Viral Haemorrhagic Fevers — Questions

a. Recognise and pause. Treat the request as a possible viral haemorrhagic fever (VHF); do not process the sample routinely, and check it against the current suspected-case definition (fever or a compatible symptom, travel to the outbreak area within 21 days and contact with a case, with malaria excluded).

b. Consult and notify. Telephone the National Institute for Communicable Diseases (NICD) hotline for a risk assessment before handling the sample further, alert the receiving reference laboratory, and notify the case as a Category 1 Notifiable Medical Condition and to the provincial coordinator.

c. Handle and package safely. Contain the sample under enhanced precautions; if VHF testing is agreed, submit one clotted and one EDTA tube with the case investigation form, in Category A packaging to UN2814, kept cold, by arranged courier to the reference laboratory.

d. Essential tests and isolation. Ensure the patient is isolated with barrier precautions, run only the clinically essential tests on site under precautions, and exclude malaria in parallel.

• Prior consultation: the sample is sent only after discussion, through the hotline, with an NICD medical officer and the receiving laboratory.
• Specimen and form: one clotted-blood tube and one EDTA tube, with the completed case investigation form.
• Packaging: Category A triple packaging to UN2814 under International Air Transport Association (IATA) packing instruction 620, with biohazard marking.
• Temperature: kept cold with cold packs; whole blood is not frozen.
• Courier: moved by a dedicated arranged courier, not routine transport.

Crimean-Congo haemorrhagic fever virus infects mononuclear phagocytes (monocytes and macrophages), dendritic cells, endothelial cells and hepatocytes.

Infection of macrophages and dendritic cells triggers release of pro-inflammatory cytokines which, with direct infection of endothelium, increases vascular permeability and activates coagulation, producing capillary leak and disseminated intravascular coagulation. Infection of hepatocytes causes hepatic necrosis. Together these drive the multi-organ failure of severe disease.

• Heavy rainfall: prolonged rains, often in an El Nino year, flood shallow depressions (dambos).
• Mosquito hatching: flooding hatches Aedes eggs already carrying the virus through transovarial transmission.
• Livestock amplification: the virus amplifies in sheep, cattle and goats, producing abortion storms that act as a sentinel.
• Secondary vectors: Culex and other mosquitoes amplify transmission further.
• Human spillover: people are infected by mosquito bites and by contact with infected animal tissues at slaughter, veterinary work or nursing sick animals.

• Marburg reservoir (confirmed): the Egyptian rousette bat, a cave- and mine-dwelling fruit bat from which the virus has been repeatedly isolated.
• Ebolavirus reservoir (unconfirmed): fruit bats are strongly suspected on antibody and genome-fragment evidence, but infectious virus has never been isolated from a wild bat.
• Endemism: Marburg spillover tracks the range of the Egyptian rousette and cave or mine exposure, while ebolavirus spillover occurs in the forest zones of central and West Africa.
• Non-human primates and forest antelope are amplifying spillover hosts for both, not reservoirs.

Triple packaging protects handlers and the environment through three layers:

• Primary receptacle: the sealed, leak-proof specimen tube, wrapped in enough absorbent material to soak up the entire contents if it breaks.
• Secondary packaging: a durable, leak-proof, sealed container enclosing the primary receptacle.
• Outer packaging: a rigid shipping container of adequate strength, bearing the biohazard and Category A labelling.

For a suspected VHF specimen the system is classified Category A, UN2814, under International Air Transport Association (IATA) packing instruction 620, kept cold and moved only by prior arrangement.

The primary vector is the Hyalomma tick (notably Hyalomma marginatum and H. rufipes).

• Long mouthparts: a long hypostome and palps, longer than in most other hard ticks.
• Banded legs: pale and dark striping along the legs.
• Eyes on the scutum: distinct eyes at the margins of the shield, on a relatively large red-brown body.

• Semen (male genital tract): persistence for up to around two years.
• The eye: persistence causing uveitis.
• The central nervous system: rarely, a late relapse as meningoencephalitis.

Implication: persistence allows late transmission, particularly sexual transmission from male survivors, which can reseed an outbreak after it appears controlled, so survivor follow-up and safe-sex advice are part of the outbreak response.

Tropism: filoviruses first infect monocytes, macrophages and dendritic cells, then spread to a broad range of tissues including endothelium, hepatocytes and the adrenal cortex.

Interferon inhibition: the VP35 protein masks viral RNA from the sensor RIG-I (retinoic acid inducible gene I) and blocks interferon induction; in the ebolaviruses VP24 additionally blocks interferon signalling through STAT1 (signal transducer and activator of transcription 1), while the marburgviruses use VP40 for the same effect. This lets the virus replicate to high titre before the immune response engages.

• Hyalomma tick exposure: the Hyalomma tick is both reservoir and vector, and farming and outdoor work in the drier interior bring people into contact with infected ticks.
• Livestock contact at slaughter: viraemic cattle, sheep and goats transmit through blood and tissues during slaughter, dehorning and castration, so abattoir and farm workers are at risk.
• Nosocomial and contact spread: a viraemic patient’s blood and body fluids transmit to carers and health workers, extending outbreaks beyond the animal exposure.

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 complete answer covers the biphasic course and notes the clinical similarity of Ebola and Marburg disease.

Incubation. After an incubation of about 2 to 21 days, illness begins abruptly.

Dry phase. Fever, severe malaise, headache and myalgia, before the prominent fluid losses appear.

