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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.
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.
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. 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.
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. Lassa fever can be asymptomatic. It has been imported into Western Europe and the USA by travellers from Africa on commercial airlines.
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. 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].
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.
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. 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.
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. 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:
- 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.
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.
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.
- 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:
- Sore throat.
- Conjunctival injection.
- Mild hypotension.
- Marked exhaustion.
- Myalgia with tender muscles - this can be very marked.
- Sore throat.
- Abdominal pain.
Physical signs may vary from minimal to gross, with many of them non-specific. They include:
- High temperature.
- Pharyngitis, conjunctival injection.
- Oedema, not dependent.
- Maculopapular, petechial or ecchymotic rash.
- Hypotension or shock.
- Haemorrhage in mucous membranes.
- 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.
- Disseminated intravascular coagulation (DIC).
- Salmonella spp. infection.
- Haemolytic uraemic syndrome.
- Systemic lupus erythematosus.
- Leptospirosis (Weil's disease).
- Malaria (a much more common cause of febrile illness in returning travellers).
- Typhoid fever.
- Scrub typhus.
- HIV seroconversion.
- Infectious mononucleosis.
- Coxsackievirus and other enteroviruses.
- Rickettsial infections.
- Parvovirus B19.
- Kawasaki disease.
- Meningococcal septicaemia.
- Encephalitic viruses - eg, West Nile virus.
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.
- 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.
- 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.
- 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.
- A test assaying salivary and urine IgM and IgG levels in dengue has been investigated, with promising results.
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.
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. 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.
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.
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.
- The 2013 Ebola virus epidemic in West Africa infected over 26,000 people, of whom around 40% died.
- 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. 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.
- Case fatality rates in Marburg virus have been reported as 24-88%.
- Yellow fever is often asymptomatic but in patients who go on to develop toxic disease, mortality is around 50%.
- Zika virus is usually mild or asymptomatic. Its serious sequelae are those for the fetus of a pregnant patient, not for the patient themself.
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).
- Control programmes for rodents and mosquitoes are required in endemic areas.
- 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.
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.
- 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.
- 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.
- A vaccine against CCHF looked promising in mouse trials; however, it failed to confer the necessary immunity.
- Computer models using variables such as rainfall and temperature have been used to predict likely risk areas for Lassa fever in West Africa.
- 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.
- The ability to make rapid diagnosis depends on investment in laboratory services and disease surveillance.
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.
- 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.
Further reading and references
; Public Health England, 2016
; Centers for Disease Control and Prevention
; Health Protection Agency (archived content)
; Public Health England
; Department of Health, November 2015
; Public Health England, November 2014
; Studies of reservoir hosts for Marburg virus. Emerg Infect Dis. 2007 Dec13(12):1847-51.
; New opportunities for field research on the pathogenesis and treatment of Lassa fever. Antiviral Res. 2007 Dec 17.
; Development of a new vaccine for the prevention of Lassa fever. PLoS Med. 2005 Jun2(6):e183. Epub 2005 Jun 28.
; Weekly Epidemiological Record No. 2 2008, 83, 17–24, World Health Organization
; Steep rise in notified hantavirus infections in Germany, April 2010. Euro Surveill. 2010 May 2015(20). pii: 19574.
; Rise in the number of notified human hantavirus infections since October 2011 in Baden-Wurttemberg, Germany. Euro Surveill. 2012 May 2417(21). pii: 20180.
; Insect-specific flaviviruses, a worldwide widespread group of viruses only detected in insects. Infect Genet Evol. 2016 Jun40:381-8. doi: 10.1016/j.meegid.2015.07.032. Epub 2015 Jul 31.
; Emerging zoonoses and pathogens of public health significance--an overview. Rev Sci Tech. 2004 Aug23(2):435-42.
; Zika virus in the Americas: Early epidemiological and genetic findings. Science. 2016 Apr 15352(6283):345-9. doi: 10.1126/science.aaf5036. Epub 2016 Mar 24.
; World Health Organization, January 2015
; Hantavirus regulation of endothelial cell functions. Thromb Haemost. 2009 Dec102(6):1030-41.
; Rapid diagnosis of Ebola hemorrhagic fever by reverse transcription-PCR in an outbreak setting and assessment of patient viral load as a predictor of outcome. J Virol. 2004 Apr78(8):4330-41.
; Reverse ELISA for IgG and IgM antibodies to detect Lassa virus infections in Africa. J Clin Virol. 2006 Dec37(4):277-81. Epub 2006 Sep 25.
; High-throughput molecular detection of hemorrhagic fever virus threats with applications for outbreak settings. J Infect Dis. 2007 Nov 15196 Suppl 2:S205-12.
; Performance of the GeneXpert Ebola Assay for Diagnosis of Ebola Virus Disease in Sierra Leone: A Field Evaluation Study. PLoS Med. 2016 Mar 2913(3):e1001980. doi: 10.1371/journal.pmed.1001980. eCollection 2016 Mar.
; Hantavirus infections in Europe. Lancet Infect Dis. 2003 Oct3(10):653-61.
; Value of Routine Dengue Diagnostic Tests in Urine and Saliva Specimens. PLoS Negl Trop Dis. 2015 Sep 259(9):e0004100. doi: 10.1371/journal.pntd.0004100. eCollection 2015 Sep.
; Public Health England, March 2016
; Crimean-Congo haemorrhagic fever. Lancet Infect Dis. 2006 Apr6(4):203-14.
; Sequelae of Ebola virus disease: the emergency within the emergency. The Lancet Infectious Diseases, Volume 16, Issue 6, e82-e91
; World Health Organization, July 2016
; World Health Organization, 10 June 2016
; World Health Organization, Updated March 2016
; World Health Organization, 2016
; World Health Organization, November 2012
; World Health Organization, May 2016
; World Health Organization, September 2016
; World Health Organization (Statement), 31 August 2016
; Poor housing quality increases risk of rodent infestation and Lassa fever in refugee camps of Sierra Leone. Am J Trop Med Hyg. 2007 Jul77(1):169-75.
; Lassa fever in West African sub-region: an overview. J Vector Borne Dis. 2007 Mar44(1):1-11.
; Yellow fever as an endemic/epidemic disease and priorities for vaccination. Bull Soc Pathol Exot. 2006 Dec99(5):341-7.
; Tetravalent Dengue Vaccine: A Review in the Prevention of Dengue Disease. Drugs. 2016 Sep76(13):1301-12. doi: 10.1007/s40265-016-0626-8.
; Dengue vaccines: Are they safe for travelers? Travel Med Infect Dis. 2016 Jul-Aug14(4):378-83. doi: 10.1016/j.tmaid.2016.06.005. Epub 2016 Jun 22.
; Clinical development of Ebola vaccines. Ther Adv Vaccines. 2015 Sep3(5-6):125-38. doi: 10.1177/2051013615611017.
; A Crimean-Congo hemorrhagic fever (CCHF) viral vaccine expressing nucleoprotein is immunogenic but fails to confer protection against lethal disease. Hum Vaccin Immunother. 201612(2):519-27. doi: 10.1080/21645515.2015.1078045.
; Risk maps of Lassa fever in West Africa. PLoS Negl Trop Dis. 20093(3):e388. Epub 2009 Mar 3.
; 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 28:29.
; Emerging and reemerging infections in africa: the need for improved laboratory services and disease surveillance. Microbes Infect. 2000 Apr2(5):489-95.
; Emergence and persistence of hantaviruses. Curr Top Microbiol Immunol. 2007315:217-52.
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