Description

The viral haemorrhagic fevers (VHFs) are caused by four types of RNA virus:

• Filoviruses cause Ebola haemorrhagic fever (HF) and Marburg HF
• Arenaviruses cause Lassa fever, Argentine HF and Bolivian HF
• Bunyaviruses cause Korean HF (Hantavirus), Rift Valley fever and Crimean-Congo HF
• Flaviviruses cause yellow fever and dengue

Of these, Lassa fever, Marburg HF and Ebola HF are the most significant.

Pathogenesis

Infected dendritic cells are largely impaired in their activation potency, likely contributing to the immune suppression that occurs during filovirus infection. Monocytes/macrophages, however, immediately activate after viral contact and release reasonable amounts of cytokines that target the vascular system, particularly the endothelial cells.^[1] Fibroblastic reticular cells, another prevalent infected cell type, are known to be a key regulator of circulatory and immune functions.^[2] Similar processes are thought to occur in arenavirus infection.^[3]

Epidemiology

These three diseases are almost invariably found in Central Africa where outbreaks are usually sporadic but very infectious and have a very high mortality rate. A study in Gabon showed that 6% of the population had had contact with Ebola HF^[4] but not Marburg HF or Lassa fever. Cases imported from endemic areas have been reported sporadically in the United Kingdom. ^[5][6]

• Lassa fever affects between 300,000 and 500,000 people annually in West Africa, of whom about 5,000 die.^[7]
• Probably 80% of Lassa fever is subclinical but in the other 20% it can take a complicated course. Subclinical infection with Marburg or Ebola virus is much rarer.
• Ebola HF outbreaks are more sporadic but mortality is 50-90%.^[8]
• Marburg HF outbreaks are also sporadic. There have been recent ones in the Congo and Angola. Deaths in Europe have occurred in laboratory workers who handled green monkeys.^[9]

There is no apparent difference in predilection between sex and races.

Risk factors

• Lassa fever is transmitted directly to humans by rodents, insect bites (especially mosquito), primates and patients.
• Marburg HF originated from a group of African green monkeys imported from Uganda but the usual vector for Ebola and Marburg HF is not known.
• There is transmission between humans in all three diseases. This tends to be from body fluids rather than droplet spread.
• In some African hospitals needles are used for more than one patient, patients may share beds and soiled sheets can transmit disease. This is called nosocomial infection and is a major cause of spread.^[10]
• Doctors and nurses who operate on infected patients are at risk.

In recent years some new VHFs have emerged in various parts of the world, usually where human habitation has encroached on rain forests.

It is said that both the USA and the former USSR developed the VHF viruses, especially Lassa, Marburg and Ebola, for use in biological warfare. Conceivably other states and terrorist organisations could do the same^[11] and the lack of familiarity with such diseases would increase the risk.^[12]

Presentation

• The incubation period is 4 to 21 days.
• Symptoms start with fever, headaches, myalgia and conjunctival suffusion.
• On about the fifth day of illness, a maculopapular rash may appear, mostly on the trunk.

Many systems are affected:

Gastrointestinal tract

• Nausea and vomiting (perhaps bloody)
• Diarrhoea (bloody)
• Abdominal pain
• Constipation
• Dysphagia
• Hepatitis with jaundice or pancreatitis

Cardiovascular system

• Pericarditis
• Hypertension or hypotension
• Tachycardia

Respiratory tract

• Cough
• Chest pain
• Dyspnoea
• Pharyngitis

Nervous system

• Encephalitis
• Meningitis
• Unilateral or bilateral deafness (usually Lassa fever)
• Seizures

Bleeding occurs in the nose, intestines or genitalia. Symptoms may increase in severity with rapid weight loss, prostration, delirium, shock, hepatic failure, massive haemorrhage and multi-organ failure. Bleeding is a less notable feature of Lassa fever than the others.

The disease is usually fatal within a few days.

Differential diagnosis

This is mostly between the various other VHFs. Serological tests can establish the exact cause and strain.

• Meningococcal septicaemia
• Henoch-Schönlein purpura
• Measles
• Hepatitis
• Malaria
• Haemolytic uraemic syndrome

Investigations

• FBC shows reduced leukocytes (except in Lassa fever) and platelets.
• Transaminases are elevated and INR prolonged.
• There may be signs of disseminated intravascular coagulation (DIC).

Note: keep investigations to a minimum to protect laboratory staff and handle all specimens with extreme care.

Management

Non-drug

Treatment is symptomatic. Attention to hydration and blood loss may be required with IV fluids, blood, plasma and platelets. Oxygen may be needed.

Secondary prevention requires total isolation of affected patients.

Drugs

• No effective treatments, prophylactic measures, therapies or vaccines are approved to treat or prevent Ebola HF and Marburg HF.^[13]
• Lassa fever, South American HFs and possibly Crimean-Congo fever and Rift Valley HF may be treated by a slow intravenous infusion of ribavirin.
• Adults require a loading dose of 2 grams (30 mg/kg) followed by 1 gram (15 mg/kg) every six hours for four days, followed by 500 mg (7.5 mg/kg) every eight hours for six days.
• The dose in children is uncertain.
• It should be started as soon as possible; however, the cost of this drug in Central African countries is often prohibitive.

Analgesics and antipyretics may be required. Avoid aspirin and IM injections because of bleeding.

Complications

• Hepatic failure is more common in Marburg HF and Ebola HF, as is DIC.
• In pregnancy, fetal loss exceeds 80%.
• Deafness occurs in 25% of cases of Lassa fever, with half recovering some hearing after 3 months.
• Acute kidney injury is an uncommon complication of VHF but acute renal dysfunction has been reported.^[14]

Prognosis

• Marburg HF has a mortality rate around 25%. Ebola HF kills between 50 and 90%.^[8]
• There are five different strains of Ebola HF: Bundibugyo, C(te d'Ivoire, Reston, Sudan and Zanre. Ebola Zaire is the deadliest known strain of the virus with a mortality rate as high as 90%.
• In Lassa fever, of those who are admitted to hospital, about 15 to 20% die, giving an overall mortality of between 1 and 3%; however, in epidemics it can be up to 50%. Mortality tends to be higher in children and the elderly. It is more severe if contracted from a patient.
• Those who recover from these infections have long-lasting immunity but life-long immunity has not been demonstrated.

Prevention

• Of the various haemorrhagic fevers, only yellow fever has a vaccine. A vaccine against Lassa fever^[15] and Ebola HF^[16] may not be far off.
• A vaccine for Marburg HF is being developed.^[17]
• Patients are infectious as long as they are pyrexial but corpses are also infectious.
• Keep away from vectors such as rodents or infected primates. Control rodent populations, prevent them from entering homes and workplaces and clean up droppings. Avoid mosquito bites - along the same principles as with malaria. When treating patients use gloves, gowns, masks and goggles, as infection acquired from patients seems to be particularly virulent.
• Close surveillance of contacts for 3 weeks with isolation if they become pyrexial.