Viral Haemorrhagic Fevers. VHF Information and advice | Patient See also: Yellow Fever Immunisation written for patients This is a notifiable disease in the UK. See the Notifiable Diseases article for more detail. Viral haemorrhagic fevers (VHFs) are extremely rare in the UK. However, they can occur in returning travellers and should be in the differential diagnosis for cases of unexplained fever in a returning traveller from a relevant area. Not all VHFs are confined by vector to the tropics, as some are highly contagious. This means that the potential for outbreak is real if imported cases go undetected. VHF should be on the differential diagnosis of travellers with unexplained pyrexia returning from an affected area. It should rise very high on the list of differential diagnosis if there are features suggesting bleeding, hypovolaemia, increased vascular permeability, or organ failure. Suspected VHF is a medical and public health emergency and immediate advice should be sought from the local Communicable Disease Consultant on how to proceed[ 1 ]. Pathogens VHFs are caused by five types of ribonucleic acid (RNA) virus: Filoviruses: only two so far have been identified as causing human disease.

These are the Ebola and Marburg viruses. Arenaviruses: there are a number of arenaviruses, including Lassa fever, Argentine haemorrhagic fever (HF), Bolivian HF, Brazilian HF, Venezuelan HF and lymphocytic choriomeningitis. Bunyaviruses: there are a great many bunyaviruses. They cause Korean HF (Hantavirus), Rift Valley fever (RVF) and Crimean-Congo HF (CCHF). Flaviviruses: these cause yellow fever, Zika virus, Japanese encephalitis, tick-borne encephalitis, West Nile virus, Omsk HF, Alkhurma disease and dengue fever. Paramyxoviruses: these are a rare cause of VHF, as the most recognised human disease viruses in this group are measles and mumps. However, Hendra virus and Nipah virus have been described as causing VHFs. Click to find out more » Filoviridae This group includes the Marburg and Ebola viruses. Most outbreaks originate from Africa.

In the Congo and in Kenya, fruit bats are the natural host of Marburg virus, although non-human primates can also be infected[ 2 ]. The natural host of Ebola virus is unknown; however, it is thought most probably also to be bats. Both diseases are severe: mortality is significant and healthcare workers are often amongst the victims. Marburg and Ebola viruses are regarded as potential bioterrorism weapons, although it is difficult to envisage how they could be used without ultimately affecting combatants and civilians on both sides of a conflict. Arenaviridae These viruses infect rodents and occasionally humans. At least eight arenaviruses are known to cause human disease. The diseases range in severity - the most common is Lassa fever. Others include Junin virus (JUNV), Lujo virus (LUJV) and Whitewater Arroyo virus (WWAV). The natural reservoir of Lassa fever is the multimammate rat. The virus is transmitted to humans by rodents and via mosquito and other bites, from primates, including people. It is highly contagious. Medical staff are at high risk of catching it from patients.

Up to 300,000 infections and 5,000 deaths from Lassa fever are estimated to occur yearly, mostly in Sierra Leone, Liberia and Guinea[ 3 ]. Lassa fever can be asymptomatic. It has been imported into Western Europe and the USA by travellers from Africa on commercial airlines[ 4 ]. Bunyaviridae These viruses are all transmitted by arthropods (mosquitoes, ticks and sandflies) which are both the reservoir and the vector, with the exception of Hantavirus (whose reservoir is in rodents). They include Hantaviruses, Rift Valley fever (RVF) and Crimean-Congo haemorrhagic fever (CCHF). RVF is transmitted to humans and domesticated animals by mosquitoes and by the slaughter of infected livestock[ 5 ]. CCHF is carried by ticks and causes a fulminant disease that can also be transmitted by aerosol. Outbreaks of CCHF have occurred in Africa, Asia and Europe. Hantaviruses exist throughout the world. Infection occurs after exposure of skin or mucous membranes to aerosolised urine, droppings, or saliva of infected rodents or after exposure to dust from their nests.

Transmission may also occur through bites from infected animals. Human-to-human transmission is possible, but rare. Hantaviruses cause two main syndromes: haemorrhagic fever with renal syndrome (HFRS) which is found mainly in Europe, Africa and Asia, and Hantavirus pulmonary syndrome (HPS) which is found mainly in the Americas. HPS is a severe flu-like illness followed by acute pulmonary inflammation and oedema, with a mortality rate of about 40%. HFRS has a slower course and causes similar initial symptoms but progresses to hypotension, vascular leakage and acute kidney injury. The mortality of HFRS varies between pathogens and is 1-15%. A new Hantavirus, sin nombre virus, caused an outbreak of highly lethal HPS in the southwestern USA in 1993. Several steep increases in Hantavirus infections in Southern Germany in 2010-2012, with nearly 1,000 cases in winter 2011/12, related to an increase in the population of the natural animal reservoir, the bank vole[ 6 , 7 ].

Flaviviridae There are over a hundred viruses in this group but yellow fever, Zika virus and dengue (formerly referred to as dengue fever) are the best known. The natural reservoirs are in non-human primates, and they are spread by the female Aedes mosquito. Since the launch of the Yellow Fever Initiative of mass vaccination in 2006, significant progress in combatting the disease has been made in West Africa[ 8 ]. Emergence of viral haemorrhagic fevers Many VHFs are emerging diseases, many of which made the species leap relatively recently. Ebola virus was first identified in human beings in 1976. Marburg virus was first recognised in Europe in 1967[ 9 ]. Lassa fever first appeared in Lassa in Nigeria in 1969, but genetic analysis suggests its presence as a pathogen in rats, at least, for a thousand years. Dengue fever made the cross-species leap from monkeys in the last 800 years, and yellow fever first appeared in humans in the mid seventeenth century.

(The 1793 outbreak in Philadelphia, then the US capital, killed more than 9% of the population and drove the American government, including George Washington, to flee and create a new capital, Washington.) More recently, dengue has been rapidly emerging as a global threat, with over half the world's population susceptible. Zika virus, first described in Africa and Asia in 1947, has recently spread across the Pacific to South America. The reasons for disease emergence are multiple; however, the two main factors are expansion of the human population and globalisation of trade. Current issues such as the increasing movement of a variety of animal species, ecological disruption, mass migration and bioterrorism, continue to create the conditions for new diseases to emerge and spread. What we can learn from management of the VHFs may assist with these future challenges[ 9 ]. Viral haemorrhagic fever epidemics VHF epidemics may arise through several factors, including: Change in the host susceptibility (eg, increased susceptible numbers). Change in the pathogen (increased infectivity). Introduction of a pathogen to a naive host population. Optimised conditions for transmission.

Epidemics of yellow fever occur when infected people introduce the virus into populous areas with high mosquito density where the population has low immunity, due to lack of vaccination. Analysis of the current Zika virus epidemic suggests that it arrived in Brazil from Polynesia in 2013 during the FIFA Confederation Cup, when the Tahitian team played in several Brazilian cities[ 10 ]. Zika virus usually has very mild symptoms, so it took almost a year for Brazil to confirm the first case. By then the outbreak was already widespread. Factors associated with the rapid spread of Zika virus in Brazil include the non-immune population, high population density, tropical climate and inadequate control of Aedes mosquitoes in the country. The West African Ebola virus outbreak may have begun with a single individual exposed to insect-eating bats. World Health Organization (WHO) analysis of why this outbreak grew to epidemic proportions makes interesting reading to those concerned about containment of any epidemic VHF[ 11 ]: Countries in equatorial Africa have experienced Ebola virus outbreaks for four decades, so clinicians suspect Ebola virus when a 'mysterious' disease occurs. Laboratory capacity is in place. Staff know where to send samples for rapid diagnosis.

