and the heart is unable to keep up. This can occur in overload situations such as blood or serum infusions, kidney diseases, chronic severe anemia , beriberi (vitamin B 1 / thiamine deficiency), hyperthyroidism , cirrhosis , Paget's disease , multiple myeloma , arteriovenous fistulae , or arteriovenous malformations . Chronic stable heart failure may easily decompensate. This most commonly results from a concurrent illness (such as myocardial infarction (a heart attack) or pneumonia ), abnormal heart rhythms , uncontrolled hypertension , or a person's failure to maintain a fluid restriction, diet, or medication. Other factors that may worsen CHF include: anemia, hyperthyroidism, excessive fluid or salt intake, and medication such as NSAIDs and thiazolidinediones . NSAIDs increase the risk twofold. A number of medications may cause or worsen the disease. This includes NSAIDs , COX-2 inhibitors , a number of anesthetic agents such as ketamine , thiazolidinediones, some cancer medications , several antiarrhythmic medications , pregabalin , alpha-2 adrenergic receptor agonists , minoxidil , itraconazole , cilostazol , anagrelide , stimulants (e.g., methylphenidate ), tricyclic antidepressants , lithium , antipsychotics , dopamine agonists , TNF inhibitors , calcium channel blockers (especially verapamil and diltiazem ), salbutamol , and tamsulosin . By inhibiting the formation of prostaglandins , NSAIDs may exacerbate heart failure through several mechanisms, including promotion of fluid retention, increasing blood pressure , and decreasing a person's response to diuretic medications. Similarly, the ACC/AHA recommends against the use of COX-2 inhibitor medications in people with heart failure. Thiazolidinediones have been strongly linked to new cases of heart failure and worsening of pre-existing congestive heart failure due to their association with weight gain and fluid retention. Certain calcium channel blockers, such as diltiazem and verapamil , are known to decrease the force with which the heart ejects blood , thus are not recommended in people with heart failure with a reduced ejection fraction. Breast cancer patients are at high risk of heart failure due to several factors. After analysing data from 26 studies (836,301 patients), the recent meta-analysis found that breast cancer survivors demonstrated a higher risk heart failure within first ten years after diagnosis (hazard ratio = 1.21; 95% CI: 1.1, 1.33). The pooled incidence of heart failure in breast cancer survivors was 4.44 (95% CI 3.33-5.92) per 1000 person-years of follow-up. Certain alternative medicines carry a risk of exacerbating existing heart failure, and are not recommended. This includes aconite , ginseng , gossypol , gynura , licorice , lily of the valley , tetrandrine , and yohimbine . Aconite can cause abnormally slow heart rates and abnormal heart rhythms such as ventricular tachycardia. Ginseng can cause abnormally low or high blood pressure, and may interfere with the effects of diuretic medications. Gossypol can increase the effects of diuretics, leading to toxicity. Gynura can cause low blood pressure. Licorice can worsen heart failure by increasing blood pressure and promoting fluid retention. Lily of the valley can cause abnormally slow heart rates with mechanisms similar to those of digoxin. Tetrandrine can lead to low blood pressure through inhibition of L-type calcium channels . Yohimbine can exacerbate heart failure by increasing blood pressure through alpha-2 adrenergic receptor antagonism. High-output heart failure happens when the amount of blood pumped out is more than typical and the heart is unable to keep up. This can occur in overload situations such as blood or serum infusions, kidney diseases, chronic severe anemia , beriberi (vitamin B 1 / thiamine deficiency), hyperthyroidism , cirrhosis , Paget's disease , multiple myeloma , arteriovenous fistulae , or arteriovenous malformations . Chronic stable heart failure may easily decompensate. This most commonly results from a concurrent illness (such as myocardial infarction (a heart attack) or pneumonia ), abnormal heart rhythms , uncontrolled hypertension , or a person's failure to maintain a fluid restriction, diet, or medication. Other factors that may worsen CHF include: anemia, hyperthyroidism, excessive fluid or salt intake, and medication such as NSAIDs and thiazolidinediones . NSAIDs increase the risk twofold. A number of medications may cause or worsen the disease. This includes NSAIDs , COX-2 inhibitors , a number of anesthetic agents such as ketamine , thiazolidinediones, some cancer medications , several antiarrhythmic medications , pregabalin , alpha-2 adrenergic receptor agonists , minoxidil , itraconazole , cilostazol , anagrelide , stimulants (e.g., methylphenidate ), tricyclic antidepressants , lithium , antipsychotics , dopamine agonists , TNF inhibitors , calcium channel blockers (especially verapamil and diltiazem ), salbutamol , and tamsulosin . By inhibiting the formation of prostaglandins , NSAIDs may exacerbate heart failure through several mechanisms, including promotion of fluid retention, increasing blood pressure , and decreasing a person's response to diuretic medications. Similarly, the ACC/AHA recommends against the use of COX-2 inhibitor medications in people with heart failure. Thiazolidinediones have been strongly linked to new cases of heart failure and worsening of pre-existing congestive heart failure due to their association with weight gain and fluid retention. Certain calcium channel blockers, such as diltiazem and verapamil , are known to decrease the force with which the heart ejects blood , thus are not recommended in people with heart failure with a reduced ejection fraction. Breast cancer patients are at high risk of heart failure due to several factors. After analysing data from 26 studies (836,301 patients), the recent meta-analysis found that breast cancer survivors demonstrated a higher risk heart failure within first ten years after diagnosis (hazard ratio = 1.21; 95% CI: 1.1, 1.33). The pooled incidence of heart failure in breast cancer survivors was 4.44 (95% CI 3.33-5.92) per 1000 person-years of follow-up. Certain alternative medicines carry a risk of exacerbating existing heart failure, and are not recommended. This includes aconite , ginseng , gossypol , gynura , licorice , lily of the valley , tetrandrine , and yohimbine . Aconite can cause abnormally slow heart rates and abnormal heart rhythms such as ventricular tachycardia. Ginseng can cause abnormally low or high blood pressure, and may interfere with the effects of diuretic medications. Gossypol can increase the effects of diuretics, leading to toxicity. Gynura can cause low blood pressure. Licorice can worsen heart failure by increasing blood pressure and promoting fluid retention. Lily of the valley can cause abnormally slow heart rates with mechanisms similar to those of digoxin. Tetrandrine can lead to low blood pressure through inhibition of L-type calcium channels . Yohimbine can exacerbate heart failure by increasing blood pressure through alpha-2 adrenergic receptor antagonism. Heart failure is caused by any condition that reduces the efficiency of the heart muscle, through damage or overloading . Over time, these increases in workload, which are mediated by long-term activation of neurohormonal systems such as the renin–angiotensin system and the sympathoadrenal system, lead to fibrosis , dilation, and structural changes in the shape of the left ventricle from elliptical to spherical. The heart of a person with heart failure may have a reduced force of contraction due to overloading of the ventricle . In a normal heart, increased filling of the ventricle results in increased contraction force by the Frank–Starling law of the heart , and thus a rise in cardiac output . In heart failure, this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. This is due to reduced ability to cross-link actin and myosin myofilaments in over-stretched heart muscle. No diagnostic criteria have been agreed on as the gold standard for heart failure, especially heart failure with preserved ejection fraction (HFpEF). In the UK , the National Institute for Health and Care Excellence recommends