Viral Haemorrhagic Fevers: an Overview — Questions

A complete answer covers the common self-limited illness and the severe minority forms.

Uncomplicated illness. After an incubation of about 2 to 6 days, most people develop an abrupt influenza-like illness with fever, headache, myalgia and photophobia, resolving within a week.

Ocular disease. One to three weeks later a minority develop retinitis and retinal vasculitis, which may leave permanent loss of central vision.

Neurological disease. A late meningoencephalitis can occur, with confusion, headache and focal signs.

Haemorrhagic disease. A small proportion develop jaundice, mucosal and gastrointestinal bleeding and hepatic necrosis, the form with the highest mortality.

A febrile returning traveller is at least a thousand times more likely to have malaria than a viral haemorrhagic fever, so malaria must be excluded first while VHF risk is judged from the exposure history.

Isolation follows only once the history makes VHF plausible, and empirical ribavirin, antivirals or discharge are inappropriate as the immediate step.

Crimean-Congo haemorrhagic fever virus is a nairovirus, family Nairoviridae, within the order Bunyavirales, and is transmitted by Hyalomma ticks.

Rift Valley fever is a phenuivirus, while the filoviruses, arenaviruses and flaviviruses are the other VHF groups.

The dominant lesion is a cytokine-driven increase in vascular permeability, the same capillary leak seen in septic shock, which collapses intravascular volume and blood pressure.

Endothelial infection can occur but is not the main driver, frank haemorrhage is usually a minor feature, and neither autoantibodies nor myocardial infection explains the shock.

Recent appraisal regards the benefit of ribavirin in Lassa fever and Crimean-Congo haemorrhagic fever as unproven, though older evidence supported its use in Lassa and in haemorrhagic fever with renal syndrome.

Ribavirin is an antiviral, not a vaccine, has no role against Ebola, and is neither universally contraindicated nor a pre-exposure prophylactic.

A 21-day window from last possible exposure is used operationally, reflecting an incubation period across the syndrome of about 2 to 21 days.

The other intervals are too short or too long to match the syndrome’s incubation.

Up to about a third of survivors of clinical Lassa fever develop permanent sensorineural hearing loss, making Lassa a leading cause of acquired deafness in its endemic region.

The other sequelae are not characteristic of Lassa fever.

Rift Valley fever reaches people from mosquitoes and infected animal tissue, not readily from person to person, so it poses little direct threat to staff.

Ebola, Marburg, Lassa and Crimean-Congo haemorrhagic fever all spread through blood and body fluids and have caused nosocomial outbreaks.

Marburg virus is a BSL-4 agent, with the other filoviruses, Lassa, Lujo, Crimean-Congo haemorrhagic fever and the New World arenaviruses.

Dengue and the yellow fever vaccine strain are handled at lower containment, and Rift Valley fever and hantaviruses at BSL-3.

The viruses first replicate in monocytes, macrophages and dendritic cells, disabling early defence and carrying virus to lymph nodes and organs.

Hepatocytes and endothelium are infected later in broad-tropism agents, and renal tubular and neutrophil infection is not the initiating event.

The shared evasion strategy is suppression of the type I interferon response, for example the Ebola proteins VP35 and VP24, which block interferon induction and signalling, allowing unchecked replication.

Complement, mucosal antibody, gastric acid and phagocytosis are not the pathway these viruses principally target.

Third-trimester Lassa and filovirus infection carries maternal and fetal mortality approaching 100%.

The other listed conditions do not carry this near-uniform third-trimester lethality.

Non-steroidal anti-inflammatory drugs, aspirin and corticosteroids are avoided, the first two for bleeding and renal risk and steroids for lack of benefit.

Fluids, electrolyte correction, blood products and volume monitoring are mainstays of supportive care.

Thrombocytopenia is essentially universal, although it is usually not severe enough on its own to explain bleeding.

Leukopenia is common rather than neutrophilia, and the other abnormalities are not characteristic.

Viral haemorrhagic fever (VHF) is a clinical syndrome, not a single disease, caused by unrelated enveloped RNA viruses that produce fever with increased vascular permeability, coagulopathy and, in severe cases, shock and multi-organ failure. Almost all are zoonotic.

Examples relevant to Africa:

• Filoviruses: Ebola (Zaire, Sudan, Bundibugyo) and Marburg.
• Arenaviruses: Lassa (West Africa) and Lujo (southern Africa).
• Crimean-Congo haemorrhagic fever: tick-borne, endemic to southern Africa.
• Rift Valley fever: mosquito-borne and livestock-associated.
• Yellow fever: the severe flaviviral haemorrhagic fever.