Health systems are prepared, some with isolation wards and staff trained in infection control. Governments treat a confirmed case as a national emergency. All previous outbreaks were controlled within three months. West African countries had never experienced an Ebola virus outbreak and were ill-prepared for this unfamiliar and unexpected disease. Clinicians had never managed cases. No laboratory had ever diagnosed a patient specimen. No government had witnessed the upheaval of an outbreak. Populations did not understand it. Ebola virus was thus an old disease in a new context that favoured rapid and initially invisible spread. As a result of these and other factors, the virus behaved differently in West Africa than in equatorial Africa. Pathophysiology[ 12 ] Although these are many different VHF viruses in many parts of the world, they have much in common in terms of pathology and clinical manifestations. Incubation periods are typically in the range 2-21 days, a few slightly longer. The initial stage of viraemia affects the vascular system, causing flushing, conjunctival injection and petechial haemorrhages, often with fever and myalgia. Viraemia may be overwhelming if there is inadequate or delayed immune response.

The central pathological process which marks more severe disease is the development of increased vascular permeability. Later, obvious mucous membrane haemorrhage and hypovolaemia may occur, with hypotension, shock and circulatory collapse. Direct organ damage may be caused by the viruses themselves; multiorgan damage may also result from shock and hypovolaemia. Different VHFs vary in their infectivity, virulence and tendency to affect specific sites such as liver, brain, kidney and lungs. Presentation The presentation and severity vary with the virus, viral load and route of exposure. Some VHFs (eg, dengue, Zika virus) are more typically mild. Others, such as Ebola virus, are more often catastrophic. However, it is possible to generalise, as the VHFs share many common features. History Presentation is usually with a febrile illness and, at this stage, the range of differential diagnosis is wide. There may be a history of foreign travel, or of recent contact with someone who has become unwell. Remembered exposure to rodents, bats and insect bites may be significant, as may the consumption of unusual meat which might be bat or primate. Flu-like symptoms are nonspecific and typically include: Temperature.

Jaundice - sometimes seen where there is hepatic involvement. Oedema secondary to acute kidney injury In advanced disease there may be altered mental state and circulatory collapse. This may be terminal. More florid and potentially diagnostic symptoms occur after a few days, as result from altered vascular permeability with capillary leakage. This is generally a marker for severity and is a central pathological process via which VHFs exert their more serious effects. They include: Coagulopathy: very marked with Ebola virus, Marburg virus, CCHF and the South American arenaviruses, with severe bleeding a consequence. Haemorrhagic complications include hepatic damage, myocarditis, encephalitis, consumptive coagulopathy and primary marrow injury to megakaryocytes. Multisystem organ failure often accompanies vascular involvement. Infected organs may become necrotic. Hepatic involvement can occur with Ebola virus, Marburg virus, RVF, CCHF and yellow fever. Pulmonary oedema is a particular feature in Hantavirus infection. Acute kidney injury with oliguria is common in Hantavirus infection and may be seen in other VHFs when hypotension occurs.

VHF should be suspected in febrile returning travellers if there are features suggesting bleeding, hypovolaemia, increased vascular permeability, or organ failure. Differential diagnosis Encephalitic viruses - eg, West Nile virus . Investigations Infected material is potentially dangerous and so investigations should be restricted to the necessary and specimens must carry warning labels, even if the diagnosis is only suspected. When the diagnosis has been made, it is a notifiable disease. Tests for VHF FBC shows leukopenia and thrombocytopenia, although this may not be so with Lassa fever. LFTs show elevated transaminases (in Lassa fever this predicts a high mortality). Coagulation screen: partial thromboplastin time (PTT), INR and clotting times are all prolonged. There may be evidence of DIC. D-dimer may be markedly elevated and fibrinogen levels low. Diagnostic tests Most patients have viraemia at presentation and specific antibody tests can be used identify the virus[ 13 , 14 ]. Speed is important during outbreaks and high-throughput protocols for RNA extraction and reverse-transcription polymerase chain reaction (PCR) analysis have been used during outbreaks[ 15 ].

During the 2013-16 Ebola virus outbreak, testing relied on complex, multi-step real-time reverse transcription PCR (RT-PCR) assays performed in the field; however, improved assays were under investigation and are now available[ 16 ]. Virus-specific IgM may be assayed. For Hantavirus, virus-specific IgM is usually assayed, as the viraemia is brief. Typing of a specific Hantavirus infection (because of the difference in severity of symptoms of the various types) requires specialist assays[ 17 ]. A test assaying salivary and urine IgM and IgG levels in dengue has been investigated, with promising results[ 18 ]. Management Suspected VHF should be notified at once, and advice should be sought on precautions against potential further transmission. Family members and healthcare workers who have looked after the patient may be at risk. Doctors requesting advice on possible VHF cases should contact their local Communicable Disease Consultant in the first instance. If they agree that VHF is suspected they will contact the Imported Fever Service. Public Health England offers online advice for the procedure[ 19 ].

If the differential diagnosis includes VHF capable of transmission in the UK then infection control procedures will be initiated. Patients with suspected contagious VHF require barrier nursing. Visitors should be restricted. Management is supportive, focusing on blood volume management, clotting and care of major organs, including heart and lungs. Lassa fever and HFRS due to Hantavirus respond to the antiviral ribavirin. Ribavirin might be suitable for other arenaviruses and bunyaviruses, including CCHF; however, treatment must be started early[ 20 ]. Ribavirin is also recommended for post-exposure prophylaxis. Antivirals are of no value for Ebola virus or Marburg virus. A sudden, large number of simultaneous cases would raise the suspicion of bioterrorism. Complications These include retinitis, orchitis , hepatitis , transverse myelitis and uveitis , together with psychological sequelae. In those who recover from Lassa fever, deafness is the most common complication. Miscarriage is also common. Renal insufficiency occurs in HFRS infection. Recovery from Ebola virus may be followed by relapse.

Sequelae of Ebola virus can be severe, such as arthritis and vision-threatening uveitis. The mental health effects on survivors is profound. Ebola virus may also persist for weeks or months in selected body compartments of survivors, most notably in the semen of men, bringing risk of renewed transmission where it has previously been eliminated[ 21 ]. Prognosis Fatality rates vary but VHFs are capable of high lethality - for example: The fatality rate for dengue, overall, is less than 1%; however, this rises as high as 50% in untreated, severe disease[ 22 ]. The 2013 Ebola virus epidemic in West Africa infected over 26,000 people, of whom around 40% died[ 23 ]. Lassa fever infection can be asymptomatic; however, about 20% develop severe disease which is commonly fatal, and there is evidence for increased virulence of the virus[ 24 ]. In 2016 the ‘Lassa season’ was longer and generated more cases than usual, with a case mortality above 50%.

The high number of cases reported in Nigeria may be partly due to better detection but genetic sequencing showed a new lineage of the Lassa virus. The outbreaks may also be due to increasing urbanisation and to climatic conditions favouring the rat[ 25 ]. Case fatality rates in Marburg virus have been reported as 24-88%[ 26 ]. Yellow fever is often asymptomatic but in patients who go on to develop toxic disease, mortality is around 50%[ 27 ]. Zika virus is usually mild or asymptomatic. Its serious sequelae are those for the fetus of a pregnant patient, not for the patient themself[ 28 ]. Prevention The WHO has stated that the best way to prepare for an epidemic is to strengthen vaccination campaigns, to have an effective disease surveillance system, to be able to dispatch emergency workers and stockpiled vaccines quickly and to have a legitimate way to guarantee the safety and health of health workers themselves (this latter was one of the early barriers to effective containment of the West African Ebola virus epidemic)[ 29 ]. Vector control Control programmes for rodents and mosquitoes are required in endemic areas[ 30 ].

Aedes mosquitos, which act as vectors for yellow fever, Zika virus, dengue and chikungunya fever, are day feeders so that night-time mosquito nets offer insufficient protection. System preparation This needs adequate training of healthcare workers in diagnostics, intensive care of patients under isolation, contact tracing, adequate precautionary measures in handling infectious laboratory specimens, control of the vector and care and disposal of infectious waste[ 31 ]. Vaccination The only current UK-licensed vaccine against a VHF is that against yellow fever ; however, work continues in this area. Vaccination programmes for yellow fever vaccine have been extremely effective. It has been incorporated into childhood vaccination programmes in Africa and endemic areas of South America. Certification of current vaccination is required when entering many countries which host Aedes mosquitoes, particularly if entering from a country in which yellow fever is endemic[ 32 ]. Tetravalent, live-attenuated, dengue vaccine (Dengvaxia(®)) is approved in several countries for the prevention of dengue caused by virus serotypes 1-4.