Wet phase. Profuse vomiting and watery diarrhoea within days, causing the fluid and electrolyte loss that drives shock; a maculopapular rash and conjunctival injection are common.

Haemorrhage and outcome. Frank bleeding occurs in a minority and is usually late. Marburg and Ebola disease are clinically very similar and cannot be reliably distinguished at the bedside, so laboratory testing is required.

A complete answer distinguishes supportive care, which is available, from specific countermeasures, which are not yet licensed.

Supportive care. The foundation of treatment is meticulous supportive care: aggressive fluid and electrolyte replacement, correction of coagulopathy, and organ support, which improves survival.

Specific therapeutics. There is no licensed antiviral or monoclonal antibody for Marburg virus, and the Zaire-specific Ebola antibodies do not apply. Candidate monoclonal antibodies and antivirals are investigational.

Vaccines. There is no licensed Marburg vaccine; candidate vaccines are in clinical trials. Prevention therefore rests on avoiding cave and mine exposure, infection control and outbreak response.

A complete answer explains that essential tests are still done, but under precautions, and that Ebola confirmation is handled separately.

Do the essential tests. Life-saving and monitoring tests (full blood count, malaria smear, coagulation, urea and electrolytes, liver function, cross-match) are performed on site and never withheld while viral haemorrhagic fever (VHF) is being considered.

Under enhanced precautions. A small team of experienced staff works in a demarcated area; any aerosol-generating or open step is done inside a biosafety cabinet under enhanced protective equipment; closed automated systems are used where possible; and waste is handled as high-risk.

Inactivation and closed systems. Where possible, samples are chemically inactivated before analysis, and closed analysers reduce exposure.

Ebola confirmation is separate. The Ebola test itself is not done in the routine laboratory: a specimen is sent, after prior consultation and under Category A packaging, to the reference laboratory. The routine samples are traced and treated as potentially infectious, and destroyed only after consulting the reference laboratory.

A complete answer covers the virus itself, its reservoir and transmission, the clinical disease, how it is diagnosed, how it is treated, and how it is prevented.

Virus and reservoir

Lassa virus is an Old World arenavirus (Mammarenavirus lassaense), an enveloped, bisegmented, ambisense RNA virus. Its reservoir is the multimammate rat Mastomys natalensis, which is infected for life and sheds virus in its excreta.

Epidemiology and transmission

Endemic to rural West Africa (notably Nigeria, Sierra Leone, Liberia and Guinea), with an estimated ~100,000 to 300,000 infections a year. Humans are infected through contact with rodent excreta, by inhalation, ingestion or contamination of broken skin. Lassa also spreads person to person, with nosocomial outbreaks, and transmission peaks in the dry season.

Clinical features

After an incubation of about 6 to 21 days, ~80% of infections are mild or subclinical. Symptomatic disease begins insidiously with fever, sore throat, retrosternal pain and proteinuria; a minority progress to facial and neck swelling, mucosal bleeding, encephalopathy and shock. Sensorineural hearing loss affects a quarter to a third of survivors of clinical disease, and the illness is far more severe in pregnancy, with third-trimester fetal loss approaching 100%.

Diagnosis

RT-PCR is the mainstay, supported by antigen-capture and IgM/IgG antibody assays run in tandem. Malaria must always be excluded in parallel, and confirmatory work is done at biosafety level 4.

Management

Intensive supportive care with cautious fluid replacement (to avoid pulmonary oedema), plus intravenous ribavirin as the specific agent, most useful when started early.

Prevention

Rodent control and avoidance of rodent excreta; barrier nursing and viral haemorrhagic fever precautions to prevent nosocomial spread; oral ribavirin for high-risk exposures; and 21-day monitoring of contacts. There is no licensed vaccine, though a recombinant vesicular stomatitis virus candidate is in advanced trials. Lassa fever is a notifiable condition.

The current emergency is caused by Bundibugyo virus, for which no vaccine or specific therapeutic is licensed; the licensed countermeasures protect only against Zaire ebolavirus.

Sudan virus also has no licensed vaccine but is not the cause here, Reston is non-pathogenic in humans, and Taï Forest has caused only a single case.

A contact of a filovirus, Lassa or Lujo case has temperature recorded twice daily for 21 days from the last contact.

The window is 14 days for Crimean-Congo haemorrhagic fever, and Rift Valley fever needs no such observation; the other intervals are wrong.

Infection of the fetal or newborn mouse, before the immune system matures, produces lifelong tolerant carriage with high virus levels but no disease.

This observation was central to the concept of immunological tolerance; the other outcomes do not describe it.

The pathogenic New World (clade B) arenaviruses enter cells through transferrin receptor 1, whereas the Old World viruses and clade C use alpha-dystroglycan.

Sialic acid, CD4 and angiotensin-converting enzyme 2 are receptors for other viruses, not the arenaviruses.

The licensed antibodies Inmazeb and Ebanga target the Zaire glycoprotein, so for Sudan and Bundibugyo virus disease there is no licensed specific treatment, and broadly reactive agents such as the monoclonal MBP134 and the antiviral remdesivir are being evaluated in trials.

Ervebo prevents rather than treats infection, and ribavirin has no established role in filovirus disease.

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

The other complications listed are not characteristic sequelae of Lassa fever.

A suspected VHF specimen is a Category A infectious substance, shipped under UN2814 with International Air Transport Association (IATA) packing instruction 620.

Routine diagnostic samples are the lower Category B (UN3373); the exempt, non-hazardous and Category C options do not apply.

