Viral haemorrhagic fevers

Viral haemorrhagic fevers (VHFs) are extremely rare in the UK; there have been fewer than 20 cases in the last 50 years. They should be in the differential diagnosis for cases of unexplained fever in a returning traveller from a relevant area. Some are highly contagious and therefore the potential for outbreak is real if imported cases go undetected.

Suspected VHF is a medical and public health emergency and immediate advice should be sought from the local infectious diseases team on how to proceed.

Pathogens

VHFs are caused by four types of ribonucleic acid (RNA) virus:

• Filoviruses: Only two (though with various subtypes) so far have been identified as causing human disease:

  • Bundibugyo ebolavirus (BDBV) - Ebola virus disease.

  • Marburg marburgvirus (MARV) - Marburg haemorrhagic fever.

  • Sudan ebolavirus (SUDV) - Ebola virus disease.

  • Taï Forest ebolavirus (TAFV) - Ebola virus disease.

  • Zaire ebolavirus (EBOV) - Ebola virus disease.

• Arenaviruses: Arenaviruses include:

  • Chapare virus (CHPV) - Chapare haemorrhagic fever.

  • Guanarito virus (GTOV) - Venezuelan haemorrhagic fever.

  • Junin virus (JUNV) - Argentine haemorrhagic fever.

  • Lassa virus (LASV) - Lassa fever.

  • Lujo virus (LUJV) - Lujo haemorrhagic fever.

  • Lymphocytic choriomeningitis virus (LCMV) - Lymphocytic choriomeningitis.

  • Machupo virus (MACV) - Bolivian haemorrhagic fever.

  • Sabia virus (SABV) - Brazilian haemorrhagic fever.

• Bunyaviruses: Bunyaviruses include:

  • Crimean-Congo haemorrhagic virus (CCHFV) - Crimean-Congo haemorrhagic fever.

  • Dobrava-Belgrade virus (DOBV) - Haemorrhagic fever with renal syndrome.

  • Hantaan virus (HTNV) - Haemorrhagic fever with renal syndrome.

  • Puumalavirus (PUUV) - Haaemorrhagic fever with renal syndrome.

  • Rift Valley fever virus (RVFV) - Rift Valley fever.

  • Saaremaa virus (SAAV) - Haemorrhagic fever with renal syndrome.

  • Seoul virus (SEOV) - Haemorrhagic fever with renal syndrome.

  • Sin Nombre virus (SNV)- Hantavirus pulmonary syndrome.

  • Severe fever and thrombocytopenia syndrome virus (SFTSV) - Severe fever and thrombocytopenia syndrome.

  • Tula virus (TULV) - Haemorrhagic fever with renal syndrome.

• Flaviviruses:

  • Dengue virus (DENV-1-4) - Dengue fever.

  • Kyasanur forest disease virus (KFDV) - Kyasanur forest disease.

  • Omsk haemorrhagic fever virus (OHFV) - Omsk haemorrhagic fever.

  • Yellow fever virus (YFV) - Yellow fever.

Ebola virus, Marburg virus, Lassa fever, Hantavirus, Zika virus, yellow fever and dengue have their own separate articles in which they are covered in detail.

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 both Ebola and Marburg viruses, although non-human primates can also be infected.¹² Both diseases are severe; mortality is between 80 and 90% in the countries which see outbreaks.

Arenaviridae

These viruses are borne by rodents. Infection occurs via contact with rodent urine or droppings and can also occur via aerosol transmission when rodent excrement is stirred up, causing viral particles to get into the air. Some viruses can also cause human-to-human and nosocomial infections. The diseases range in severity; the most common is Lassa fever which has fatality rates of up to 50%. Up to 300,000 infections and 5,000 deaths from Lassa fever are estimated to occur yearly, mostly in Sierra Leone, Liberia, and Guinea.

Bunyaviridae

These viruses are transmitted by arthropods (mosquitoes, ticks, and sandflies) and rodents. CCHF is carried by ticks and causes a fulminant disease that can also be transmitted by aerosol. Disease can be mild to severe but the mortality rate is high in severe disease.

Hantaviruses exist throughout the world. Patients usually present after contact with rodents, their faeces, or a rodent bite. Farmers, those in forestry occupations, or people with a history of cleaning rodent-infested areas are especially vulnerable. Those who have close contacts of such persons are also at risk. Initial complaints are often flu-like and nonspecific. 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 50-70%. 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%.³⁴⁵⁶

Flaviviridae

There are over a hundred viruses in this group but yellow fever, Zika virus, and dengue are the best known. 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.⁷

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 1967.⁸ 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 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 significant increases in incidence. 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; increased globalisation and travel are relevant factors.⁸

Viral haemorrhagic fever epidemics⁹

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 naïve 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 ongoing 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 in 2013 may have begun with a single individual exposed to insect-eating bats. World Health Organization (WHO) analysis is useful to understand why this outbreak grew to epidemic proportions.¹¹ The latest outbreak has been experienced in the Democratic Republic of the Congo.¹²

Pathophysiology²¹³¹⁴

Although there are many different viruses causing viral haemorrhagic fevers in many parts of the world, they have much in common in terms of pathology and clinical manifestations.