It requires three doses administered over the course of one year - in trials it reduced the chances of developing the disease by about 60% during the one-year follow-up. It is only approved for use in people aged 9-45 years who live in dengue-endemic areas - it seems to be least effective in children aged under 6 years. Long-term immunity is not yet demonstrated and there are concerns that later infections might have a greater chance of leading to severe dengue. The WHO has recommended that countries with high dengue endemicity consider introducing the vaccine as part of an integrated disease prevention strategy. Two other dengue vaccines are entering phase III testing. One is promising as a travel vaccine, as a single dose fully protected susceptible adults[ 33 , 34 ]. Ebola virus vaccination became a priority during the recent outbreak and advances were made, with a number of different possible vaccines being evaluated[ 35 ]. A vaccine against CCHF looked promising in mouse trials; however, it failed to confer the necessary immunity[ 36 ]. Surveillance Computer models using variables such as rainfall and temperature have been used to predict likely risk areas for Lassa fever in West Africa[ 37 ].

Syndromic surveillance (the surveillance of a population using symptom groups) has been used by the military to detect possible biological warfare activity and was used to detect an early outbreak of dengue fever in French Guyana in 2006[ 38 ]. The ability to make rapid diagnosis depends on investment in laboratory services and disease surveillance[ 39 ]. Case containment Rapid detection and isolation of confirmed cases reduces the risk of outbreak and epidemic. If there is no virus circulating in the local population then levels in the local arthropod vectors will also reduce. Historical Ebola virus first was described in 1976 after outbreaks of illness were reported along the Ebola River in Zaire (now the Democratic Republic of the Congo) and Sudan. In 1995, an outbreak in Kikwit, Zaire, led to 317 confirmed cases, with an 81% mortality rate. Two thirds of the cases were health workers caring for infected people. The 2013-2016 outbreak in West Africa was, by a long way, the largest to date. Marburg virus was named after the German town where it first was reported in 1967 but it is traced to central Africa.

It has been endemic since 1998 in Durba, Democratic Republic of the Congo. Yellow fever and dengue fever have had devastating effects on historical military campaigns. It is thought that yellow fever was brought to America by slaves. The control of mosquitoes to control yellow fever was an essential component of the project that made it possible to dig the Panama Canal. Korean haemorrhagic fever was first noticed in the Korean War in 1951 when around 3,000 soldiers developed a disease characterised by fever and renal failure, with a fatality rate of 10%. It took until 1976 to identify the virus[ 40 ]. Second meeting of the Emergency Committee under the International Health Regulations (2005) concerning yellow fever ; World Health Organization (Statement), 31 August 2016 Bonner PC, Schmidt WP, Belmain SR, et al ; Poor housing quality increases risk of rodent infestation and Lassa fever in refugee camps of Sierra Leone. Am J Trop Med Hyg. 2007 Jul;77(1):169-75.

Ogbu O, Ajuluchukwu E, Uneke CJ ; Lassa fever in West African sub-region: an overview. J Vector Borne Dis. 2007 Mar;44(1):1-11. Monath TP ; Yellow fever as an endemic/epidemic disease and priorities for vaccination. Bull Soc Pathol Exot. 2006 Dec;99(5):341-7. Scott LJ ; Tetravalent Dengue Vaccine: A Review in the Prevention of Dengue Disease. Drugs. 2016 Sep;76(13):1301-12. doi: 10.1007/s40265-016-0626-8. Halstead SB, Aguiar M ; Dengue vaccines: Are they safe for travelers? Travel Med Infect Dis. 2016 Jul-Aug;14(4):378-83. doi: 10.1016/j.tmaid.2016.06.005. Epub 2016 Jun 22.

Sridhar S ; Clinical development of Ebola vaccines. Ther Adv Vaccines. 2015 Sep;3(5-6):125-38. doi: 10.1177/2051013615611017. Dowall SD, Buttigieg KR, Findlay-Wilson SJ, et al ; A Crimean-Congo hemorrhagic fever (CCHF) viral vaccine expressing nucleoprotein is immunogenic but fails to confer protection against lethal disease. Hum Vaccin Immunother. 2016;12(2):519-27. doi: 10.1080/21645515.2015.1078045. Fichet-Calvet E, Rogers DJ ; Risk maps of Lassa fever in West Africa. PLoS Negl Trop Dis. 2009;3(3):e388. Epub 2009 Mar 3.

Meynard JB, Chaudet H, Texier G, et al ; Value of syndromic surveillance within the Armed Forces for early warning during a dengue fever outbreak in French Guiana in 2006. BMC Med Inform Decis Mak. 2008 Jul 2;8:29. Shears P ; Emerging and reemerging infections in africa: the need for improved laboratory services and disease surveillance. Microbes Infect. 2000 Apr;2(5):489-95. Klein SL, Calisher CH ; Emergence and persistence of hantaviruses. Curr Top Microbiol Immunol. 2007;315:217-52. Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but makes no warranty as to its accuracy. Consult a doctor or other healthcare professional for diagnosis and treatment of medical conditions. For details see our conditions . Original Author: WHO | Marburg haemorrhagic fever Marburg haemorrhagic fever The Marburg virus causes severe viral haemorrhagic fever in humans.

Case fatality rates in Marburg haemorrhagic fever outbreaks have ranged from 24% to 88%. Rousettus aegypti, fruit bats of the Pteropodidae family, are considered to be natural hosts of Marburg virus. The Marburg virus is transmitted to people from fruit bats and spreads among humans through human-to-human transmission. No specific antiviral treatment or vaccine is available. Marburg virus is the causative agent of Marburg haemorrhagic fever (MHF), a disease with a case fatality ratio of up to 88%. Marburg haemorrhagic fever was initially detected in 1967 after simultaneous outbreaks in Marburg, from which the disease takes its name, and Frankfurt in Germany; and in Belgrade, Serbia. Marburg and Ebola viruses are the two members of the Filoviridae family (filovirus). Though caused by different viruses, the two diseases are clinically similar. Both diseases are rare and have the capacity to cause dramatic outbreaks with high fatality rates.

Outbreaks Two large outbreaks that occurred simultaneously in Marburg and Frankfurt in Germany, and in Belgrade, Serbia, in 1967, led to the initial recognition of the disease. The outbreak was associated with laboratory work using African green monkeys (Cercopithecus aethiops) imported from Uganda. Subsequently, outbreaks and sporadic cases have been reported in Angola, Democratic Republic of the Congo, Kenya, South Africa (in a person with recent travel history to Zimbabwe) and Uganda. In 2008, two independent cases were reported in travelers who visited a cave inhabited by Rousettus bat colonies in Uganda. Transmission Originally, human infection results from prolonged exposure to mines or caves inhabited by Rousettus bats colonies. Transmission is mainly human-to-human, resulting from close contact with the blood, secretions, organs or other bodily fluids of infected persons. Burial ceremonies where mourners have direct contact with the body of the deceased can play a significant role in the transmission of Marburg. Transmission via infected semen can occur up to seven weeks after clinical recovery. Transmission to health-care workers has been reported while treating Marburg patients, through close contact without the use of correct infection control precautions.

Transmission via contaminated injection equipment or through needle-stick injuries is associated with more severe disease, rapid deterioration, and, possibly, a higher fatality rate. Signs and symptoms The incubation period (interval from infection to onset of symptoms) varies from 2 to 21 days. Illness caused by Marburg virus begins abruptly, with high fever, severe headache and severe malaise. Muscle aches and pains are a common feature. Severe watery diarrhoea, abdominal pain and cramping, nausea and vomiting can begin on the third day. Diarrhoea can persist for a week. The appearance of patients at this phase has been described as showing “ghost-like” drawn features, deep-set eyes, expressionless faces, and extreme lethargy. In the 1967 European outbreak, non-itchy rash was a feature noted in most patients between 2 and 7 days after onset of symptoms. Many patients develop severe haemorrhagic manifestations between 5 and 7 days, and fatal cases usually have some form of bleeding, often from multiple areas. Fresh blood in vomitus and faeces is often accompanied by bleeding from the nose, gums, and vagina.