measuring N-terminal pro-BNP (NT-proBNP) followed by an ultrasound of the heart if positive. In Europe , the European Society of Cardiology , and in the United States, the AHA / ACC / HFSA , recommend measuring NT-proBNP or BNP followed by an ultrasound of the heart if positive. This is recommended in those with symptoms consistent with heart failure such as shortness of breath . The European Society of Cardiology defines the diagnosis of heart failure as symptoms and signs consistent with heart failure in combination with "objective evidence of cardiac structural or functional abnormalities". This definition is consistent with an international 2021 report termed "Universal Definition of Heart Failure". : 3613 Score-based algorithms have been developed to help in the diagnosis of HFpEF , which can be challenging for physicians to diagnose. : 3630 The AHA / ACC / HFSA defines heart failure as symptoms and signs consistent with heart failure in combination with shown "structural and functional alterations of the heart as the underlying cause for the clinical presentation", for HFmrEF and HFpEF specifically requiring "evidence of spontaneous or provokable increased left ventricle filling pressures". : e276–e277 The European Society of Cardiology has developed a diagnostic algorithm for HFpEF , named HFA-PEFF. : 3630 HFA-PEFF considers symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes, elderly, atrial fibrillation), and diagnostic laboratory tests, ECG, and echocardiography. : e277 One historical method of categorizing heart failure is by the side of the heart involved (left heart failure versus right heart failure). Right heart failure was thought to compromise blood flow to the lungs compared to left heart failure compromising blood flow to the aorta and consequently to the brain and the remainder of the body's systemic circulation. However, mixed presentations are common and left heart failure is a common cause of right heart failure. More accurate classification of heart failure type is made by measuring ejection fraction , or the proportion of blood pumped out of the heart during a single contraction. Ejection fraction is given as a percentage with the normal range being between 50 and 75%. The types are: Heart failure may also be classified as acute or chronic. Chronic heart failure is a long-term condition, usually kept stable by the treatment of symptoms. Acute decompensated heart failure is a worsening of chronic heart failure symptoms, which can result in acute respiratory distress . High-output heart failure can occur when there is increased cardiac demand that results in increased left ventricular diastolic pressure which can develop into pulmonary congestion (pulmonary edema). Several terms are closely related to heart failure and may be the cause of heart failure, but should not be confused with it. Cardiac arrest and asystole refer to situations in which no cardiac output occurs at all. Without urgent treatment, these events result in sudden death. Myocardial infarction ("Heart attack") refers to heart muscle damage due to insufficient blood supply, usually as a result of a blocked coronary artery . Cardiomyopathy refers specifically to problems within the heart muscle, and these problems can result in heart failure. Ischemic cardiomyopathy implies that the cause of muscle damage is coronary artery disease. Dilated cardiomyopathy implies that the muscle damage has resulted in enlargement of the heart. Hypertrophic cardiomyopathy involves enlargement and thickening of the heart muscle. An echocardiogram ( ultrasound of the heart) is commonly used to support a clinical diagnosis of heart failure. This can determine the stroke volume (SV, the amount of blood in the heart that exits the ventricles with each beat), the end-diastolic volume (EDV, the total amount of blood at the end of diastole), and the SV in proportion to the EDV, a value known as the ejection fraction (EF). In pediatrics, the shortening fraction is the preferred measure of systolic function. Normally, the EF should be between 50 and 70%; in systolic heart failure, it drops below 40%. Echocardiography can also identify valvular heart disease and assess the state of the pericardium (the connective tissue sac surrounding the heart). Echocardiography may also aid in deciding specific treatments, such as medication, insertion of an implantable cardioverter-defibrillator , or cardiac resynchronization therapy . Echocardiography can also help determine if acute myocardial ischemia is the precipitating cause, and may manifest as regional wall motion abnormalities on echo. Chest X-rays are frequently used to aid in the diagnosis of CHF. In a person who is compensated, this may show cardiomegaly (visible enlargement of the heart), quantified as the cardiothoracic ratio (proportion of the heart size to the chest). In left ventricular failure, evidence may exist of vascular redistribution (upper lobe blood diversion or cephalization), Kerley lines , cuffing of the areas around the bronchi , and interstitial edema. Ultrasound of the lung may also be able to detect Kerley lines. An electrocardiogram (ECG or EKG) may be used to identify arrhythmias , ischemic heart disease , right and left ventricular hypertrophy , and presence of conduction delay or abnormalities (e.g. left bundle branch block ). Although these findings are not specific to the diagnosis of heart failure, a normal ECG virtually excludes left ventricular systolic dysfunction. N-terminal pro-BNP (NT-proBNP) is the favoured biomarker for the diagnosis of heart failure, according to guidelines published 2018 by NICE in the UK . Brain natriuretic peptide 32 (BNP) is another biomarker commonly tested for heart failure. An elevated NT-proBNP or BNP is a specific test indicative of heart failure. Additionally, NT-proBNP or BNP can be used to differentiate between causes of dyspnea due to heart failure from other causes of dyspnea. If myocardial infarction is suspected, various cardiac markers may be used. Blood tests routinely performed include electrolytes ( sodium , potassium ), measures of kidney function , liver function tests , thyroid function tests , a complete blood count , and often C-reactive protein if infection is suspected. Hyponatremia (low serum sodium concentration) is common in heart failure. Vasopressin levels are usually increased, along with renin, angiotensin II, and catecholamines to compensate for reduced circulating volume due to inadequate cardiac output. This leads to increased fluid and sodium retention in the body; the rate of fluid retention is higher than the rate of sodium retention in the body, this phenomenon causes hypervolemic hyponatremia (low sodium concentration due to high body fluid retention). This phenomenon is more common in older women with low body mass. Severe hyponatremia can result in accumulation of fluid in the brain, causing cerebral edema and intracranial hemorrhage . Angiography is the X-ray imaging of blood vessels , which is done by injecting contrast agents into the bloodstream through a thin plastic tube ( catheter ), which is placed directly in the blood vessel. X-ray images are called angiograms. Heart failure may be the result of coronary artery disease, and its prognosis depends in part on the ability of the coronary arteries to supply blood to the myocardium (heart muscle). As a result, coronary catheterization may be used to identify possibilities for revascularisation through percutaneous coronary intervention or bypass surgery . Heart failure is commonly stratified by the degree of functional impairment conferred by the severity of the heart failure, as reflected in the New York Heart Association (NYHA) functional classification . The NYHA functional classes (I–IV) begin with class I, which is defined as a person who experiences no limitation in any activities and has no symptoms from ordinary activities. People with NYHA class II heart failure have slight, mild limitations with everyday activities; the person is comfortable at rest or with mild exertion. With NYHA class III heart failure, a marked limitation occurs with any activity; the person is comfortable only at rest. A person with NYHA class IV heart failure is symptomatic at rest and