Viral Haemorrhagic Fevers

Synonym: VHF

This disease is notifiable in the UK under the Public Health (Infectious Diseases) Regulations 1988.

The viral haemorrhagic fevers (VHF) are caused by 4 types of RNA virus:¹

• Filoviruses cause Ebola and Marburg.
• Arenaviruses cause Lassa Fever, Argentine HF, Bolivian HF, Brazilian HF and Venezuelan HF.
• Bunyaviruses cause Korean HF (Hantavirus), Rift Valley Fever and Crimean-Congo HF.
• Flaviviruses cause Yellow Fever and Dengue.

Ebola, Marburg, Lassa Fever and Yellow Fever have their own articles in which they are covered in rather more detail. They are all highly infectious and lead to a potentially fatal disease with fever, malaise, vomiting, mucosal and gastrointestinal bleeding, oedema, and hypotension.

Arenaviridae

The most significant of these viruses is Lassa Fever. Lassa fever is transmitted directly to humans by rodents, insect bites, especially mosquitoes, from primates and from patients. Nosocomial infection is very common where precautions against cross infection are minimal. Medical staff are also at risk of catching it from patients. Up to 300,000 infections and 5000 deaths from Lassa Fever are estimated to occur yearly, the highest incidence occurring in Sierra Leone, Liberia, and Guinea.² Lassa fever has recently been imported into Germany, the Netherlands, the United Kingdom, and the United States by travellers on commercial airlines from Africa.³

Bunyaviridae

They include Rift Valley fever (RVF), Crimean-Congo haemorrhagic fever (CCHF), and a number of hantaviruses. RVF and CCHF are both spread by arthropods. RVF is an important African pathogen that is transmitted to humans and livestock by mosquitoes and by the slaughter of infected livestock.⁴ CCHF virus is carried by ticks and causes a fulminant disease that can be transmitted by aerosol particles. Outbreaks of CCHF have occurred in Africa, Asia, and Europe.

Hantaviruses exist throughout the world, causing 2 main syndromes. They are haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). They are divided into Old World hantaviruses like the Korean virus, which usually cause HFRS, and New World hantaviruses that cause HPS. Both are transmitted by rodents. A new Hantavirus that was called Sin Nombre virus, caused an outbreak of highly lethal HPS in the southwestern USA in 1993. Sin nombre is Spanish for without name.

Filoviridae

This group includes the Marburg and Ebola viruses. Most outbreaks are in or originate from Africa. In the Congo, bats have been implicated as a possible source of an outbreak of Marburg infection.⁵ The mortality is often around 80% and healthcare workers are often amongst the victims. More detail about Marburg and Ebola is available in its own article.

Flaviviridae

Yellow fever and dengue fever are the best known diseases caused by this group. Mosquitoes are the vectors for both. Yellow fever is found in tropical Africa and South America, and dengue fever is found in Asia, Africa, and the Americas. It has recently been shown that dengue virus targets mannose receptors on macrophages.⁶

Although these are many different viruses spread throughout many parts of the world, they have much in common in terms of pathology and clinical manifestations. The basic problem in patients with VHF is increased vascular permeability. They affect the vascular system, initially causing flushing, conjunctival injection, and petechial haemorrhages, often with fever and myalgia. Later, obvious mucous membrane haemorrhage may occur, with hypotension, shock, and circulatory collapse. The severity of the disease may vary according to the virus, the viral load, and the route of exposure. In acute infection, there is marked viraemia and inadequate or delayed immune response may lead to rapid development of overwhelming viraemia. Infected organs may become necrotic. Haemorrhagic complications include hepatic damage (hence yellow fever), consumptive coagulopathy, and primary marrow injury to megakaryocytes.

Multisystem organ failure can involve the haematopoietic system, the CNS, and lungs and often accompanies vascular involvement. Hepatic involvement varies with the infecting organism and is at times seen with Ebola, Marburg, RVF, CCHF, and yellow fever. Renal failure with oliguria is common in Hantavirus infection and may be seen in other VHFs as intravascular volume falls. Bleeding is marked with Ebola, Marburg, CCHF, and the South American arenaviruses.

History

When seeing a patient with a strange and exotic disease, ask about foreign travel. Ask about exposure to rodents and insect bites although these are not always remembered and aerosol transmission and other routes may be involved. For Ebola and Marburg virus the route of transmission is unknown. Family members and healthcare workers who have looked after the patient are at risk. If large numbers of people are suddenly affected, it must not be forgotten that these viruses have been developed in the past for biological warfare and a rogue state or terrorist organisation may be responsible.

Incubation period ranges from 2 days to 3 weeks. Complaints include:

• High temperature, headache, myalgia and fatigue
• Abdominal pain and prostration
• In more advanced cases haematemesis and bloody diarrhoea may occur

Examination

Physical signs may vary from minimal to gross.

• High temperature
• Pharyngitis, conjunctival injection
• Oedema, not dependent
• Rash may be petechial or ecchymoses
• Hypotension or shock
• Haemorrhage in mucous membranes
• In very advanced disease there may be altered mental state and circulatory collapse. This may be terminal.