Spontaneous bleeding at venepuncture sites (where intravenous access is obtained to give fluids or obtain blood samples) can be particularly troublesome. During the severe phase of illness, patients have sustained high fever. Involvement of the central nervous system can result in confusion, irritability, and aggression. Orchitis has been reported occasionally in the late phase of disease (15 days). In fatal cases, death occurs most often between 8 and 9 days after symptom onset, usually preceded by severe blood loss and shock. Diagnosis The differential diagnoses usually include malaria, typhoid fever, shigellosis, cholera, leptospirosis, plague, rickettsiosis, relapsing fever, meningitis, hepatitis and other viral haemorrhagic fevers. Marburg virus infections can be diagnosed definitively only in laboratories, by a number of different tests: enzyme-linked immunosorbent assay (ELISA); reverse-transcriptase polymerase chain reaction (RT-PCR) assay; and virus isolation by cell culture. Tests on clinical samples present an extreme biohazard risk and are conducted only under maximum biological containment conditions.

Treatment and vaccine Severe cases require intensive supportive care, as patients are frequently in need of intravenous fluids or oral rehydration with solutions containing electrolytes. No specific treatment or vaccine is yet available for MHF. Several vaccine candidates are being tested but it could be several years before any are available. New drug therapies have shown promising results in laboratory studies and are currently being evaluated. Natural hosts of Marburg virus In Africa, the Old World fruit bats of the family Pteropodidae, particularly species belonging to the genus Rousettus aegyptiacus are considered natural hosts for Marburg virus. There is no apparent disease in the fruit bats. As a result, the geographic distribution of Marburg virus may overlap with the range of Rousettus bats. Marburg virus in animals African green monkeys (Cercopithecus aethiops) imported from Uganda were the source of infection for humans during the first Marburg outbreak. Experimental inoculations in pigs with different Ebola viruses have been reported and show that pigs are susceptible to filovirus infection and shed the virus. Therefore pigs should be considered as a potential amplifier host during MHF outbreaks.

Although no other domestic animals have yet been confirmed as having an association with filovirus outbreaks, as a precautionary measure they should be considered as potential amplifier hosts until proven otherwise. Prevention Precautionary measures for pig farms in endemic zones Precautionary measures are needed in pig farms in Africa to avoid pigs becoming infected through contact with fruit bats. Such infection could potentially amplify the virus and cause or contribute to MHF outbreaks. Reducing the risk of infection in people In the absence of effective treatment and human vaccine, raising awareness of the risk factors for Marburg infection and the protective measures individuals can take to reduce human exposure to the virus, are the only ways to reduce human infections and deaths. During MHF outbreaks in Africa, public health educational messages for risk reduction should focus on: Reducing the risk of bat-to-human transmission arising from prolonged exposure to mines or caves inhabited by fruit bats colonies. During work or research activities or tourist visits in mines or caves inhabited by fruit bat colonies, people should wear gloves and other appropriate protective clothing (including masks). Reducing the risk of human-to-human transmission in the community arising from direct or close contact with infected patients, particularly with their body fluids. Close physical contact with Marburg patients should be avoided.

Gloves and appropriate personal protective equipment should be worn when taking care of ill patients at home. Regular hand washing should be performed after visiting sick relatives in hospital, as well as after taking care of ill patients at home. Communities affected by Marburg should make efforts to ensure that the population is well informed, both about the nature of the disease itself and about necessary outbreak containment measures, including burial of the dead. People who have died from Marburg should be promptly and safely buried. Controlling infection in health-care settings Human-to-human transmission of Marburg virus is primarily associated with direct contact with blood and body fluids, and Marburg virus transmission associated with provision of health care has been reported when appropriate infection control measures have not been observed. Health-care workers caring for patients with suspected or confirmed Marburg virus should apply infection control precautions to avoid any exposure to blood and body fluids and to direct unprotected contact with possibly contaminated environment. Therefore, provision of health care for suspected or confirmed Marburg patients requires specific control measures and reinforcement of standard precautions, particularly hand hygiene, use of personal protective equipment (PPE), safe injection practices, and safe burial practices. Laboratory workers are also at risk.

Samples taken from suspected human and animal Marburg cases for diagnosis should be handled by trained staff and processed in suitably equipped laboratories. WHO response WHO has been involved in all past Marburg outbreaks by providing expertise and documentation to support disease investigation and control. Recommendations for infection control while providing care to patients with suspected or confirmed Marburg haemorrhagic fever is provided in the: Interim infection control recommendations for care of patients with suspected or confirmed filovirus (Ebola, Marburg) Haemorrhagic Fever, March 2008. WHO has created an aide–memoire for standard precautions in health care. Standard precautions are meant to reduce the risk of transmission of bloodborne and other pathogens. If universally applied, the precautions would help prevent most transmission through exposure to blood and body fluids. Standard precautions are recommended in the care and treatment of all patients regardless of their perceived or confirmed infectious status. They include the basic level of infection control and include hand hygiene, use of personal protective equipment to avoid direct contact with blood and body fluids, prevention of injuries from needle sticks and from other sharp instruments, and a set of environmental controls. Table: Chronology of major Marburg Haemorrhagic Fever outbreaks.

Year Factsheet for health professionals Factsheet for health professionals Updated on 16 October 2015 AGENTS Ebola and Marburg viruses are members of the Filoviridae family. The Ebolavirus genus includes five distinct species: Zaire ebolavirus, Sudan ebolavirus, Bundibugyoebola virus, Taï Forest ebolavirus and Reston ebolavirus. Zaire, Sudan , Bundibugyo and Taï Forest ebolaviruses occur in Africa and cause serious illness in humans. Reston ebolavirus present in the Philippines only causes asymptomatic illness in human. The Marburgvirus genus contains only one species, Marburg virus (MARV) which is responsible of several outbreaks of haemorrhagic fever in Africa. Ebola viruses and Marburg virus are classified as biosafety level 4 (BSL-4) pathogens and require special containment and barrier protection measures, in particular for people taking care of infected patients or bodies.

RESERVOIRS OF EBOLAVIRUS AND MARBURGVIRUS Ebola viruses have been isolated from several fruit bats of the Pteropodidae family in central and western Africa, particularly of the species hammer-headed bat (Hypsignathus monstrosus), Franquet's epauletted fruit bat (Epomops franqueti) and little collared fruit bat (Myonycteris torquata), which are considered natural reservoirs. On the African continent, human Ebolavirus infections have been linked to direct contact with gorillas, chimpanzees, monkeys, forest antelope and porcupines found dead in the rainforest. Ebola viruses (Zaire and Taï Forest ebolaviruses) have been detected in the wild in carcasses of chimpanzees (in Cote d’Ivoire and Congo), gorillas (Gabon and Congo) and forest antilopes (Congo). Reston ebolavirus caused severe outbreaks in macaque monkeys in the Philippines and asymptomatic infections have been reported in pigs.

Scientific studies implicate African fruit bats, particularly the Egyptian fruit bat or Egyptian rousette (Rousettus aegypticus) as the reservoir of the Marburg virus. Several outbreaks were linked to visits to caves colonized by bats. TRANSMISSION MODES Ebola and Marburg viruses are highly transmissible by direct contact with organs, blood or other bodily fluids (e.g. saliva, urine, vomit) of living or dead infected persons or any soiled material. Transmission by sexual contact can occur up to six months after clinical recovery. Viral genome was recovered in semen up to 9 months after onset of illness. Transmission can also occur by contact with dead or living infected animals including bushmeat (e.g. monkeys, chimpanzees, forest antelopes and bats) or visiting caves colonized by bats. Nosocomial transmission can occur. Healthcare workers can be infected through close contact with infected patients. The risk for infection can be significantly reduced through the appropriate use of infection control precautions and adequate barrier procedures. This is especially important when performing invasive procedures.