becomes quite uncomfortable with any physical activity. This score documents the severity of symptoms and can be used to assess response to treatment. While its use is widespread, the NYHA score is not very reproducible and does not reliably predict the walking distance or exercise tolerance on formal testing. In its 2001 guidelines, the American College of Cardiology / American Heart Association working group introduced four stages of heart failure: Stage A: People at high risk for developing HF in the future, but no functional or structural heart disorder Stage B: A structural heart disorder, but no symptoms at any stage Stage C: Previous or current symptoms of heart failure in the context of an underlying structural heart problem, but managed with medical treatment Stage D: Advanced disease requiring hospital-based support, a heart transplant, or palliative care The ACC staging system is useful since stage A encompasses "pre-heart failure" – a stage where intervention with treatment can presumably prevent progression to overt symptoms. ACC stage A does not have a corresponding NYHA class. ACC stage B would correspond to NYHA class I. ACC stage C corresponds to NYHA class II and III, while ACC stage D overlaps with NYHA class IV. Histopathology can diagnose heart failure in autopsies . The presence of siderophages indicates chronic left-sided heart failure, but is not specific for it. It is also indicated by congestion of the pulmonary circulation.The European Society of Cardiology has developed a diagnostic algorithm for HFpEF , named HFA-PEFF. : 3630 HFA-PEFF considers symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes, elderly, atrial fibrillation), and diagnostic laboratory tests, ECG, and echocardiography. : e277 One historical method of categorizing heart failure is by the side of the heart involved (left heart failure versus right heart failure). Right heart failure was thought to compromise blood flow to the lungs compared to left heart failure compromising blood flow to the aorta and consequently to the brain and the remainder of the body's systemic circulation. However, mixed presentations are common and left heart failure is a common cause of right heart failure. More accurate classification of heart failure type is made by measuring ejection fraction , or the proportion of blood pumped out of the heart during a single contraction. Ejection fraction is given as a percentage with the normal range being between 50 and 75%. The types are: Heart failure may also be classified as acute or chronic. Chronic heart failure is a long-term condition, usually kept stable by the treatment of symptoms. Acute decompensated heart failure is a worsening of chronic heart failure symptoms, which can result in acute respiratory distress . High-output heart failure can occur when there is increased cardiac demand that results in increased left ventricular diastolic pressure which can develop into pulmonary congestion (pulmonary edema). Several terms are closely related to heart failure and may be the cause of heart failure, but should not be confused with it. Cardiac arrest and asystole refer to situations in which no cardiac output occurs at all. Without urgent treatment, these events result in sudden death. Myocardial infarction ("Heart attack") refers to heart muscle damage due to insufficient blood supply, usually as a result of a blocked coronary artery . Cardiomyopathy refers specifically to problems within the heart muscle, and these problems can result in heart failure. Ischemic cardiomyopathy implies that the cause of muscle damage is coronary artery disease. Dilated cardiomyopathy implies that the muscle damage has resulted in enlargement of the heart. Hypertrophic cardiomyopathy involves enlargement and thickening of the heart muscle. One historical method of categorizing heart failure is by the side of the heart involved (left heart failure versus right heart failure). Right heart failure was thought to compromise blood flow to the lungs compared to left heart failure compromising blood flow to the aorta and consequently to the brain and the remainder of the body's systemic circulation. However, mixed presentations are common and left heart failure is a common cause of right heart failure. More accurate classification of heart failure type is made by measuring ejection fraction , or the proportion of blood pumped out of the heart during a single contraction. Ejection fraction is given as a percentage with the normal range being between 50 and 75%. The types are: Heart failure may also be classified as acute or chronic. Chronic heart failure is a long-term condition, usually kept stable by the treatment of symptoms. Acute decompensated heart failure is a worsening of chronic heart failure symptoms, which can result in acute respiratory distress . High-output heart failure can occur when there is increased cardiac demand that results in increased left ventricular diastolic pressure which can develop into pulmonary congestion (pulmonary edema). Several terms are closely related to heart failure and may be the cause of heart failure, but should not be confused with it. Cardiac arrest and asystole refer to situations in which no cardiac output occurs at all. Without urgent treatment, these events result in sudden death. Myocardial infarction ("Heart attack") refers to heart muscle damage due to insufficient blood supply, usually as a result of a blocked coronary artery . Cardiomyopathy refers specifically to problems within the heart muscle, and these problems can result in heart failure. Ischemic cardiomyopathy implies that the cause of muscle damage is coronary artery disease. Dilated cardiomyopathy implies that the muscle damage has resulted in enlargement of the heart. Hypertrophic cardiomyopathy involves enlargement and thickening of the heart muscle. An echocardiogram ( ultrasound of the heart) is commonly used to support a clinical diagnosis of heart failure. This can determine the stroke volume (SV, the amount of blood in the heart that exits the ventricles with each beat), the end-diastolic volume (EDV, the total amount of blood at the end of diastole), and the SV in proportion to the EDV, a value known as the ejection fraction (EF). In pediatrics, the shortening fraction is the preferred measure of systolic function. Normally, the EF should be between 50 and 70%; in systolic heart failure, it drops below 40%. Echocardiography can also identify valvular heart disease and assess the state of the pericardium (the connective tissue sac surrounding the heart). Echocardiography may also aid in deciding specific treatments, such as medication, insertion of an implantable cardioverter-defibrillator , or cardiac resynchronization therapy . Echocardiography can also help determine if acute myocardial ischemia is the precipitating cause, and may manifest as regional wall motion abnormalities on echo. Chest X-rays are frequently used to aid in the diagnosis of CHF. In a person who is compensated, this may show cardiomegaly (visible enlargement of the heart), quantified as the cardiothoracic ratio (proportion of the heart size to the chest). In left ventricular failure, evidence may exist of vascular redistribution (upper lobe blood diversion or cephalization), Kerley lines , cuffing of the areas around the bronchi , and interstitial edema. Ultrasound of the lung may also be able to detect Kerley lines. An electrocardiogram (ECG or EKG) may be used to identify arrhythmias , ischemic heart disease , right and left ventricular hypertrophy , and presence of conduction delay or abnormalities (e.g. left bundle branch block ). Although these findings are not specific to the diagnosis of heart failure, a normal ECG virtually excludes left ventricular systolic dysfunction. N-terminal pro-BNP (NT-proBNP) is the favoured biomarker for the diagnosis of heart failure, according to guidelines published 2018 by NICE in the UK . Brain natriuretic peptide 32 (BNP) is another biomarker commonly tested for heart failure. An elevated NT-proBNP or BNP is a specific test indicative of heart failure. Additionally, NT-proBNP or BNP can be used to differentiate between causes of dyspnea due to heart failure from other causes of dyspnea. If myocardial