Blood RT-PCR can be negative in the first days of symptoms because viraemia may be below the detection threshold, so a symptomatic contact who tests negative early should be retested after about 72 hours before Ebola is excluded.

Discharge, IgG serology, routine-laboratory culture and antigen testing alone are all inadequate for exclusion at that stage.

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.

About a tenth of patients given immune plasma for Argentine haemorrhagic fever develop a late, self-limiting neurological syndrome with fever and cerebellar signs, some weeks after apparent recovery.

The other complications are not features of this treatment.

Acute diagnosis rests on reverse transcription polymerase chain reaction and antigen detection, performed under maximum containment, because the antibody response develops too slowly to help early.

Serology is for later or for surveillance, and dengue is an important early differential.

Inside the acidifying endosome, cathepsins B and L trim the glycoprotein, removing the glycan cap and mucin-like domain to expose the site that binds the intracellular receptor NPC1, which then triggers fusion.

Entry does not depend on surface furin cleavage, neuraminidase, plasma-membrane fusion, or a single specific surface receptor; attachment is promiscuous.

At the acidic pH of the endosome, Lassa virus hands off from alpha-dystroglycan to the lysosomal protein LAMP1, which triggers the GP2 change that fuses the membranes.

Neuropilin-2 and CD36 serve Lujo virus, while DC-SIGN and integrins are not the fusion-triggering switch here.

An early negative must be backed by a convalescent antibody sample, because virus can still grow in culture days after antigen, genome and antibody are negative.

Discharge, no further testing, a malaria smear or antibiotics do not address an early false negative.

Oral ribavirin can be given as post-exposure prophylaxis after a defined high-risk exposure to Lassa virus, and is converted to intravenous treatment if illness develops.

The rVSV vaccine is not licensed for this use, and the immunoglobulins and oseltamivir target other agents.

Only about 1% to 2% of infections progress to severe disease; the great majority are a self-limiting febrile illness.

Severe disease is uncommon, but the scale of epizootics still yields many such cases.

The live-attenuated Junin vaccine Candid #1, in use since the late 1980s, has sharply reduced Argentine haemorrhagic fever.

Ribavirin and immune plasma are treatments rather than population-level control, the rodent reservoir has not been eliminated, and there is no inactivated Lassa vaccine nor a mosquito vector to target.

Necrosis of the adrenal cortex impairs the cortisol-dependent control of blood pressure, compounding the hypovolaemic and distributive shock of severe disease.

The thyroid, pituitary, pancreas and spleen are not the principal contributors to the shock.

CCHFV is the most widely distributed tick-borne virus, endemic across Africa, the Balkans, the Middle East, Central Asia and the Indian subcontinent, following the range of Hyalomma ticks.

It is an Old World, tick-borne virus, not mosquito-borne, rodent-borne or geographically confined.

The cellular protease SKI-1/S1P cleaves the glycoprotein precursor into GP1 and GP2, a step essential for infectivity and a target of experimental antivirals.

Furin, TMPRSS2 and caspase-3 process other proteins, and arenaviruses encode no 3C-like protease.

Severe Lassa fever is driven by increased vascular permeability and endothelial dysfunction, without the florid disseminated intravascular coagulation (DIC) or cytokine storm of Ebola.

Bleeding owes more to thrombocytopenia and impaired platelet function than to consumption of clotting factors.

The South American arenaviral haemorrhagic fevers feature prominent neurological signs, such as tremor and ataxia, more than Lassa fever does.

Deafness is the Lassa sequela, chronic human carriage does not occur, a rash is common, and arenaviruses are not mosquito-transmitted.

The South American haemorrhagic fevers carry a more prominent neurological picture than Lassa, with thrombocytopenia and leucopenia but a normal or only mildly raised aspartate aminotransferase.

Marked hepatitis, an absence of blood-count changes, a chickenpox-like rash and isolated renal failure are not their pattern.

A virus-specific T-cell response, rather than antibody, controls Lassa fever; antibody appears late and neutralises weakly, and fatal cases show a defective, delayed T-cell response with rising viraemia.

The other mechanisms are not the decisive arm of control.

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.

Ribavirin has been used for decades and may help when started early, but recent meta-analyses question its benefit and several investigators have called for randomised trials.

It is still given in many endemic settings, particularly when CCHF cannot be distinguished from other haemorrhagic fevers, so it is neither proven nor contraindicated.

Acquired from an infected donor, LCMV causes a severe and frequently fatal multisystem illness in the immunosuppressed recipient, with fever, hepatitis, encephalopathy and multiorgan failure within weeks; across five US clusters most of the 17 recipients died.

Donors cannot practically be screened for this rare infection, so it is recognised after the event.

Filovirus can persist in immune-privileged sites such as the semen for up to around two years, allowing occasional sexual transmission that reseeds outbreaks.

The virus does not persist long term in the bloodstream, muscle, bile or sweat glands in this way.

Only for Marburg virus is the reservoir firmly established: the Egyptian rousette bat, from which the virus has been repeatedly isolated.

The ebolavirus reservoir is unconfirmed, since infectious virus has not been isolated from a wild bat, and filoviruses are not rodent- or tick-borne.

RVFV shows only about 4% to 5% nucleotide diversity among strains since the 1970s and behaves as a single antigenic type, so one well-matched vaccine can protect broadly.

It does not undergo antigenic shift or drift into escape serotypes.

Guanarito virus, the cause of Venezuelan haemorrhagic fever, is carried by the cane mouse Zygodontomys brevicauda in the states of Portuguesa and Barinas.