Filoviruses can survive in liquid or dried material for many days.They are inactivated by gamma irradiation, heating for 60 minutes at 60°C or boiling for five minutes, and are sensitive to sodium hypochlorite and other disinfectants. Freezing or refrigeration will not inactivate Filoviruses. EPIDEMIOLOGY In 1967, isolated cases of haemorrhagic fever occurred among laboratory workers handling tissues from monkeys (Chlorocebus aethiops) from Uganda and in medical personnel who attended the laboratory workers. This was a new virus named Marburg virus after the city in Germany where it was first characterised. In 1976, epidemics of severe haemorrhagic fever occurred simultaneously in Sudan and Democratic Republic of Congo (former Zaïre); a new virus was identified and named after a small river in Democratic Republic of Congo. Later studies showed some differences between the virus isolated in Democratic of Congo and the virus isolated from Sudan. These viruses were also serologically distinct from the Marburg virus. Multiple outbreaks of infection with both Ebola virus and Marburg virus have been identified since their initial discovery.

From 1976 to 2012, 2387 cases of ebolavirus infections and 1590 deaths have been reported (Case Fatalty Rate [CFR] 66.6%) and from 1967 to 2012, 571 cases of Marburg virus infections including 470 deaths (CFR 82.3%). Oubreaks of Ebolavirus have been reported in mainly Democratic Republic of Congo , Congo, Gabon, and Sudan and outbreaks of Marburg virus in Kenya, Uganda and Angola. In 2008, two tourists (one from the USA and one from the Netherlands) became infected after visiting, several months apart, a cave in Maramagambo forest in Uganda; one of the cases died. In March 2014, an outbreak of Zaire ebolavirus was reported in Eastern Guinea. The disease spread rapidely in neighboring countries, Sierra Leone and Liberia. The disease further spread to Nigeria and Senegal. This is the first outbreak of ebolavirus in West Africa and the worst ever reported.

Another unrelated outbreak also due to Zaire ebolavirus was reported in August 2014 in Democratic Republic of Congo. CLINICAL PRESENTATION The typical incubation period for these viruses ranges from 2 to 21 days. Short incubation periods are likely in case of exposure to high contaminated materials (e.g. needle mishap). In most cases, an infected patient experiences sudden onset of flu-like illness, with fever, malaise (weakness), muscle and joint pains and headache, followed by progressive weakness, anorexia (lack of appetite), diarrhoea (watery stools sometimes containing blood and mucus), nausea and vomiting. This first set of symptoms corresponds to the prodromal phase (duration up to 10 days). The next stage of the disease is characterised by symptoms and clinical manifestations from several organ systems. Symptoms can be gastrointestinal (vomiting, diarrhoea, anorexia and abdominal pain), neurological (headaches, confusion), vascular (conjunctival/pharyngeal injections), cutaneous (maculopapular rash), and respiratory (cough, chest pain, shortness of breath), and can include complete exhaustion (prostration).

After one week of evolution, haemorrhagic manifestations can appear in more than half of the patients (bloody diarrhoea, nosebleeds, hematemesis, petechiae, ecchymosis and prolonged bleeding from needle puncture sites). Some patients develop profuse internal and external haemorrhages and disseminated intravascular coagulation. Patients in the final stage of disease die in the clinical picture of tachypnea, anuria, hypovolemic shock and multi-organ failure. Depending on the viral species, 25% to 90% of cases may die. DIAGNOSIS Laboratory tests on blood specimens detect viral material (viral genome or antigen) or specific antibodies. Only a few tests are commercially available. Samples from infected patients should be handled under strict biological containment conditions in biosafety level 3 or 4 laboratories. Any attempt for viral replication should be handled in biosafety level 4 laboratories. THERAPY No curative treatment is presently available and validated for filovirus infections. Treatment is supportive (oral rehydration with solutions containing electrolytes or intravenous fluids) and severe cases require intensive care. Research on vaccine and drug therapy is ongoing.

INFECTION CONTROL AND PREVENTION The goal of outbreak control is to interrupt direct human-to-human transmission through the early identification and systematic isolation of cases, timely contact-tracing, proper personal protection, safely conducted burials, and improved community awareness about risk factors of viral infection and individual protective measures. Quarantine of infected patients has been shown to effectively stop the spread of the disease in previous outbreaks. Healthcare workers have frequently been infected while treating patients with suspected or confirmed Ebola or Marburg infection. This occurred through close contact with patients when infection control precautions were not strictly practiced or haemorrhagic viral etiology not recognized. The risk for infection can be significantly reduced through the appropriate use of infection control precautions and adequate and strict barrier nursing procedures. It is advised to avoid, in areas/countries where Ebola and Marburg disease were reported, habitats which might be populated by bats such as caves, and any form of close contact with wild animals (including monkeys, forest antelopes, rodents and bats), both alive and dead, and consumption of type of ‘bush meat’. Implementation of appropriate infection control measures in healthcare settings, including use of personal protective equipment, is effective in minimising the risk for transmission of filoviruses. REFERENCES 1.

World Health Organization. Interim infection prevention and control guidance for care of patients with suspected or confirmed Filovirus haemorrhagic fever in health-care settings, with focus on Ebola. Geneva: World Health Organisation, 2014. 2. World Health Organization. Ebola virus disease (Fact sheet N°103) [internet]. WHO Media centre; 2014 [updated Apr 2014; cited 2014 Mar 20]. Available from: . 3. World Health Organization. Marburg haemorrhagic fever Geneva: World Health Organization; 2014 [4/9/2014]. Available from: . 4. World Health Organization. INTERIM version 1.2 Ebola and Marburg virus disease epidemics: preparedness, alert, control, and evaluation. Geneva: World Health Organization, 2014. 5. European Network for Diagnostics of Imported Viral Diseases. Management and Control of Viral Haemorrhagic Fevers and other highly contagious viral pathogens [internet]. ENVID Scientific Advisory Committee; 2014 [cited 2014 Mar 22]. Available from: 6.

European Centre for Disease Prevention and Control. Risk assessment guidelines for diseases transmitted on aircraft (Part 2). 2010 2. 7. European Centre for Disease Prevention and Control. Outbreak of Ebola virus disease in West Africa. Fourth update, 3 September 2014. Stockholm: ECDC, 2014. The Discovery of Filoviruses | ViroBlogy The Discovery of Filoviruses The discovery of filoviruses: Marburg and Ebola Marburg virus In 1967, the world was introduced to a new virus : thirty-one people in Marburg and Frankfurt in Germany, and Belgrade in the then Yugoslavia, became infected in a linked outbreak with a novel haemorrhagic fever agent. Twenty-five of them were laboratory workers associated with research centres, and were directly infected via contact with infected vervet monkeys (Chlorocebus aethiops) imported to all three centres from Uganda. Seven people died.

In what what was a remarkably short period of time for that era – given that this was pre-sequencing and cloning of nucleic acids , let alone viruses – it took less than three months for scientists from Marburg and Hamburg to isolate and characterise what was being called “green monkey virus” virus. The new agent was named Marburg virus (MARV), after the city with the greatest number of cases. The first electron micrograph of the virus clearly exhibits the filamentous nature of the particles, complete with the now-famous “shepherd’s crook”. The virus disappeared until 1975, when an Australian hitchhiker who had travelled through what is now Zimbabwe was hospitalised in Johannesburg, South Africa, with symptoms reminiscent of Marburg disease. He died, and his female companion and then a nurse also became infected with what was suspected to be yellow fever or Lassa viruses. In an example for later outbreaks, this led to rapid implementation of strict barrier nursing and isolation of the patients and their contacts, which resulted in quick containment of the outbreak – with recovery of the two secondary cases. MARV was later identified in all three patients.