The pathogens causing viral haemorrhagic fevers can replicate within macrophages and dendritic cells, allowing for rapid dissemination within the host. Macrophages are triggered to release cytokines and chemokines, which cause increased vascular permeability and a procoagulant state. These viruses can also trigger mechanisms resulting in disseminated intravascular coagulation. Infected dendritic cells are impaired, and the loss of its appropriate function can result in the deaths of lymphocytes.

Incubation periods are typically in the range 2-21 days, although some are longer.

The initial stage of viraemia affects the vascular system, causing flushing, conjunctival injection, and petechial haemorrhages, often with fever and myalgia. Retro-orbital pain, joint pains, eye redness, abdominal pain, vomiting, and diarrhoea occur commonly in viral haemorrhagic fevers. Later, obvious mucous membrane haemorrhage (such as epistaxis or bleeding gums) and hypovolaemia may occur, with hypotension, shock, and circulatory collapse.

Direct organ damage may be caused by the viruses themselves but multiorgan damage may also result from shock and hypovolaemia.

Presentation

The presentation and severity vary with the virus, viral load and route of exposure. Some viral haemorrhagic fevers (eg, dengue, Zika virus) are more typically mild. Others, such as Ebola virus, are more often catastrophic. However, the viral haemorrhagic fevers 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.

  • Sore throat.

  • Headache.

  • Conjunctival injection.

  • Mild hypotension.

  • Marked exhaustion.

  • Myalgia with tender muscles - this can be very marked.

  • Cough.

  • Sore throat.

  • Abdominal pain.

  • Nausea/vomiting.

Examination

Physical signs include:

• Fever.

• Pharyngitis, and conjunctival injection.

• 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 of altered vascular permeability with capillary leakage. This is generally a marker for severity and is a central pathological process via which viral haemorrhagic fevers 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

• 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.

• Typhus.

• Scrub typhus.

• HIV seroconversion.

• Infectious mononucleosis.

• Coxsackievirus and other enteroviruses.

• Rickettsial infections.

• Measles.

• Rubella.

• Parvovirus B19.

• Influenza.

• Kawasaki disease.

• Meningococcal septicaemia.

• Encephalitic viruses - eg, West Nile virus.

Investigations

Infected material is potentially dangerous and thus should be carried out under carefully controlled conditions 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

Although serological testing for virus-specific IgM and IgG can be performed, it is not as sensitive or specific as molecular-based testing. Reverse transcriptase-polymerase chain reaction and virus isolation via cell culture can be used for diagnostic testing.

Management⁹¹⁵

Suspected viral haemorrhagic fever 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 viral haemorrhagic fever cases should contact an infectious disease team. If they agree that VHF is suspected they will contact the Imported Fever Service.¹⁶

Patients with suspected contagious viral haemorrhagic fever 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.¹⁷ Ribavirin is also recommended for post-exposure prophylaxis.

Antivirals are of no value for Ebola virus or Marburg virus.

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 effect on survivors can be profound and include anxiety, depression, post-traumatic-stress disorder, survivors' guilt, and insomnia. 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.¹⁸

Prognosis

Fatality rates vary but viral haemorrhagic fevers can have high mortality rates.

The fatality rate for dengue, overall, is less than 1%; however, this rises as high as 50% in untreated, severe disease.¹⁹

The 2013 Ebola virus epidemic in West Africa infected over 26,000 people, of whom around 40% died.²⁰

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.²¹ 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.²²

• Case fatality rates in Marburg virus have been reported as 24-88%.²²³

• Yellow fever is often asymptomatic but, in patients who go on to develop toxic disease, mortality is around 50%.²⁴

• Zika virus is usually mild or asymptomatic. Its serious sequelae are limited to the foetus of a pregnant woman who has been infected.²⁵

Prevention⁹¹⁵²⁶

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).²⁷

Vector control²⁸

• Control programmes for rodents and mosquitoes are required in endemic areas.²⁹

• Aedes mosquitos, which act as vectors for yellow fever, Zika virus, dengue, and chikungunya fever, are day feeders so 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.³⁰

Vaccination

• There are two UK-licensed vaccine against viral haemorrhagic fevers: those against yellow fever and dengue; however, work continues to develop vaccines.

• 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.³¹

• A vaccine against dengue has been developed (QDenga) relatively recently. It is recommended for children aged between 6 and 16 years living in high transmission settings.³² It is also available as a private travel vaccine in the UK for patients from the age of 4. At the time of writing, there are trials currently taking place to assess other potential vaccines - some of these have reached Phase III trials. ³³³⁴

• Ebola virus vaccination has been shown to be safe and effective.³⁵ Current vaccines are only available against the Zaire strain but a new vaccine against the Bundibugyo strain is being evaluated at the time of writing.³⁶³⁷

• Initial vaccines against CCHF looked promising but failed to confer immunity;³⁸ however, at the time of writing, further vaccine trials against CCHF are occurring.³⁹

Surveillance⁹

• Computer models using variables such as rainfall and temperature have been used to predict likely risk areas for Lassa fever in West Africa.⁴⁰

• 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 2006.⁴¹

• The ability to make rapid diagnosis depends on investment in laboratory services and disease surveillance.⁴²

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 which was named after the local river, the Hantaan.⁴³

Dr Mary Lowth is an author or the original author of this leaflet.