Calomys species are the Argentine and Bolivian reservoirs; the house mouse and ticks are not involved.

Marburg virus and Ravn virus are two distinct viruses within a single species, Orthomarburgvirus marburgense, in the genus Orthomarburgvirus, and they cause the same disease.

They are not separate genera or families, are not ebolaviruses, and are genetically distinct rather than identical strains.

At a run of seven uridines the polymerase stutters and inserts an extra nucleotide, shifting the reading frame so one gene yields both the structural spike GP1,2 and a secreted decoy glycoprotein, sGP. Marburg virus lacks this editing and makes no sGP.

The mechanism is cotranscriptional editing, not splicing, stop-codon read-through, a second gene, or cleavage by the receptor NPC1.

Marburg virus is taken up by macropinocytosis, after which endosomal cathepsins prime the glycoprotein to bind the intracellular receptor NPC1, the same receptor used by the ebolaviruses, triggering fusion.

It does not fuse at the plasma membrane, rely on a single specific surface receptor, use sialic acid, or enter through the transferrin receptor.

Marburg virus expresses its glycoprotein from a single reading frame and makes no secreted glycoprotein, unlike the ebolaviruses, which use cotranscriptional editing to produce both the surface spike and a secreted decoy (sGP).

It does not edit its glycoprotein gene, has a single such gene, and does carry a surface glycoprotein.

The CCHFV L and M segments are markedly larger than in other bunyavirals, the oversized L protein carrying a cap-snatching endonuclease and an OTU deubiquitinase domain in addition to the polymerase.

The genome is negative-sense, tripartite RNA; an ambisense S segment is a phlebovirus feature, seen in Rift Valley fever virus, not CCHFV.

The L polymerase cleaves short capped fragments from host messenger RNAs and uses them to prime transcription (cap-snatching), a strategy shared across the bunyavirals and carried out entirely in the cytoplasm.

Protein-primed and self-priming mechanisms belong to other virus groups.

The Lassa nucleoprotein carries an exonuclease that digests the double-stranded RNA the cell would otherwise sense, suppressing type I interferon induction.

Arenaviruses do not evade immunity by cleaving MHC, neutralising antibody, blocking apoptosis or degrading complement in this way.

A suspected VHF is notified as a Category 1 Notifiable Medical Condition through the Notifiable Medical Conditions application, alongside the hotline call, without waiting for laboratory confirmation.

It is not reported by a routine return or only after confirmation, and the World Health Organization is notified by the national department, not the clinician.

Acute disease is confirmed by RT-PCR for viral RNA in blood, with a reactive screen confirmed by a virus-specific assay, and all work performed under biosafety level 4 precautions.

Routine blood culture, serology alone, an antigen skin test and electron microscopy of urine are not the diagnostic approach.

The tick is both vector and reservoir: it passes CCHFV transstadially across its moults and transovarially into its eggs, so the enzootic cycle persists without the vertebrate host being permanently infected.

Humans are dead-end hosts, and mosquitoes play no part in the cycle.

Lassa virus diversity is strongly geographic and is greatest in Nigeria, consistent with a Nigerian origin; six major lineages are currently recognised.

The diversity is not a single clone, is not clock-like or drift-driven, and is not confined to one region.

Transfusion of immune convalescent plasma is established for Argentine haemorrhagic fever and reduces mortality substantially when given within roughly the first week.

It is not a general treatment for the other arenaviruses, and its benefit depends on early administration.

Specific IgM and IgG appear around days five to seven only in those who survive; fatal cases usually die before they seroconvert.

Molecular detection, not serology, is therefore decisive in severe disease, and a negative antibody result never excludes CCHF in a severely ill patient.

Malaria is the priority exclusion in every suspected VHF, because it is far more common in the same patients and can coexist with a VHF.

The other conditions are not the critical parallel diagnosis.

Viral loads above roughly 10⁸ genome copies per millilitre predict a fatal course, whereas lower loads accompany milder disease.

Viral load, platelet count and clotting times are combined in severity scores; a high load signals worse, not milder, disease.

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.

Lassa fever is a category 1 notifiable medical condition in South Africa, requiring immediate reporting on suspicion, and any suspected case is managed through the national viral haemorrhagic fever pathway with reference-laboratory confirmation.

It is not endemic in South Africa but is an importation risk, and it demands maximum-containment isolation rather than standard ward care.

Ebola disease is a Category 1 Notifiable Medical Condition, requiring immediate reporting on clinical suspicion, before laboratory confirmation, so that isolation and the outbreak response can begin without delay.

Waiting for confirmation, reporting weekly or monthly, or reporting only fatal cases would all breach the immediate-notification requirement.

Rift Valley fever and Crimean-Congo haemorrhagic fever are Category 1 notifiable medical conditions and must be notified within 24 hours, reflecting their haemorrhagic-fever severity.

All other arboviral infections, whether endemic or imported, are Category 3 and reported through routine channels.

Every Lujo case after the index patient was acquired in hospital, by person-to-person spread to those providing care.

No vector, water or rodent-exposure route was involved in the secondary cases, which is why infection prevention and control is the central lesson of the outbreak.

In the adult mouse the fatal disease is caused by the cytotoxic T-lymphocyte response, the classic demonstration that a virus-specific T-cell response can mediate immunopathology as well as viral clearance.

It is not due to direct neuronal lysis, antibody or complement, bacterial superinfection or immune-complex vasculitis.