Ebola virus Ebola viruses burst from obscurity in 1976, with two spectacular outbreaks of severe haemorrhagic fever in people – both in Africa. In the better-known outbreak for which the viruses were later named, Ebola virus (EBOV) was first associated with an outbreak that eventually totalled 318 cases, starting in September 1976. This was in the Bumba Zone of the Equateur Region in the north of what was then Zaire, and is now the Democratic Republic of the Congo (DRC). The index case in the outbreak, as well as many of those subsequently infected, was treated in the Yambuku Mission Hospital. He was injected with chloroquine to treat his presumptive malaria: within a few days fever symptoms developed again; within a week, several others who had received injections around the same time also developed fevers which in several cases had haemorrhagic complications. Interestingly, women 15-29 years of age were most affected by the disease: this was strongly correlated with their attending antenatal clinics at the hospital, where they regularly received injections. Apparently the hospital had only five old-style syringes and needles, and these were reused without proper sterilisation.

Nearly all cases in this outbreak either received injections at the hospital, or had close contact with those who had. Most people were infected within the first four weeks of the outbreak, after which the hospital was closed because 11 of 17 staff had died. Another 269 people died, for a total estimated case-fatality rate of 88%. The incubation period for needle- transmitted Ebola virus was 5 to 7 days and that for person to person transmitted disease was 6 to 12 days. Interestingly, in post-epidemic serosurveys in DRC, antibody prevalence to the “Zaire Ebola virus” has been 3 to 7%: this indicates that subclinical infections with the disease agent may well be reasonably common. The team that discovered the virus at the Antwerp Institute of Tropical Medicine in Belgium, did so after receiving blood samples in September 1976 from a sick Belgian nun with haemorrhagic symptoms who had been evacuated from Yambuku to Kinshasa in the DRC, for them to investigate a possible diagnosis of yellow fever. Following her death, liver biopsy samples were also shipped to Antwerp – where the team had already ruled out yellow fever and Lassa fever .

Because of the severe nature of the disease, and its apparently novel agent, the World Health Organisation (WHO) arranged that samples be sent to other reference centres for haemorrhagic viruses, including the Centres for Disease Control (CDC) in Atlanta, USA. The Belgian team were the first to image the virus derived from cell cultures on an electron microscope – when it was obvious that the only thing it resembled was Marburg virus. Image copyright CDC / Frederick A Murphy, 1976 The CDC quickly confirmed that it was Marburg-like, with possibly the most famous virus image in the world, but that it was a distinct and new virus. This meant it needed a name – and it was given one derived from the Ebola River that was supposed to be near the town of Yambuku.

Google map of the area where the first Ebola haemorrhagic fever outbreaks occurred Another, minor outbreak of the virus occurred in June 1997 in Tandala in north-western DRC: one young child died, and virus was recovered from her – and subsequent investigations showed that “ two previous clinical infections with Ebola virus had occurred in 1972 and that about 7% of the residents had immunofluorescent antibodies to the virus”. This further reinforced the idea that subclinical infections were possible. Sudan virus In June 1976 – before the Yambuku epidemic in DRC – an outbreak of a haemorrhagic fever began in the southern Sudanese town of Nzara. The presumed index case was a storekeeper in a cotton factory, who was hospitalised on June 30th, and died within a week . There were a total of 284 cases in this outbreak: there were 67 in Nzara, where it is presumed to have originated, and where infection spread from factory workers to their familes.

There were also 213 in Maridi, a few hours drive away – where, as in Yambuku, the outbreak was amplified by “nosocomial” or hospital-acquired transmission in a large hospital. In this case, transmission seems to have been associated with nursing of patients. The incubation period in this outbreak was 7 – 14 days, with a case mortality rate of 53%. Two viral isolates were made from sera from Maridi hospital patients in November 1976. Antibodies to the now-identified “Ebola virus” from DRC were detected in 42 of 48 patients clinically-diagnosed patients from Maridi – but in only 6 of 31 patients from Nzara. However, it was subsequently shown that the Sudan and DRC Ebola viruses were different enough from one another to be separate viral species (see later), which undoubtedly affected the results. Interestingly, 19% of the Maridi case contacts had antibodies to the virus – with very few of them with any history of illness. This strongly indicates that the Sudan virus can cause mild or even subclinical infections.

An indication of the possible origin of the epidemic is the fact that 37% of the workers in the Nzara cotton factory appeared to have been infected, with 6 independently-acquired infections – and that this was concentrated in the cloth room, where there were numerous rats as well as thousands of insectivorous bats in the roof. However, subsequent study of antibodies in the bats failed to detect evidence of infection, and no virus was isolated from bat tissue. There was another outbreak of the same type of Ebola haemorrhagic fever in the area of Nzara in July – October 1979: this resulted in 34 cases, 22 of them fatal, with the index patient working at the cotton factory and all others being infected via the hospital he was admitted to. It is interesting that antibodies to the Sudan virus were detected in 18% of adults not associated with the outbreak, leading the report’s authors to speculate that the virus was endemic in this region.

It was thought that the Sudan and DRC outbreaks were linked: the original WHO Bulletin report on the Sudan outbreak even speculates that extensive truck-borne commercial goods traffic between Bumba in DRC and Nzara in what is now South Sudan could have caused the DRC outbreak. However, comparisons between the viruses isolated from the two epidemics later showed that they were distinct , both in terms of virulence, and antigenicity – meaning the Sudan virus got its own name. Epidemics and outbreaks have resulted from person to person transmission, nosocomial or in-hospital spread, or laboratory infections. The mode of primary infection and the natural ecology of these viruses are unknown. Association with bats has been implicated directly in at least 2 episodes when individuals entered the same bat-filled cave in Eastern Kenya. Ebola infections in Sudan in 1976 and 1979 occurred in workers of a cotton factory containing thousands of bats in the roof. However, in all early instances, study of antibody in bats failed to detect evidence of infection, and no virus was isolated form bat tissue. Discovered a disease? WHO has new rules for avoiding offensive names | Science | AAAS Discovered a disease?

WHO has new rules for avoiding offensive names By Kai Kupferschmidt May. 11, 2015 , 11:45 AM The World Health Organization (WHO) mostly works to reduce the physical toll of disease. But last week it turned to another kind of harm: the insult and stigma inflicted by diseases named for people, places, and animals. Among the existing monikers that its new guidelines “for the Naming of New Human Infectious Diseases” would discourage: Ebola, swine flu, Rift Valley Fever, Creutzfeldt-Jakob disease, and monkey pox. Instead, WHO says researchers, health officials, and journalists should use more neutral, generic terms, such as severe respiratory disease or novel neurologic syndrome. Many scientists agree that disease names can be problematic, but they aren’t sure the new rulebook is necessarily an improvement. “It will certainly lead to boring names and a lot of confusion,” predicts Linfa Wang, an expert on emerging infectious diseases at the Australian Animal Health Laboratory in Geelong. “You should not take political correctness so far that in the end no one is able to distinguish these diseases,” says Christian Drosten, a virologist at the University of Bonn, Germany.

Naming diseases has long been a fraught process. Badly chosen names can stigmatize people, as did gay-related immune deficiency, an early name for AIDS. They can also lead to confusion and hurt tourism and trade. The so-called swine flu, for instance, is not transmitted by pigs, but some countries still banned pork imports or slaughtered pigs after a 2009 outbreak. More recently, some Arab countries were unhappy that a new disease caused by a coronavirus was dubbed Middle East respiratory syndrome. Although “it’s usually scientists who come up with these names … the WHO gets the diplomatic pressure” if someone takes offense, Drosten says. The new guidelines, released 8 May, aim to smooth the process. “The WHO had to do something to take itself out of the firing line,” Drosten says. Given that news of a new pathogen often spreads quickly, “it is important that an appropriate disease name is assigned by those who first report” the disease, WHO's guidance notes.