infarction is suspected, various cardiac markers may be used. Blood tests routinely performed include electrolytes ( sodium , potassium ), measures of kidney function , liver function tests , thyroid function tests , a complete blood count , and often C-reactive protein if infection is suspected. Hyponatremia (low serum sodium concentration) is common in heart failure. Vasopressin levels are usually increased, along with renin, angiotensin II, and catecholamines to compensate for reduced circulating volume due to inadequate cardiac output. This leads to increased fluid and sodium retention in the body; the rate of fluid retention is higher than the rate of sodium retention in the body, this phenomenon causes hypervolemic hyponatremia (low sodium concentration due to high body fluid retention). This phenomenon is more common in older women with low body mass. Severe hyponatremia can result in accumulation of fluid in the brain, causing cerebral edema and intracranial hemorrhage . Angiography is the X-ray imaging of blood vessels , which is done by injecting contrast agents into the bloodstream through a thin plastic tube ( catheter ), which is placed directly in the blood vessel. X-ray images are called angiograms. Heart failure may be the result of coronary artery disease, and its prognosis depends in part on the ability of the coronary arteries to supply blood to the myocardium (heart muscle). As a result, coronary catheterization may be used to identify possibilities for revascularisation through percutaneous coronary intervention or bypass surgery .Heart failure is commonly stratified by the degree of functional impairment conferred by the severity of the heart failure, as reflected in the New York Heart Association (NYHA) functional classification . The NYHA functional classes (I–IV) begin with class I, which is defined as a person who experiences no limitation in any activities and has no symptoms from ordinary activities. People with NYHA class II heart failure have slight, mild limitations with everyday activities; the person is comfortable at rest or with mild exertion. With NYHA class III heart failure, a marked limitation occurs with any activity; the person is comfortable only at rest. A person with NYHA class IV heart failure is symptomatic at rest and becomes quite uncomfortable with any physical activity. This score documents the severity of symptoms and can be used to assess response to treatment. While its use is widespread, the NYHA score is not very reproducible and does not reliably predict the walking distance or exercise tolerance on formal testing. In its 2001 guidelines, the American College of Cardiology / American Heart Association working group introduced four stages of heart failure: Stage A: People at high risk for developing HF in the future, but no functional or structural heart disorder Stage B: A structural heart disorder, but no symptoms at any stage Stage C: Previous or current symptoms of heart failure in the context of an underlying structural heart problem, but managed with medical treatment Stage D: Advanced disease requiring hospital-based support, a heart transplant, or palliative care The ACC staging system is useful since stage A encompasses "pre-heart failure" – a stage where intervention with treatment can presumably prevent progression to overt symptoms. ACC stage A does not have a corresponding NYHA class. ACC stage B would correspond to NYHA class I. ACC stage C corresponds to NYHA class II and III, while ACC stage D overlaps with NYHA class IV.Histopathology can diagnose heart failure in autopsies . The presence of siderophages indicates chronic left-sided heart failure, but is not specific for it. It is also indicated by congestion of the pulmonary circulation.A person's risk of developing heart failure is inversely related to level of physical activity . Those who achieved at least 500 MET-minutes/week (the recommended minimum by U.S. guidelines) had lower heart failure risk than individuals who did not report exercising during their free time; the reduction in heart failure risk was even greater in those who engaged in higher levels of physical activity than the recommended minimum. Heart failure can also be prevented by lowering high blood pressure and high blood cholesterol, and by controlling diabetes. Maintaining a healthy weight, and decreasing sodium, alcohol, and sugar intake, may help. Additionally, avoiding tobacco use has been shown to lower the risk of heart failure. According to Johns Hopkins and the American Heart Association there are a few ways to help to prevent a cardiac event. Johns Hopkins states that stopping tobacco use, reducing high blood pressure, physical activity and your diet can drastically effect the chances of developing heart disease. High blood pressure accounts for most cardiovascular deaths. High blood pressure can be lowered into the normal range by making dietary decisions such as consuming less salt. Exercise also helps to bring blood pressure back down. One of the best ways to help avoid heart failure is to promote healthier eating habits like eating more vegetables, fruits, grains, and lean protein. Diabetes is a major risk factor for heart failure. For women with Coronary Heart disease (CHD), diabetes was the strongest risk factor for heart failure. Diabetic women with depressed creatinine clearance or elevated BMI were at the highest risk of heart failure. While the annual incidence rate of heart failure for non-diabetic women with no risk factors is 0.4%, the annual incidence rate for diabetic women with elevated body mass index (BMI) and depressed creatinine clearance was 7% and 13%, respectively. Treatment focuses on improving the symptoms and preventing the progression of the disease. Reversible causes of heart failure also need to be addressed (e.g. infection , alcohol ingestion, anemia, thyrotoxicosis , arrhythmia , and hypertension). Treatments include lifestyle and pharmacological modalities, and occasionally various forms of device therapy. Rarely, cardiac transplantation is used as an effective treatment when heart failure has reached the end stage. In acute decompensated heart failure , the immediate goal is to re-establish adequate perfusion and oxygen delivery to end organs. This entails ensuring that airway, breathing, and circulation are adequate. Immediate treatments usually involve some combination of vasodilators such as nitroglycerin , diuretics such as furosemide , and possibly noninvasive positive pressure ventilation . Supplemental oxygen is indicated in those with oxygen saturation levels below 90%, but is not recommended in those with normal oxygen levels in normal atmosphere. The goals of the treatment for people with chronic heart failure are the prolongation of life, prevention of acute decompensation, and reduction of symptoms, allowing for greater activity. Heart failure can result from a variety of conditions. In considering therapeutic options, excluding reversible causes is of primary importance, including thyroid disease , anemia , chronic tachycardia , alcohol use disorder , hypertension , and dysfunction of one or more heart valves . Treatment of the underlying cause is usually the first approach to treating heart failure. In the majority of cases, though, either no primary cause is found or treatment of the primary cause does not restore normal heart function. In these cases, behavioral , medical and device treatment strategies exist that can provide a significant improvement in outcomes, including the relief of symptoms, exercise tolerance, and a decrease in the likelihood of hospitalization or death. Breathlessness rehabilitation for chronic obstructive pulmonary disease and heart failure has been proposed with exercise training as a core component. Rehabilitation should also include other interventions to address shortness of breath including psychological and educational needs of people and needs of caregivers. Iron supplementation appears to reduce hospitalization but not all-cause mortality in patients with iron deficiency and heart failure. The latest evidence indicates that advance care planning (ACP) may help to increase documentation by medical staff regarding discussions with participants, and improve