In the ebolaviruses, VP24 blocks interferon signalling through STAT1 (signal transducer and activator of transcription 1), while VP35 is the shared antagonist masking viral RNA from RIG-I (retinoic acid inducible gene I) and the marburgviruses use VP40 for the same effect.

VP24 is not the polymerase, matrix protein or nucleoprotein, and it does not edit the glycoprotein gene.

The 1976 Yambuku outbreak was amplified by the reuse of unsterilised needles and syringes, which spread the virus among patients and staff and gave an early lesson in health-care transmission.

Ebola virus is not airborne and is not spread by mosquitoes or by water; contact with an animal source seeds the index case but does not sustain hospital amplification.

Because viraemia is high in the acute phase, reverse-transcription polymerase chain reaction (RT-PCR) and immunoglobulin M (IgM) capture ELISA on blood are the mainstays, supported by virus isolation and paired serology.

RVF is mosquito-borne, so there is no tick to identify.

Lassa fever is far more severe in pregnancy, with fetal loss approaching 100% in the third trimester and high maternal mortality; evacuation of the uterus improves maternal survival.

Pregnancy worsens rather than protects, and the danger is greatest late, not confined to early gestation.

Lassa virus was first isolated in 1969 in the town of Lassa, north-eastern Nigeria, after a mission nurse fell fatally ill and the infection spread to those who cared for her.

Sierra Leone, Liberia and Guinea are all part of the endemic zone but not the site of the 1969 identification, and the virus is not native to the Democratic Republic of the Congo.

Like the other Old World arenaviruses, LCMV binds alpha-dystroglycan to enter cells, followed by endocytosis and low-pH fusion.

Transferrin receptor 1 serves the New World arenaviruses and neuropilin-2 serves Lujo; CD4 and sialic acid are not its receptor.

LCMV was isolated in 1933 by Armstrong and Lillie during an investigation of a presumed St. Louis encephalitis outbreak, and was soon recognised as a distinct cause of aseptic meningitis.

The other conditions were not the setting of its discovery.

Lujo virus binds neuropilin-2 at the cell surface and depends on the tetraspanin CD63 in the late endosome to trigger fusion, a pathway independent of the usual arenavirus receptors.

Alpha-dystroglycan and transferrin receptor 1 serve the other arenaviruses; CD4 and LAMP1 are not its surface receptor.

Lujo virus was discovered by unbiased metagenomic deep sequencing within days of the outbreak, when conventional tests had failed, making it one of the first human pathogens found this way.

Culture, antigen ELISA, microscopy and antibody tests did not identify the novel agent; today diagnosis uses RT-PCR under maximum containment.

Congenital lymphocytic choriomeningitis virus infection causes fetal death, hydrocephalus and chorioretinitis, so it belongs in the differential of congenital infection.

The virus does not typically cause adult haemorrhagic fever, tick-borne encephalitis, post-transfusion hepatitis or chronic renal failure.

Machupo virus causes Bolivian haemorrhagic fever, identified in 1963 by Karl Johnson’s team during an outbreak in the Beni region and carried by the rodent Calomys callosus.

The other diseases are caused by different arenaviruses.

Although mosquitoes drive the animal epizootic, most people are infected by direct contact with the blood or tissues of infected livestock, during slaughter, birthing and the handling of aborted material.

Mosquito bite is a lesser route, and there is no person-to-person spread.

Gn and Gc are arranged as an ordered icosahedral lattice on the lipid envelope, a more regular surface than the pleomorphic nairoviruses, and there is no matrix protein.

The genome exists as a ribonucleoprotein, not an icosahedral capsid.

LCMV does not spread by ordinary contact; the only recognised human-to-human routes are across the placenta and through organ transplantation.

Respiratory, sexual, faecal-oral and vector transmission between people are not features of the virus.

Control of the New World haemorrhagic fevers depends chiefly on the antibody response, which is why passive transfer of immune plasma is effective in Argentine haemorrhagic fever.

This contrasts with Lassa fever, where T-cell immunity is decisive; the other mechanisms are not the main route of recovery.

Retinitis typically develops one to three weeks after the initial symptoms, sometimes after the fever has settled, and where it involves the macula it can cause permanent visual loss.

RVFV is a phlebovirus in the family Phenuiviridae, order Bunyavirales.

Nairoviridae (Crimean-Congo haemorrhagic fever) and Hantaviridae are the other bunyavirus families of note; filoviruses and flaviviruses are unrelated.

Daubney and Hudson described the disease from an outbreak of abortions and lamb deaths on a farm in Kenya’s Rift Valley, naming it enzootic hepatitis.

The Egyptian, Congo and Crimean events belong to other viruses or to much later outbreaks.

RVFV is highly infectious by aerosol, which caused many laboratory-acquired infections before modern biosafety practice, and is one reason it is handled under enhanced containment.

It does not spread from patient to patient by droplets.

Sabia virus is known from only a few cases, including laboratory-acquired infections, one following a centrifuge accident, which underlined the hazard of handling these viruses.

It has not caused a large epidemic or the other listed events.

Treatment is supportive, with ribavirin used by analogy with Lassa fever; the single survivor of the 2008 cluster received it early.

No Lujo-specific antiviral or proven plasma therapy exists, and corticosteroids and aciclovir have no role.

The course runs through incubation, a prehaemorrhagic phase, a haemorrhagic phase and convalescence.

The febrile-hypotensive-oliguric-diuretic sequence describes hantavirus haemorrhagic fever with renal syndrome, and a latent-reactivation pattern belongs to the herpesviruses.