Following the guidelines, it adds, could “minimize unnecessary negative impact of disease names on trade, travel, tourism or animal welfare, and avoid causing offence to any cultural, social, national, regional, professional or ethnic groups.” To that end, new disease names should not include geographic locations; the names of people, occupations, animals, or food; or “terms that incite undue fear” (such as unknown, fatal, and epidemic). Instead, the names should use generic descriptions of symptoms (respiratory disease or watery diarrhea) and specific terms describing patients, epidemiology or the environment (juvenile, maternal, seasonal, summer, coastal), as well as pathogen names and arbitrary identifiers (alpha, beta, 1, 2, 3). The group that came up with these recommendations met “more than a few times” over the course of a year, says Kazuaki Miyagishima, director for food safety, zoonoses, and foodborne diseases at WHO, and a member of the panel.

Among the ideas they discussed: naming diseases after Greek gods, using a system similar to the one used to name comets or alternating male and female names as is done with hurricanes.”But while naming a hurricane Katrina may not offend people, if we do it for a disease, it’s not just a hurricane for 1 week. It will make its way into the history of human suffering," Miyagishima says. The guide is well intentioned, but goes too far, says Ian Lipkin, a virologist at Columbia University. “I don’t see how it will be helpful to eliminate names like monkey pox that provide insights into natural hosts and potential sources of infection,” he says. It could also become harder to easily distinguish diseases. For instance, under the new rules, Marburg disease (named after a city in Germany) might have been called filovirus-associated haemorrhagic fever 1, while Ebola ( named after a river ) might have been filovirus-associated haemorrhagic fever 2. Such bland names “lose something that is more than just quaint,” says Howard Markel, a medical historian at the University of Michigan in Ann Arbor. Drosten adds that geographic names are sometimes justified.

It was clear that MERS, for example, was associated with the Middle East. “Would it have been better if we had named it novel betacoronavirus clade C, type 1?” he asks. The new rules make for more difficult names, Miyagishima admits. “But we think we have left a fairly large area for freedom. We do not want to kill the creativity of researchers completely.” Linfa Wang knows all about the difficulty of naming diseases. Two decades ago, he named a virus and the disease it causes after Hendra, a suburb of Brisbane, Australia; he still gets angry calls from residents complaining that the name has hurt property values. These days his strategy is to “go small.” Recently, he named a new henipavirus isolated in a neighborhood called Cedar Grove simply Cedar virus. Virologists encountered other sensitivities with Norwalk virus, named for a city in Ohio. The pathogen is the only species in the genus Norovirus and usually that name is used. In 2011, however, a Japanese individual asked for a change because many people in Japan carry the surname Noro. The International Committee on Taxonomy of Viruses recommended using "Norwalk virus” instead.

Acronyms are another good solution, says Ab Osterhaus, a virologist at Erasmus MC in Rotterdam, because they keep names short (another WHO recommendation) and people often forget what the letters stand for. But even acronyms can cause controversy. In 2003, WHO officials coined SARS (severe acute respiratory syndrome) to describe a novel pneumonia spreading in Asia, partly to avoid a name like “Chinese flu.” SARS did not go down well in Hong Kong, however, which is officially known as Hong Kong SAR, for special administrative region. Giving new diseases a number may be the only way to avoid such issues, researchers say. There is precedent. Growing up in China in the late 1960s, Wang remembers that diseases had digits. “I was really scared of number 5 disease,” he recalls. “I don’t know why, you just really did not want to get disease number 5.” Posted in: VHF | CIDRAP Pathogenesis Agents A wide range of viruses can cause viral hemorrhagic fever (VHF) and hence are designated as hemorrhagic fever viruses.

All possess single-stranded RNA (which requires reverse transcriptase for multiplication or amplification by polymerase chain reaction [PCR]) All possess a lipid envelope Hemorrhagic fever viruses belong to four taxonomic families, only one of which, Filoviridae, has been assigned to an order (Mononegavirales): Filoviridae Bunyaviridae Flaviviridae Specific hemorrhagic fever viruses in each of the four families and key characteristics are included in the table below. The table includes the predominant hemorrhagic fever viruses but is not a comprehensive list. For example, a new arenavirus (Lujo virus) was identified in 2008 as a cause of illness in humans in Africa (Peters 2010: Lymphocytic choriomeningitis, Lassa virus, and South American hemorrhagic fevers).

Characteristics of Hemorrhagic Fever Viruses Familya Back to top Pathogenesis The pathogenesis of hemorrhagic fever viruses is not completely understood; however, key points include the following ( Peters 2002 ): Hemorrhagic fever viruses enter the bloodstream through various mechanisms (eg, the bite of a mosquito or tick, inhalation, mucous membrane exposure, parenteral exposure), and all (except hantaviruses) cause disease during the period of viremia. The infectious dose for hemorrhagic fever viruses appears to be low (1 to 10 organisms) ( Franz 1997 ). Endothelial infection occurs with most hemorrhagic fever viruses and may be limited or widespread, depending on the virus. Hemorrhagic manifestations occur as a result of thrombocytopenia or severe platelet dysfunction along with endothelial dysfunction. Increased vascular permeability is common and may result in periorbital edema and hemoconcentration. Vascular dysregulation also often occurs, manifested by flushing of the face and chest. Hemorrhagic fever viruses can cause necrosis and hemorrhage in most organs; however, hepatic involvement often is particularly prominent.

Hantaviruses, New World arenaviruses, and Ebola, Marburg, and Lassa viruses cause cytokine activation ( Gomez 2011 ; Feldmann 2011 ; Peters 2010: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Peters 2010: Marburg and Ebola virus hemorrhagic fevers). The relative lack of histologic lesions in fatal cases and the lack of immunopathology suggest that cytokines are the primary mediators of hemorrhagic fever in arenavirus infections and that they play a major role in the clinical features of filovirus infections as well Studies in primates demonstrate that Ebola and Marburg viruses lead to a dysregulation of the immune response, with elevated circulating levels of cytokines and chemokines ( Geisbert 2003 : Pathogenesis of Ebola hemorrhagic fever in primate models; Hensley 2011 ). Ebola, Marburg, yellow fever, and Rift Valley fever viruses have a marked cytopathic effect (ie, are highly destructive to the cells they infect).

Ebola and Lassa viruses also appear to infect monocyte-derived dendritic cells; dendritic cells exposed to these viruses do not up-regulate, fail to secrete pro-inflammatory or immunoregulatory cytokines, and do not effectively stimulate T cells ( Bosio 2003 , Mahanty 2003 ). These changes delay an effective early host response. Ebola, Marburg, Rift Valley fever, and Crimean-Congo hemorrhagic fever viruses can cause disseminated intravascular coagulation (DIC); the other hemorrhagic fever viruses generally do not. Coagulation abnormalities noted with Ebola virus infection appear to be triggered by immune-mediated mechanisms rather than occurring as the result of direct cytolysis of endothelial cells ( Geisbert 2003 : Pathogenesis of Ebola hemorrhagic fever in primate models). Findings from a study in rhesus macaques suggest that a mixed anti-inflammatory response syndrome (MARS) occurs following Ebola virus infection, similar to what is seen in severe sepsis and septic shock ( Ebihara 2011 ).

Suppression of the host antiviral response appears to play a critical role in the pathogenesis of Ebola virus infection (Peters 2010: Marburg and Ebola virus hemorrhagic fevers; Ebihara 2006 ). Failure to mount an effective immune response may be related to an immunosuppressive amino acid sequence in the filovirus glycoprotein or the secretion of a soluble glycoprotein by infected cells (Peters 2010: Marburg and Ebola virus hemorrhagic fevers). In addition, extensive lymphoid necrosis (in the spleen, thymus, and lymph nodes) and lymphocyte depletion through apoptosis also may play a role in suppression of the immune response ( Feldmann 2011 ); however, one report suggests that lymphocyte apoptosis may be not be essential for disease progression ( Bradfute 2010 ).