an individual's depression. This involves discussing an individual's future care plan in consideration of the individual's preferences and values. The findings are however, based on low-quality evidence. The various measures often used to assess the progress of people being treated for heart failure include fluid balance (calculation of fluid intake and excretion) and monitoring body weight (which in the shorter term reflects fluid shifts). Remote monitoring can be effective to reduce complications for people with heart failure. Behavior modification is a primary consideration in chronic heart failure management program, with dietary guidelines regarding fluid and salt intake. Fluid restriction is important to reduce fluid retention in the body and to correct the hyponatremic status of the body. The evidence of benefit of reducing salt, however, is poor as of 2018. Thirst is a common and burdensome symptom for patients to cope with. Chewing gum has been shown to be an effective intervention to relieve thirst in patients experiencing heart failure, although patient acceptability remains an issue. Exercise should be encouraged and tailored to suit individual's capabilities. A meta-analysis found that centre-based group interventions delivered by a physiotherapist are helpful in promoting physical activity in HF. There is a need for additional training for physiotherapists in delivering behaviour change intervention alongside an exercise programme. An intervention is expected to be more efficacious in encouraging physical activity than the usual care if it includes Prompts and cues to walk or exercise, like a phone call or a text message. It is extremely helpful if a trusted clinician provides explicit advice to engage in physical activity ( Credible source ). Another highly effective strategy is to place objects that will serve as a cue to engage in physical activity in the everyday environment of the patient ( Adding object to the environment ; e.g., exercise step or treadmill). Encouragement to walk or exercise in various settings beyond CR (e.g., home, neighbourhood, parks) is also promising ( Generalisation of target behaviour ). Additional promising strategies are Graded tasks (e.g., gradual increase in intensity and duration of exercise training), Self-monitoring , Monitoring of physical activity by others without feedback , Action planning , and Goal-setting . The inclusion of regular physical conditioning as part of a cardiac rehabilitation program can significantly improve quality of life and reduce the risk of hospital admission for worsening symptoms, but no evidence shows a reduction in mortality rates as a result of exercise. Home visits and regular monitoring at heart-failure clinics reduce the need for hospitalization and improve life expectancy . Quadruple medical therapy using a combination of angiotensin receptor-neprilysin inhibitors (ARNI) , beta blockers , mineralocorticoid receptor antagonists (MRA) , and sodium/glucose cotransporter 2 inhibitors (SGLT2 inhibitors) is the standard of care as of 2021 for heart failure with reduced ejection fraction (HFrEF). There is no convincing evidence for pharmacological treatment of heart failure with preserved ejection fraction (HFpEF). Medication for HFpEF is symptomatic treatment with diuretics to treat congestion. Managing risk factors and comorbidities such as hypertension is recommended in HFpEF. Inhibitors of the renin–angiotensin system (RAS) are recommended in heart failure. The angiotensin receptor-neprilysin inhibitors (ARNI) sacubitril/valsartan is recommended as first choice of RAS inhibitors in American guidelines published by AHA/ACC in 2022. Use of angiotensin-converting enzyme (ACE) inhibitors (ACE-I) , or angiotensin receptor blockers (ARB) if the person develops a long-term cough as a side effect of the ACE-I, is associated with improved survival, fewer hospitalizations for heart failure exacerbations, and improved quality of life in people with heart failure. European guidelines published by ESC in 2021 recommends that ARNI should be used in those who still have symptoms while on an ACE-I or ARB , beta blocker , and a mineralocorticoid receptor antagonist . Use of the combination agent ARNI requires the cessation of ACE-I or ARB therapy at least 36 hours before its initiation. Beta-adrenergic blocking agents (beta blockers) add to the improvement in symptoms and mortality provided by ACE-I/ARB. The mortality benefits of beta blockers in people with systolic dysfunction who also have atrial fibrillation is more limited than in those who do not have it. If the ejection fraction is not diminished (HFpEF), the benefits of beta blockers are more modest; a decrease in mortality has been observed, but reduction in hospital admission for uncontrolled symptoms has not been observed. In people who are intolerant of ACE-I and ARB or who have significant kidney dysfunction, the use of combined hydralazine and a long-acting nitrate, such as isosorbide dinitrate , is an effective alternate strategy. This regimen has been shown to reduce mortality in people with moderate heart failure. It is especially beneficial in the black population. [lower-alpha 1] Use of a mineralocorticoid antagonist , such as spironolactone or eplerenone , in addition to beta blockers and ACE-I, can improve symptoms and reduce mortality in people with symptomatic heart failure with reduced ejection fraction (HFrEF). SGLT2 inhibitors are used for heart failure. Second-line medications for CHF do not confer a mortality benefit. Digoxin is one such medication. Its narrow therapeutic window, a high degree of toxicity, and the failure of multiple trials to show a mortality benefit have reduced its role in clinical practice. It is now used in only a small number of people with refractory symptoms, who are in atrial fibrillation, and/or who have chronic hypotension. Diuretics have been a mainstay of treatment against symptoms of fluid accumulation, and include diuretics classes such as loop diuretics (such as furosemide ), thiazide-like diuretics , and potassium-sparing diuretics . Although widely used, evidence on their efficacy and safety is limited, with the exception of mineralocorticoid antagonists such as spironolactone . Anemia is an independent factor in mortality in people with chronic heart failure. Treatment of anemia significantly improves quality of life for those with heart failure, often with a reduction in severity of the NYHA classification, and also improves mortality rates. European Society of Cardiology recommends screening for iron deficiency and treating with intravenous iron if deficiency is found. : 3668–3669 The decision to anticoagulate people with HF, typically with left ventricular ejection fractions <35% is debated, but generally, people with coexisting atrial fibrillation, a prior embolic event, or conditions that increase the risk of an embolic event such as amyloidosis, left ventricular noncompaction, familial dilated cardiomyopathy, or a thromboembolic event in a first-degree relative. Vasopressin receptor antagonists can also be used to treat heart failure. Conivaptan is the first medication approved by US Food and Drug Administration for the treatment of euvolemic hyponatremia in those with heart failure. In rare cases hypertonic 3% saline together with diuretics may be used to correct hyponatremia. Ivabradine is recommended for people with symptomatic heart failure with reduced left ventricular ejection fraction who are receiving optimized guideline-directed therapy (as above) including the maximum tolerated dose of beta-blocker, have a normal heart rhythm and continue to have a resting heart rate above 70 beats per minute. Ivabradine has been found to reduce the risk of hospitalization for heart failure exacerbations in this subgroup of people with heart failure. In people with severe cardiomyopathy (left ventricular ejection fraction below 35%), or in those with recurrent VT or malignant arrhythmias, treatment with an automatic implantable cardioverter-defibrillator (AICD) is indicated to reduce the risk of severe life-threatening arrhythmias. The AICD does not improve symptoms or reduce the incidence of malignant arrhythmias but does reduce mortality from those