Tacaribe virus was isolated from bats rather than rodents and does not cause human disease, making it a useful and safer laboratory surrogate for its dangerous clade B relatives.

The other statements are untrue of it.

The swollen baby syndrome is an often-fatal presentation of Lassa fever in children, combining generalised oedema, abdominal distension and bleeding.

The other descriptions belong to congenital infections and unrelated conditions.

The 1967 outbreaks struck laboratory and animal-facility staff exposed to tissue from African green monkeys imported from Uganda for vaccine and research work, infecting 31 people and killing 7.

The reservoir bat was identified only decades later; the source was not a bat colony, blood products, returning travellers or rodents.

A 2019 cluster of Chapare virus in La Paz spread to healthcare workers, with fatalities, showing that these viruses can transmit person-to-person and are not always dead-end infections.

They are rodent-borne, not mosquito-borne, and can cause severe disease and nosocomial risk.

Severe CCHF bleeding reflects a dysregulated pro-inflammatory cytokine response, with high tumour necrosis factor alpha, interleukin-6 and interleukin-8, causing endothelial dysfunction and disseminated intravascular coagulation.

Direct lysis of all endothelium, autoantibodies and vitamin K deficiency are not the principal mechanism.

Incubation is shortest after a tick bite, usually about one to three days. After exposure to infected blood or tissue it is longer, around five to seven days and occasionally up to thirteen.

All the blood- and tissue-contact routes give a longer interval than the tick bite.

The OTU domain is a deubiquitinase and deISGylase: it removes regulatory ubiquitin and ISG15 tags from innate-immune signalling proteins, damping the type I interferon response.

Glycoprotein cleavage, capping, integration and translational shut-off are unrelated to this domain.

LCMV meningitis characteristically produces a marked lymphocytic pleocytosis, sometimes over a thousand cells, with a low cerebrospinal fluid glucose.

The low glucose is a useful clue, since many viral meningitides leave it normal; the other patterns are not typical.

Lujo fever closely resembled severe Lassa fever, beginning with nonspecific fever, headache, myalgia, sore throat and diarrhoea and progressing to facial oedema, bleeding, respiratory and renal failure and circulatory collapse.

It was neither mild, rash-limited nor a pure encephalitis, and it did not differ fundamentally from Lassa.

There is no licensed human RVF vaccine; the most advanced candidate, ChAdOx1 RVF, was safe and immunogenic after a single dose in a phase 1 trial and is designed for both livestock and people.

Older inactivated preparations have protected only small numbers of laboratory and veterinary workers.

Reverse transcription polymerase chain reaction (RT-PCR) is the mainstay of early Lassa diagnosis, positive in most cases within the first ten days and able to quantify the prognostically important viral load.

IgG appears too late to diagnose acute disease, culture and electron microscopy are impractical, and a blood film addresses the malaria differential, not Lassa.

Lujo virus is known from a single event, the 2008 cluster of five cases, and its reservoir has never been identified.

Unlike Lassa it has no defined endemic zone or reservoir, and no recurrent or widespread infection has been documented.

The incubation period of Lujo fever is estimated at about 7 to 13 days, based on the 2008 cluster.

The other intervals are too short or too long for the observed course.

In 2000 RVFV appeared in Saudi Arabia and Yemen, its first confirmed spread beyond Africa, probably carried across the Red Sea in infected livestock.

Egypt and Madagascar are within Africa, and the Indian and European events did not occur.

Lassa virus has a bisegmented, ambisense RNA genome: each of the small and large segments carries one gene in each orientation, giving temporal control of gene expression.

It is neither a DNA virus, nor tripartite, nor retroviral, and it has two segments rather than three.

The haemorrhagic-hepatic form is the most lethal, with a case fatality of up to around 65%.

The milder febrile illness that most patients experience has a very low mortality.

The hepatic injury of Lassa fever is a direct viral cytopathic effect, with multifocal hepatocellular necrosis and little inflammation, unlike the immunopathology of lymphocytic choriomeningitis.

It is not immune-complex, coagulation-driven, autoimmune or purely ischaemic in origin.

The incubation period is short, usually 2 to 6 days, after which most people have a brief self-limiting fever.

The longer intervals describe other infections.

The licensed Ervebo vaccine protects against Zaire ebolavirus only.

Its glycoprotein is Zaire-specific, so cross-protection against the Sudan, Bundibugyo and Marburg viruses cannot be assumed.

Lujo is a contraction of Lusaka and Johannesburg, the two cities between which the 2008 outbreak unfolded after the index patient was evacuated from Zambia to South Africa.

The other derivations are invented.

In 1969 Jordi Casals showed that the agent of Crimean haemorrhagic fever was identical to the Congo virus isolated in the Belgian Congo in 1956, and the two names were joined.

The virus was described in the Crimea in 1944 but not isolated until 1967; it was not co-discovered, and it causes one disease across its range.

The natural reservoir of LCMV is the common house mouse (Mus musculus), which is infected for life and sheds virus in its excreta, giving the virus a worldwide distribution.

The other animals are reservoirs of unrelated agents.

The New World arenaviruses form the Tacaribe serocomplex and are carried by cricetid rodents of the Americas, each virus tied to a particular reservoir species.

Murid mice carry the Old World arenaviruses; ticks, mosquitoes and bats are not the reservoirs.

All the pathogenic New World arenaviruses, Junin, Machupo, Guanarito, Sabia and Chapare, fall in clade B.