Although there is much in common between the various haemorrhagic fevers there are differences of emphasis between them and the reader is referred to the emedicine article listed at the end under Internet for the main differential features.

Infected material is very dangerous and so investigations should be restricted to the necessary and specimens must carry warning labels, even if the diagnosis is only suspected and not yet confirmed. When the diagnosis has been made, it is a notifiable disease. Emerging and re-emerging diseases in Africa require good laboratory services that are often not available.⁷

• FBC shows leukopenia and thrombocytopenia although this may not be so with Lassa fever.
• Liver function tests show elevated transaminases and in Lassa fever this carries a high mortality.
• Assessing bleeding tendency: partial thromboplastin time (PTT), INR and clotting times are all prolonged.
• There may be evidence of disseminated intravascular coagulation. A recent study found that D-dimer levels were four times higher in patients who died from Ebola virus than those who survived.⁸
• With the exception of Hantavirus, most patients have viraemia at presentation and so it may be possible to use specific antibody tests to identify the virus.^9,10 Speed is often of the essence during outbreaks, and high-throughput protocols for RNA extraction and quantitative reverse-transcription polymerase chain reaction analysis have been developed to promote early recognition and surveillance during outbreaks.¹¹
• For Hantavirus, virus-specific IgM is usually assayed. Typing of a specific hantavirus infection (necessary because of the difference in severity of symptoms of the various types) requires neutralisation antibody assays or reverse transcriptase PCR and sequencing.¹²
• A test assaying saliva IgM and IgG levels in Dengue fever is currently being investigated.¹³

• A concerted effort by all agencies involved in the management of an outbreak has a beneficial effect on clinical outcomes and on the containment of infection. For example, in 2005, the independent humanitarian medical aid agency Medecins Sans Frontieres, together with the World Health Organisation and the Angolan Ministry of Health responded to the Marburg hemorrhagic fever (MHF) outbreak to contain the epidemic and care for those infected. This response included community epidemiological surveillance, clinical assessment and isolation of patients with MHF, safe burials and disinfection, home-based risk reduction, peripheral health facility support, psychosocial support, and information and education campaigns.¹⁴
• Patients require barrier nursing and those in proximity should wear face masks and eye shields. Visitors should be restricted.
• Intravenous fluids may be required and sometimes even blood or blood products. Oxygen may also be necessary.
• Avoid intramuscular injections and aspirin because of bleeding.
• Lassa fever and HFRS due to Hantavirus infection respond to the antiviral ribavarin.¹⁵ ribavirin might be suitable for other arenaviruses and bunyaviruses but treatment must be started early. ribavirin also is recommended for post exposure prophylaxis. Antivirals are of no value for Ebola or Marburg fever.

These include retinitis, orchitis, hepatitis, transverse myelitis, and uveitis. In those who recover from Lassa fever, deafness is the commonest complication. Miscarriage is also common. Renal insufficiency occurs in HFRS infection.

Fatality rates vary from less than 10% in Dengue to around 90% with Ebola-Zaire. An outbreak of Ebola occurred in 2007 in Uganda. The mortality rate was 36%; this lower rate was thought to be due to better infrastructure and more experienced care than that seen in previous outbreaks (e.g. Sudan, 1976, 50-70%).¹⁶

Education and control programmes for rodents and mosquitoes are required in endemic areas.¹⁷ There needs to be adequate training of health care workers regarding 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.¹⁸

Yellow fever vaccine is extremely effective and a very safe vaccine but the only currently available vaccine for this group of diseases. It has been effectively incorporated into childhood vaccination programmes in Africa and endemic areas of South America, but uptake is still patchy in non-endemic areas.¹⁹ An effective vaccine for Lassa fever is a possibility.^3,20 Development of a vaccine against Ebola fever is also feasible.²¹

• Lassa fever first appeared in Lassa in Nigeria in 1969. The origin should not be confused with Lassa or Lhasa, the capital of Tibet.
• 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. Sporadic outbreaks continue, usually in isolated areas of central Africa. An outbreak in Kikwit, Zaire, in 1995 led to 317 confirmed cases, with an 81% mortality rate. Two thirds of the cases were health workers caring for infected people. An outbreak in Uganda in late 2000 produced 425 cases and claimed 225 lives. Ebola has 4 subtypes: Ebola-Zaire, Ebola-Sudan, Ebola-Ivory Coast, and Ebola-Reston. The last causes illness only in nonhuman primates.
• Marburg virus was named after the German town where it first was reported in 1967 but it is traced to central Africa. As with Ebola, the natural host is unknown. Marburg virus was contracted by a traveller to central Africa in 1987 and has been endemic since 1998 in Durba, Democratic Republic of the Congo, and in people working in gold mines.
• Yellow fever and Dengue have been known for rather longer and have had devastating effects on historical military campaigns. It is thought that yellow fever was brought to America by infected slaves from Africa. It is thought that the first reported epidemic was in 1648 in Mexico. An epidemic in Philadelphia in 1793 killed 10% of the city's 400,000 people. 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 HF was so named as it first came to prominence in the Korean War. It killed several thousand allied soldiers as well as an unknown number on the communist side.²² It is a common finding in military campaigns that disease and endemic risks can kill more soldiers than enemy action.