• Petechiae and large ecchymoses: cutaneous and mucosal bleeding, with ecchymoses especially characteristic of Crimean-Congo haemorrhagic fever.
• Mucosal bleeding: epistaxis, gingival bleeding, haematemesis or melaena.
• Thrombocytopenia: a falling and often markedly low platelet count.
• Deranged coagulation: prolonged prothrombin and partial thromboplastin times with raised fibrin degradation products, indicating disseminated intravascular coagulation.

• Positive-pressure suit or class III cabinet: staff work in a self-contained, air-supplied suit, or through a sealed glove-box cabinet.
• Airlocked entry and exit: controlled access through sealed doors with a chemical shower on exit.
• Dedicated air handling: directional inward airflow with high-efficiency particulate air (HEPA) filtration of exhaust.
• Effluent and waste decontamination: liquid effluent and solid waste are treated before leaving the facility.

• Crimean-Congo haemorrhagic fever: family Nairoviridae (order Bunyavirales); transmitted by Hyalomma tick bite and by contact with the blood and tissues of infected livestock at slaughter.
• Rift Valley fever: family Phenuiviridae (order Bunyavirales); transmitted by mosquito bite and by contact with the blood, tissues and fluids of infected livestock.

• Retinitis and retinal vasculitis: the complication most often associated with permanent morbidity, since macular involvement can cause lasting loss of central vision.
• Meningoencephalitis: a late, immune-mediated neurological complication.
• Haemorrhagic and hepatic disease: jaundice, bleeding and hepatic necrosis, carrying the highest mortality.

The live-attenuated veterinary vaccines retain residual virulence: they are teratogenic and abortigenic in pregnant livestock and carry a risk of reversion, so they are not considered safe for human use. Inactivated preparations exist for limited occupational human use but are less immunogenic and need repeated dosing.

A complete answer contrasts the two approaches on speed, safety and yield in early disease.

Molecular assays (RT-PCR). In the first days of illness viraemia is high, so reverse transcription polymerase chain reaction is sensitive and rapid and is the method of choice. It can be run on chemically inactivated samples, which lowers the biosafety hazard, so validated molecular testing need not require maximum containment.

Virus isolation. Culture is sensitive during early viraemia but slow, and it amplifies live virus, so it demands biosafety level 4 containment and is confined to reference laboratories.

In practice RT-PCR gives the early answer safely, while isolation is reserved for characterisation under maximum containment.

A complete answer covers the shared VHF mechanism and the points of difference in tropism, immune response and bleeding.

Shared mechanism. Both first replicate in monocytes, macrophages and dendritic cells, suppress the type I interferon response, and drive a pro-inflammatory cytokine response that raises vascular permeability and activates coagulation, producing capillary leak and disseminated intravascular coagulation.

Ebola. Broad cell tropism, including endothelium, hepatocytes and adrenal cortex, causes widespread tissue destruction; the viral glycoprotein can disrupt endothelium directly, and failure of both humoral and cellular immunity marks fatal cases, so the picture resembles septic shock.

Crimean-Congo haemorrhagic fever. Prominent hepatic involvement and endothelial infection with a marked coagulopathy; large ecchymoses are characteristic, and disseminated intravascular coagulation is often severe.

Both spread person to person through blood and body fluids and have caused nosocomial outbreaks.

A complete answer links the timing of the complication to the fall in viraemia and the rising immune response.

Acute phase. Most infections are self-limited, with high viraemia cleared within a few days as antibody appears.

Late complications. In a minority, neurological disease appears in the second week, after viraemia has fallen and antibody is rising, which points to an immune-mediated rather than a directly cytolytic mechanism. Retinal vasculitis follows the same pattern, coinciding with the strongest antibody response.

Contrast. This differs from the fulminant haemorrhagic form, in which a defective immune response allows persistent viraemia and direct viral injury with hepatic necrosis.

A complete answer covers the exposure history, the differential, isolation and safe diagnosis.

Exposure history. Ask about travel to or from an endemic area in the previous 21 days, contact with animals, ticks, ill people or funerals, and healthcare or laboratory work.

Differential diagnosis. Malaria is far more likely in a febrile returning traveller and must be actively excluded, along with typhoid and other bacterial sepsis; the two can coexist.

Isolation. Once VHF is plausible, isolate the patient and apply barrier precautions before confirmation, because the risk to others is greatest in the undiagnosed phase.

Diagnosis. Seek advice before sampling; reverse transcription polymerase chain reaction (RT-PCR) on blood is the primary test, and specimens must be packaged and transported safely to a laboratory equipped for the required biosafety level.

Supportive care. Attend to circulating volume and electrolytes, and avoid non-steroidal anti-inflammatory drugs, aspirin and corticosteroids.