Clades A and C contain no confirmed human pathogens, and the Old World complex and the reptile-associated genus are separate groups.

The liver is the main target and hepatic necrosis is the central lesion of severe RVF, reflected in steeply raised transaminases and, in the worst cases, jaundice and liver failure.

Renal failure occurs but is usually secondary.

The reference laboratory accepts a VHF specimen only after prior consultation, through the hotline, with a National Institute for Communicable Diseases (NICD) medical officer and the receiving laboratory, so nothing is dispatched unannounced.

Death, a malaria result, an observation period or ministerial approval are not the gate.

Junin virus is maintained by the drylands vesper mouse Calomys musculinus, a field rodent of the Argentine pampas, which is why Argentine haemorrhagic fever tracks the maize harvest.

Mastomys is the Lassa reservoir and Zygodontomys the Guanarito reservoir; the house mouse and bats are not involved.

NSs is the dominant virulence factor: it suppresses the type I interferon response, shutting down host-cell transcription and blocking interferon-beta induction.

The polymerase, glycoproteins and nucleocapsid are separate gene products.

GP38 is a secreted glycoprotein cleaved from the M-segment precursor and an important target of protective antibodies.

The same precursor also yields the structural Gn and Gc and the non-structural NSm; the nucleoprotein is an S-segment product, and NSs is a phlebovirus protein not carried by CCHFV.

Intravenous ribavirin is the specific agent of choice for Lassa fever, thought to work best when started early, although the strength of its original evidence is now debated.

Favipiravir is experimental for Lassa, while oseltamivir, aciclovir and remdesivir target unrelated viruses.

The standard submission is one clotted-blood tube and one EDTA tube, with the completed case investigation form.

A single tube, urine or a swab alone, or a dried blood spot is not the required submission.

After an incubation of about 1 to 2 weeks, symptomatic LCMV is often a biphasic illness: a febrile phase settles briefly and is then followed in a minority by aseptic meningitis.

The other courses are not characteristic of LCMV.

The incubation period of Lassa fever is about 6 to 21 days, most often 10 to 14 days.

The illness then begins insidiously rather than abruptly, which helps distinguish it from the shorter-incubation causes of acute fever.

The incubation period is about 6 to 14 days, after which illness begins gradually rather than abruptly.

The other intervals are too short or too long.

Lassa virus is an Old World arenavirus, the African and Eurasian complex that also contains lymphocytic choriomeningitis and Lujo viruses.

The New World clades hold the South American haemorrhagic fever agents, while reptarenaviruses and hartmaniviruses infect snakes, not humans.

Most infections are an abrupt, often biphasic influenza-like illness with fever, myalgia, arthralgia and headache, sometimes with photophobia and neck stiffness that can mimic meningitis, resolving over four to seven days.

Because livestock amplify the virus and are the main source of human infection, vaccinating animals is the most effective way to protect people, the logic of One Health.

Patients are not infectious to others, and mosquito eradication is not feasible during floods.

The lymphopenia arises from bystander apoptosis of uninfected lymphocytes, since lymphocytes are not productively infected in filovirus disease.

It is not caused by direct lymphocyte infection, antibody lysis, marrow failure or splenic sequestration.

The bleeding tendency reflects disseminated intravascular coagulation triggered by tissue factor released from infected macrophages, which consumes clotting factors and platelets; overt haemorrhage is a minority, late feature.

It is not caused by direct endothelial lysis, anti-platelet autoantibodies, vitamin K deficiency, or hepatic failure alone.

Shock reflects a functional increase in vascular permeability driven by inflammation and coagulopathy; the endothelium is infected but not extensively destroyed, so survivors recover without lasting vascular damage.

It is not caused by direct destruction of the vessel wall, external exsanguination, cardiac infection or autoimmune vasculitis.

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.

Ring vaccination targets the contacts of a case, and their contacts in turn, to build a protective ring around each case, which contains spread and works even with limited vaccine supply.

It is not mass national vaccination, health-worker-only vaccination, post-exposure-only use, or animal vaccination.

The ambisense arrangement lets the virus express its genes in a set temporal order, making the nucleoprotein and polymerase first and the glycoprotein and matrix protein later.

Arenaviruses do not integrate, reverse transcribe or reassort with influenza, and the genome cannot be translated directly.

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.

The virions take up host ribosomes during assembly, giving the grainy, sand-like appearance that names the family.

The grains are not glycoprotein crystals, calcified bodies or lipid droplets, and the appearance is unrelated to nucleocapsid symmetry.

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.

Marburg virus was the first filovirus ever recognised, in 1967, nine years before Ebola virus, and it established the filamentous morphology that defines the family.

It was not discovered after or alongside Ebola, does not date from the West African epidemic, and is not an arbovirus.

In 1975 Johannesburg saw the first recognised Marburg cases outside the original 1967 European cluster, when a traveller died and two contacts, including an attending nurse, were infected and survived.

It was not the site of the first vaccine trial, the reservoir discovery, the first Ravn case, or the largest outbreak.

Filoviruses are enveloped filaments of uniform ~80 nm diameter and highly variable length, often bent into U-shapes or a figure-of-six, with a helical nucleocapsid inside; the thread-like shape gives the family its name.

They are not icosahedral, brick-shaped (poxviruses), bullet-shaped (rhabdoviruses) or compact spheres.

Marburg virus has the filovirus form: an enveloped filament of uniform ~80 nm diameter and variable length, often looped or hooked, with a helical nucleocapsid inside.