arrhythmias, often in conjunction with antiarrhythmic medications. In people with left ventricular ejection (LVEF) below 35%, the incidence of ventricular tachycardia or sudden cardiac death is high enough to warrant AICD placement. Its use is therefore recommended in AHA / ACC guidelines. Cardiac contractility modulation (CCM) is a treatment for people with moderate to severe left ventricular systolic heart failure (NYHA class II–IV), which enhances both the strength of ventricular contraction and the heart's pumping capacity. The CCM mechanism is based on stimulation of the cardiac muscle by nonexcitatory electrical signals , which are delivered by a pacemaker -like device. CCM is particularly suitable for the treatment of heart failure with normal QRS complex duration (120 ms or less) and has been demonstrated to improve the symptoms, quality of life, and exercise tolerance. CCM is approved for use in Europe, and was approved by the Food and Drug Administration for use in the United States in 2019. About one-third of people with LVEF below 35% have markedly altered conduction to the ventricles, resulting in dyssynchronous depolarization of the right and left ventricles. This is especially problematic in people with left bundle branch block (blockage of one of the two primary conducting fiber bundles that originate at the base of the heart and carry depolarizing impulses to the left ventricle). Using a special pacing algorithm, biventricular cardiac resynchronization therapy (CRT) can initiate a normal sequence of ventricular depolarization. In people with LVEF below 35% and prolonged QRS duration on ECG (LBBB or QRS of 150 ms or more), an improvement in symptoms and mortality occurs when CRT is added to standard medical therapy. However, in the two-thirds of people without prolonged QRS duration, CRT may actually be harmful. People with the most severe heart failure may be candidates for ventricular assist devices , which have commonly been used as a bridge to heart transplantation, but have been used more recently as a destination treatment for advanced heart failure. In select cases, heart transplantation can be considered. While this may resolve the problems associated with heart failure, the person must generally remain on an immunosuppressive regimen to prevent rejection, which has its own significant downsides. A major limitation of this treatment option is the scarcity of hearts available for transplantation. People with heart failure often have significant symptoms, such as shortness of breath and chest pain. Palliative care should be initiated early in the HF trajectory, and should not be an option of last resort. Palliative care can not only provide symptom management, but also assist with advanced care planning, goals of care in the case of a significant decline, and making sure the person has a medical power of attorney and discussed his or her wishes with this individual. A 2016 and 2017 review found that palliative care is associated with improved outcomes, such as quality of life, symptom burden, and satisfaction with care. Without transplantation, heart failure may not be reversible and heart function typically deteriorates with time. The growing number of people with stage IV heart failure (intractable symptoms of fatigue, shortness of breath, or chest pain at rest despite optimal medical therapy) should be considered for palliative care or hospice , according to American College of Cardiology/American Heart Association guidelines. In acute decompensated heart failure , the immediate goal is to re-establish adequate perfusion and oxygen delivery to end organs. This entails ensuring that airway, breathing, and circulation are adequate. Immediate treatments usually involve some combination of vasodilators such as nitroglycerin , diuretics such as furosemide , and possibly noninvasive positive pressure ventilation . Supplemental oxygen is indicated in those with oxygen saturation levels below 90%, but is not recommended in those with normal oxygen levels in normal atmosphere. The goals of the treatment for people with chronic heart failure are the prolongation of life, prevention of acute decompensation, and reduction of symptoms, allowing for greater activity. Heart failure can result from a variety of conditions. In considering therapeutic options, excluding reversible causes is of primary importance, including thyroid disease , anemia , chronic tachycardia , alcohol use disorder , hypertension , and dysfunction of one or more heart valves . Treatment of the underlying cause is usually the first approach to treating heart failure. In the majority of cases, though, either no primary cause is found or treatment of the primary cause does not restore normal heart function. In these cases, behavioral , medical and device treatment strategies exist that can provide a significant improvement in outcomes, including the relief of symptoms, exercise tolerance, and a decrease in the likelihood of hospitalization or death. Breathlessness rehabilitation for chronic obstructive pulmonary disease and heart failure has been proposed with exercise training as a core component. Rehabilitation should also include other interventions to address shortness of breath including psychological and educational needs of people and needs of caregivers. Iron supplementation appears to reduce hospitalization but not all-cause mortality in patients with iron deficiency and heart failure. The latest evidence indicates that advance care planning (ACP) may help to increase documentation by medical staff regarding discussions with participants, and improve an individual's depression. This involves discussing an individual's future care plan in consideration of the individual's preferences and values. The findings are however, based on low-quality evidence. The various measures often used to assess the progress of people being treated for heart failure include fluid balance (calculation of fluid intake and excretion) and monitoring body weight (which in the shorter term reflects fluid shifts). Remote monitoring can be effective to reduce complications for people with heart failure. Behavior modification is a primary consideration in chronic heart failure management program, with dietary guidelines regarding fluid and salt intake. Fluid restriction is important to reduce fluid retention in the body and to correct the hyponatremic status of the body. The evidence of benefit of reducing salt, however, is poor as of 2018. Thirst is a common and burdensome symptom for patients to cope with. Chewing gum has been shown to be an effective intervention to relieve thirst in patients experiencing heart failure, although patient acceptability remains an issue. Exercise should be encouraged and tailored to suit individual's capabilities. A meta-analysis found that centre-based group interventions delivered by a physiotherapist are helpful in promoting physical activity in HF. There is a need for additional training for physiotherapists in delivering behaviour change intervention alongside an exercise programme. An intervention is expected to be more efficacious in encouraging physical activity than the usual care if it includes Prompts and cues to walk or exercise, like a phone call or a text message. It is extremely helpful if a trusted clinician provides explicit advice to engage in physical activity ( Credible source ). Another highly effective strategy is to place objects that will serve as a cue to engage in physical activity in the everyday environment of the patient ( Adding object to the environment ; e.g., exercise step or treadmill). Encouragement to walk or exercise in various settings beyond CR (e.g., home, neighbourhood, parks) is also promising ( Generalisation of target behaviour ). Additional promising strategies are Graded tasks (e.g., gradual increase in intensity and duration of exercise training), Self-monitoring , Monitoring of physical activity by others without feedback , Action planning , and Goal-setting . The inclusion of regular physical conditioning as part of a cardiac rehabilitation program can significantly improve quality of life and reduce the risk of hospital admission for worsening symptoms, but no evidence shows a reduction in