A model of the pathogenesis of Ebola virus based on observations of infection in cynomolgus monkeys is as follows ( Geisbert 2003 : Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques): Ebola virus spreads from the initial site of infection via monocytes and dendritic cells to lymph nodes (likely via the lymphatics) and to the liver and spleen (via blood). At these sites, the virus infects tissue macrophages, dendritic cells, and fibroblastic reticular cells. A series of events then occur that lead to virus-induced immunosuppression and apoptosis of T lymphocytes. As the disease progresses, apoptosis of natural killer cells also occurs, which limits the innate immune response. Unchecked viral replication then leads to increased levels of additional proinflammatory cytokines, chemokines, and possibly other mediators, which cause vascular impairment and trigger the coagulation cascade, ultimately leading to DIC. DIC then results in hemorrhagic shock, failure of multiple organs, and death. Characteristic pathologic features of selected hemorrhagic fever viruses are shown in the table below. Pathologic Features of Selected Hemorrhagic Fever Virusesa Agent Abbreviation: DRC, Democratic Republic of the Congo.

Ebola Hemorrhagic Fever Ebola hemorrhagic fever is an important emerging infection in central Africa and has received much attention in recent years owing to the documented high case-fatality rates (50% to 90%) associated with outbreaks. Ebola virus was first recognized in 1976 when two outbreaks of VHF occurred in Africa during that year (one in southern Sudan and one in northwest Zaire [now the Democratic Republic of the Congo]) ( Peters 1999 ; Pourrut 2005 ; WHO 1978: Ebola hemorrhagic fever in Zaire). Since 1976, nearly 20 outbreaks have been recognized in Equatorial Africa ( CDC 201 1: Known cases and outbreaks of Ebola hemorrhagic fever, in chronological order). Furthermore, a geographic pattern has emerged in which the Ebola-Zaire strain affects predominantly central Africa and the Ebola-Sudan strain affects Southern Sudan and East Africa. The only strain identified in West Africa is the Ivory Coast strain, although as of mid-2012, this virus had been detected only on one occasion ( Pourrut 2005 ).

The Ebola-Bundibugyo strain has been found in East Africa (in Uganda) ( McNeil 2010 , Wamala 2010 ). The incidence of filovirus infections (with Ebola virus or Marburg virus) continues to be relatively low. As of 2008, these viruses combined have caused approximately 2,317 clinical cases and 1,671 confirmed deaths ( Leroy 2011 ). In some situations, human Ebola outbreaks have occurred in conjunction with deaths in animals species (including gorillas, chimpanzees, mandrills, and bush pigs) ( Lahm 2007 ; Vogel 2007 ). Characterization of Ebola-Zaire isolates from wild ape carcasses implicated recombinant viruses from the apes as the cause of outbreaks among humans from 2003 through 2005 ( Wittmann 2007 ). During outbreaks in rural settings, multiple introductions of the virus into the human population through wildlife likely occur; whereas, during outbreaks in urban settings, a single introduction of the virus in the community appears to be more common ( Allaranga 2010 ).

A recent large serological survey of rural populations in Gabon, using a sensitive and specific enzyme-linked immunosorbent assay (ELISA), found an overall Immunoglobulin G (IgG) seroprevalence of 15.3% to the Ebola-Zaire strain ( Becquart 2010 , Nkoghe 2011 ). The survey lasted 3 years and included 4,349 adults and 362 children from 220 randomly selected villages, representing 10.7% of all villages in Gabon. These results suggest that a large portion of the population may have been exposed to low levels of the virus through a common source, such as bat saliva on contaminated fruits. The findings also indicate that mild illness or asymptomatic infection may occur with greater frequency than previously suggested and support the perspective that the Ebola-Zaire strain is endemic in Gabon.

In addition to disease occurrence in Africa, several outbreaks of Ebola virus infection have been recognized in cynomolgus macaques in the Philippines or in monkeys imported from the Philippines into the United States or Italy; these situations have all involved the Ebola-Reston strain ( CDC 1990 :Filovirus infections among persons with occupational exposure to nonhuman primates or their tissues; CDC 1990 : Filovirus infection associated with contact with nonhuman primates or their tissues; CDC 1996 : Ebola-Reston virus infection among quarantined nonhuman primates; Miranda 1999 ). The first outbreak occurred in 1989 at a primate facility in Reston, Virginia, which is why the strain associated with these outbreaks is referred to as the Ebola-Reston strain. At that time, animal cases also occurred in primate facilities in Pennsylvania and Texas. All three locations had received monkeys from the same export facility in the Philippines. Subsequently, outbreaks also occurred at the primate facility in the Philippines that exported the infected animals.

Several persons working with infected primates had serologic evidence of recent filovirus infection; however, as of mid-2012, no clinical illnesses associated with this strain have been reported in humans. In 2008, the Ebola-Reston strain was isolated from pigs in the Philippines. At the time, an increase in mortality was occurring on swine farms and samples from pigs that had died demonstrated evidence of infection with porcine reproductive and respiratory syndrome (PRRS) virus. In additions, some pigs had evidence of co-infection with the Reston-Ebola strain ( Miranda 2011 ). Several people in contact with infected pigs had serologic evidence of infection, and all were asymptomatic; these results suggest that pigs can transmit the Ebola-Reston strain to humans. The most likely routes of transmission from pigs to humans include direct contact with the blood, secretions, organs, or other bodily fluids of infected animals and possibly respiratory transmission ( WHO 2009 : WHO expert consultation on Ebola Reston pathogenicity in humans).

Ongoing circulation of the Ebola-Reston strain in the pig population provides an unusual opportunity for continued genetic evolution to occur as a result of passage, adaptation, and possible natural selection of this virus ( WHO 2009 : WHO expert consultation on Ebola Reston pathogenicity in humans). Monitoring the virus in pig populations, therefore, is appropriate. Experimental challenge studies have demonstrated that the Ebola-Reston strain can cause asymptomatic infection in pigs and that viral shedding can occur from the nasopharynx following infection. These findings suggest that infected pigs can pose a transmission risk to farm, veterinary, and abattoir workers ( Marsh 2011 ). In response to the isolation of the Ebola-Reston strain from pigs, another group of investigators challenged domesticated pigs with the Ebola-Zaire strain. They found that pigs also can be infected with the Ebola-Zaire strain and that infected pigs develop severe respiratory disease ( Kobinger 2011 ). Furthermore, infected pigs shed virus from the nasopharynx for approximately 14 days after infection and can transmit the virus to uninfected pigs.

Ebola hemorrhagic fever cases and outbreaks identified between 1976 and mid-2012 are outlined in the table below, which can be found on the Centers for Disease Control and Prevention (CDC) Web site (CDC 2011: Known cases and outbreaks of Ebola hemorrhagic fever, in chronological order). Recognized Cases and Outbreaks of Ebola Hemorrhagic Fever, In Chronological Ordera Year(s) Abbreviation: CFR, case-fatality rate; DRC: Democratic Republic of the Congo. a CDC 201 1: Known cases and outbreaks of Ebola hemorrhagic fever, in chronological order. Marburg Hemorrhagic Fever Marburg hemorrhagic fever, like Ebola hemorrhagic fever, is an emerging disease in sub-Saharan Africa, although Marburg virus infection appears to be less common and case-fatality rates may be somewhat lower than those for Ebola virus infection. Marburg virus was first recognized in 1967 when outbreaks occurred simultaneously in laboratory workers in Marburg, Germany; Frankfort, Germany; and Belgrade, Yugoslavia (now Serbia). These outbreaks were related to contact with African green monkeys that were imported from Uganda.

The incidence of filovirus infections (with Ebola virus or Marburg virus) continues to be relatively low. As of 2008, these viruses combined have caused approximately 2,317 clinical cases and 1,671 confirmed deaths ( Leroy 2011 ). Since the initial outbreaks, several additional cases and outbreaks have been reported; all have occurred among persons living or traveling in rural southern and eastern Africa; recognized cases and outbreaks are shown in the table below ( CDC 2009 : Known cases and outbreaks of Marburg hemorrhagic fever, in chronological order). Recognized Outbreaks of Marburg Hemorrhagic Fever, in Chronological Ordera Location

Question: Which haemorrhagic fever virus is named after a city in Hessen, Germany?
Answer: Marburg Virus