mortality rates as a result of exercise. Home visits and regular monitoring at heart-failure clinics reduce the need for hospitalization and improve life expectancy . Quadruple medical therapy using a combination of angiotensin receptor-neprilysin inhibitors (ARNI) , beta blockers , mineralocorticoid receptor antagonists (MRA) , and sodium/glucose cotransporter 2 inhibitors (SGLT2 inhibitors) is the standard of care as of 2021 for heart failure with reduced ejection fraction (HFrEF). There is no convincing evidence for pharmacological treatment of heart failure with preserved ejection fraction (HFpEF). Medication for HFpEF is symptomatic treatment with diuretics to treat congestion. Managing risk factors and comorbidities such as hypertension is recommended in HFpEF. Inhibitors of the renin–angiotensin system (RAS) are recommended in heart failure. The angiotensin receptor-neprilysin inhibitors (ARNI) sacubitril/valsartan is recommended as first choice of RAS inhibitors in American guidelines published by AHA/ACC in 2022. Use of angiotensin-converting enzyme (ACE) inhibitors (ACE-I) , or angiotensin receptor blockers (ARB) if the person develops a long-term cough as a side effect of the ACE-I, is associated with improved survival, fewer hospitalizations for heart failure exacerbations, and improved quality of life in people with heart failure. European guidelines published by ESC in 2021 recommends that ARNI should be used in those who still have symptoms while on an ACE-I or ARB , beta blocker , and a mineralocorticoid receptor antagonist . Use of the combination agent ARNI requires the cessation of ACE-I or ARB therapy at least 36 hours before its initiation. Beta-adrenergic blocking agents (beta blockers) add to the improvement in symptoms and mortality provided by ACE-I/ARB. The mortality benefits of beta blockers in people with systolic dysfunction who also have atrial fibrillation is more limited than in those who do not have it. If the ejection fraction is not diminished (HFpEF), the benefits of beta blockers are more modest; a decrease in mortality has been observed, but reduction in hospital admission for uncontrolled symptoms has not been observed. In people who are intolerant of ACE-I and ARB or who have significant kidney dysfunction, the use of combined hydralazine and a long-acting nitrate, such as isosorbide dinitrate , is an effective alternate strategy. This regimen has been shown to reduce mortality in people with moderate heart failure. It is especially beneficial in the black population. [lower-alpha 1] Use of a mineralocorticoid antagonist , such as spironolactone or eplerenone , in addition to beta blockers and ACE-I, can improve symptoms and reduce mortality in people with symptomatic heart failure with reduced ejection fraction (HFrEF). SGLT2 inhibitors are used for heart failure. Second-line medications for CHF do not confer a mortality benefit. Digoxin is one such medication. Its narrow therapeutic window, a high degree of toxicity, and the failure of multiple trials to show a mortality benefit have reduced its role in clinical practice. It is now used in only a small number of people with refractory symptoms, who are in atrial fibrillation, and/or who have chronic hypotension. Diuretics have been a mainstay of treatment against symptoms of fluid accumulation, and include diuretics classes such as loop diuretics (such as furosemide ), thiazide-like diuretics , and potassium-sparing diuretics . Although widely used, evidence on their efficacy and safety is limited, with the exception of mineralocorticoid antagonists such as spironolactone . Anemia is an independent factor in mortality in people with chronic heart failure. Treatment of anemia significantly improves quality of life for those with heart failure, often with a reduction in severity of the NYHA classification, and also improves mortality rates. European Society of Cardiology recommends screening for iron deficiency and treating with intravenous iron if deficiency is found. : 3668–3669 The decision to anticoagulate people with HF, typically with left ventricular ejection fractions 35 from the CPX test. The heart failure survival score is calculated using a combination of clinical predictors and the VO 2 max from the CPX test. Heart failure is associated with significantly reduced physical and mental health, resulting in a markedly decreased quality of life. With the exception of heart failure caused by reversible conditions, the condition usually worsens with time. Although some people survive many years, progressive disease is associated with an overall annual mortality rate of 10%. Around 18 of every 1000 persons will experience an ischemic stroke during the first year after diagnosis of HF. As the duration of follow-up increases, the stroke rate rises to nearly 50 strokes per 1000 cases of HF by 5 years. In 2022, heart failure affected about 64 million people globally. Overall, around 2% of adults have heart failure. In those over the age of 75, rates are greater than 10%. Rates are predicted to increase. Increasing rates are mostly because of increasing lifespan, but also because of increased risk factors (hypertension, diabetes, dyslipidemia, and obesity) and improved survival rates from other types of cardiovascular disease (myocardial infarction, valvular disease, and arrhythmias). Heart failure is the leading cause of hospitalization in people older than 65. In the United States, heart failure affects 5.8 million people, and each year 550,000 new cases are diagnosed. In 2011, heart failure was the most common reason for hospitalization for adults aged 85 years and older, and the second-most common for adults aged 65–84 years. An estimated one in five adults at age 40 will develop heart failure during their remaining lifetimes and about half of people who develop heart failure die within 5 years of diagnosis. Heart failure – much higher in African Americans, Hispanics, Native Americans, and recent immigrants from Eastern Europe countries – has been linked in these ethnic minority populations to high incidence of diabetes and hypertension. Nearly one of every four people (24.7%) hospitalized in the U.S. with congestive heart failure are readmitted within 30 days. Additionally, more than 50% of people seek readmission within 6 months after treatment and the average duration of hospital stay is 6 days. Heart failure is a leading cause of hospital readmissions in the U.S. People aged 65 and older were readmitted at a rate of 24.5 per 100 admissions in 2011. In the same year, people under Medicaid were readmitted at a rate of 30.4 per 100 admissions, and uninsured people were readmitted at a rate of 16.8 per 100 admissions. These are the highest readmission rates for both categories. Notably, heart failure was not among the top-10 conditions with the most 30-day readmissions among the privately insured. In the UK, despite moderate improvements in prevention, heart failure rates have increased due to population growth and ageing. Overall heart failure rates are similar to the four most common causes of cancer (breast, lung, prostate, and colon) combined. People from deprived backgrounds are more likely to be diagnosed with heart failure and at a younger age. In tropical countries, the most common cause of heart failure is valvular heart disease or some type of cardiomyopathy. As underdeveloped countries have become more affluent, the incidences of diabetes , hypertension , and obesity have increased, which have in turn raised the incidence of heart failure. [ citation needed ] Men have a higher incidence of heart failure, but the overall prevalence rate is similar in both sexes since women survive longer after the onset of heart failure. Women tend to be older when diagnosed with heart failure (after menopause ), they are more likely than men to have diastolic dysfunction, and seem to experience a lower overall quality of life than men after diagnosis. Some sources state that people of Asian descent are at a higher risk of heart failure than other ethnic groups. Other sources however have found that rates of heart failure are similar to rates found in other ethnic groups. In the United States, heart failure affects 5.8 million people, and each year 550,000 new cases are diagnosed. In 2011, heart failure was the most common reason for hospitalization for adults aged 85 years and older, and the second-most common for adults aged 65–84 years. An estimated one in five adults at age 40 will develop heart failure during their remaining lifetimes and about half of people who develop heart failure die within 5 years of diagnosis. Heart failure – much higher in African Americans, Hispanics, Native Americans, and recent immigrants from Eastern Europe countries – has been linked in these ethnic minority populations to high incidence of diabetes and hypertension. Nearly one of every four people (24.7%) hospitalized in the U.S. with congestive heart failure are readmitted within 30 days. Additionally, more than 50% of people seek readmission within 6 months after treatment and the average duration of hospital stay is 6 days. Heart failure is a leading cause of hospital readmissions in the U.S. People aged 65 and older were readmitted at a rate of 24.5 per 100 admissions in 2011. In the same year, people under Medicaid were readmitted at a rate of 30.4 per 100 admissions, and uninsured people were readmitted at a rate of 16.8 per 100 admissions. These are the highest readmission rates for both categories. Notably, heart failure was not among the top-10 conditions with the most 30-day readmissions among the privately insured. In the UK, despite moderate improvements in prevention, heart failure rates have increased due to population growth and ageing. Overall heart failure rates are similar to the four most common causes of cancer (breast, lung, prostate, and colon) combined. People from deprived backgrounds are more likely to be diagnosed with heart failure and at a younger age. In tropical countries, the most common cause of heart failure is valvular heart disease or some type of cardiomyopathy. As underdeveloped countries have become more affluent, the incidences of diabetes , hypertension , and obesity have increased, which have in turn raised the incidence of heart failure. [ citation needed ]Men have a higher incidence of heart failure, but the overall prevalence rate is similar in both sexes since women survive longer after the onset of heart failure. Women tend to be older when diagnosed with heart failure (after menopause ), they are more likely than men to have diastolic dysfunction, and seem to experience a lower overall quality of life than men after diagnosis. Some sources state that people of Asian descent are at a higher risk of heart failure than other ethnic groups. Other sources however have found that rates of heart failure are similar to rates found in other ethnic groups. For centuries, the disease entity which would include many cases of what today would be called heart failure was dropsy ; the term denotes generalized edema, a major manifestation of a failing heart, though also caused by other diseases. Writings of ancient civilizations include evidence of their acquaintance with dropsy and heart failure: Egyptians were the first to use bloodletting to relieve fluid accumulation and shortage of breath, and provided what may have been the first documented observations on heart failure in the Ebers papurus (around 1500 BCE); Greeks described cases of dyspnea, fluid retention and fatigue compatible with heart failure; Romans used the flowering plant Drimia maritima (sea squill), which contains cardiac glycosides , for the treatment of dropsy; descriptions pertaining to heart failure are also known in the civilizations of ancient India and China. However, the manifestations of failing heart were understood in the context of these peoples' medical theories – including ancient Egyptian religion, Hippocratic theory of humours , or ancient Indian and Chinese medicine , and the current concept of heart failure had not developed yet. Although shortage of breath had been connected to heart disease by Avicenna round 1000 CE, decisive for modern understanding of the nature of the condition were the description of pulmonary circulation by Ibn al-Nafis in the 13th century, and of systemic circulation by William Harvey in 1628. The role of the heart in fluid retention began to be better appreciated, as dropsy of the chest (fluid accumulation in and round the lungs causing shortage of breath) became more familiar and the current concept of heart failure, which brings together swelling and shortage of breath due to fluid retention, began to be accepted, in the 17th and especially in the 18th century: Richard Lower linked dyspnea and foot swelling in 1679, and Giovanni Maria Lancisi connected jugular vein distention with right ventricular failure in 1728. Dropsy attributable to other causes, e.g. kidney failure, was differentiated in the 19th century. The stethoscope, invented by René Laennec in 1819, x-rays , discovered by Wilhelm Röntgen in 1895, and electrocardiography , described by Willem Einthoven in 1903, facilitated the investigation of heart failure. 19th century also saw experimental and conceptual advances in the physiology of heart contraction, which led to the formulation of the Frank-Starling law of the heart (named after physiologists Otto Frank and Ernest Starling ), a remarkable advance in understanding mechanisms of heart failure. One of the earliest treatments of heart failure, relief of swelling by bloodletting with various methods, including leeches , continued through the centuries. Along with bloodletting, Jean-Baptiste de Sénac in 1749 recommended opiates for acute shortage of breath due to heart failure. In 1785, William Withering described the therapeutic uses of the foxglove genus of plants in the treatment of edema; their extract contains cardiac glycosides , including digoxin, still used today in the treatment of heart failure. The diuretic effects of inorganic mercury salts , which were used to treat syphilis , had already been noted in the 16th century by Paracelsus ; in the 19th century they were used by noted physicians like John Blackall and William Stokes . In the meantime, cannulae (tubes) invented by English physician Reginald Southey in 1877 was another method of removing excess fluid by directly inserting into swollen limbs. Use of organic mercury compounds as diuretics, beyond their role in syphilis treatment, started in 1920, though it was limited by their parenteral route of administration and their side-effects. Oral mercurial diuretics were introduced in the 1950s; so were thiazide diuretics, which caused less toxicity, and are still used. Around the same time, the invention of echocardiography by Inge Edler and Hellmuth Hertz in 1954 marked a new era in the evaluation of heart failure. In the 1960s, loop diuretics were added to available treatments of fluid retention, while a patient with heart failure received the first heart transplant by Christiaan Barnard . Over the following decades, new drug classes found their place in heart failure therapeutics, including vasodilators like hydralazine ; renin-angiotensin system inhibitors; and beta-blockers . In 2011, nonhypertensive heart failure was one of the 10 most expensive conditions seen during inpatient hospitalizations in the U.S., with aggregate inpatient hospital costs more than $10.5 billion. Heart failure is associated with a high health expenditure, mostly because of the cost of hospitalizations; costs have been estimated to amount to 2% of the total budget of the National Health Service in the United Kingdom, and more than $35 billion in the United States. Some research indicates that stem cell therapy may help. Although this research indicated benefits of stem cell therapy, other research does not indicate benefit. There is tentative evidence of longer life expectancy and improved left ventricular ejection fraction in persons treated with bone marrow-derived stem cells. The maintenance of heart function depends on appropriate gene expression that is regulated at multiple levels by epignetic mechanisms including DNA methylation and histone post-translational modification . Currently, an increasing body of research is directed at understanding the role of perturbations of epigenetic processes in cardiac hypertrophy and fibrotic scarring .

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