It is not icosahedral, brick-shaped, bullet-shaped or a compact sphere.

No CCHF vaccine is widely licensed; an inactivated suckling-mouse-brain preparation used in Bulgaria is the only one in human use, and its efficacy has never been rigorously characterised.

Modern inactivated, virus-like-particle, vectored, DNA and subunit candidates remain in early development.

No Marburg vaccine is licensed; several candidates are in clinical trials, and licensure is hampered because outbreaks are sporadic and small, which makes conventional efficacy trials difficult.

No vaccine is licensed or scheduled, and the Ebola (Zaire) vaccine does not protect against Marburg.

The main cause of shock and death is fluid and electrolyte loss from the profuse vomiting and diarrhoea of the wet phase, not exsanguination.

Frank haemorrhage is usually a late and minor feature, and the other mechanisms are not the primary cause.

No vaccine or specific treatment is licensed for Marburg disease, so aggressive supportive care is the mainstay, above all fluid and electrolyte replacement.

Unlike Zaire ebolavirus disease, no monoclonal antibody or antiviral is licensed, and ribavirin and interferon have no established role.

Lassa virus is maintained by the multimammate rat Mastomys natalensis, a peridomestic rodent that sheds virus in urine in and around houses.

The house mouse is the lymphocytic choriomeningitis reservoir, Calomys rodents carry the New World agents, and ticks and bats are not arenavirus reservoirs.

Aggressive replacement of fluid and electrolytes, matching the losses from vomiting and diarrhoea, is the backbone of care and reduces mortality on its own, independent of any specific drug.

Antibiotics, corticosteroids, routine transfusion and ribavirin are not the primary intervention.

The true intracellular receptor for filoviruses is Niemann-Pick C1 (NPC1), reached deep in the endosome after the glycoprotein is cleaved.

DC-SIGN is an attachment factor rather than the receptor, and angiotensin-converting enzyme 2, CD4 and sialic acid are receptors for other viruses.

The incubation period is about 2 to 21 days, most often 5 to 10 days, after which illness begins abruptly.

It is not a matter of hours, one to two days, several months or over a year.

Ervebo is a single-dose live recombinant vesicular stomatitis virus carrying the Zaire glycoprotein.

It is not an inactivated, subunit, DNA or mRNA vaccine.

Confirmatory VHF testing is done only at the National Institute for Communicable Diseases (NICD) reference laboratory, the Special Viral Pathogens Laboratory, the only biosafety level 4 facility in Africa.

Routine, hospital, private and provincial laboratories may run supporting tests under precautions but do not perform VHF confirmation.

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.

Crimean-Congo haemorrhagic fever virus spreads from patient to staff through blood and body fluids and has caused documented nosocomial outbreaks, so suspected cases need barrier nursing and viral haemorrhagic fever isolation.

The mosquito-borne dengue, West Nile, Sindbis and chikungunya viruses do not spread from person to person.

Inmazeb and Ebanga, two antibody products against the Zaire glycoprotein, were shown effective in the PALM trial and are licensed for Zaire ebolavirus disease.

Ribavirin, favipiravir and oseltamivir have no established role, and ZMapp was superseded by the two licensed antibodies.

Lujo virus is the arenavirus that emerged within southern Africa, in the 2008 Johannesburg nosocomial cluster, and like the other haemorrhagic arenaviruses it is handled at biosafety level 4.

Junin, Guanarito and Machupo are New World agents of the Americas, and Tacaribe is a non-pathogenic bat-associated virus.

Lassa virus is the arenavirus most noted for person-to-person and nosocomial transmission, through contact with infected blood and body fluids.

Lymphocytic choriomeningitis, Tacaribe, Latino and Mopeia viruses are not significant causes of human-to-human spread.

The genome is a single molecule of negative-sense, non-segmented RNA of about 19 kilobases, the largest of the nonsegmented negative-strand RNA viruses, with the gene order NP, VP35, VP40, GP, VP30, VP24, L.

It is not positive-sense, segmented, DNA or ambisense; segmented and ambisense genomes belong to the arenaviruses and bunyaviruses.

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.

Spills of blood and body fluids are treated with 0.5% chlorine (5,000 parts per million), left in contact for at least 30 minutes.

The weaker 0.05% solution is for skin and lightly soiled items; the other concentrations are wrong.

Fever with sore throat, retrosternal pain and proteinuria is the combination most predictive of Lassa fever, since no single feature is specific.

The other clusters point instead to hepatitis, a herpes or enteroviral illness, cholera and rheumatic fever.

A non-itchy maculopapular rash appearing around the fifth day of illness is characteristic of Marburg disease and was noted in the original 1967 cases.

It is not a vesicular dermatomal rash, rose spots, a migratory erythema or palmar desquamation.

VP40 is the matrix protein: it lines the envelope, organises assembly and drives budding of progeny filaments through the host ESCRT machinery, and can release particles on its own.

VP35 is the polymerase cofactor and an interferon antagonist, VP30 the transcription activator, VP24 a nucleocapsid-associated interferon antagonist, and NP the nucleoprotein.

Reston ebolavirus infects pigs and macaques in Asia but has caused no human disease.

The Zaire, Sudan and Bundibugyo species cause large lethal outbreaks, and Taï Forest ebolavirus caused a single non-fatal human case.

Taï Forest virus has caused one recorded human infection, which was non-fatal, in an ethologist who autopsied a chimpanzee in Côte d’Ivoire in 1994.

Sudan and Bundibugyo viruses cause severe epidemic disease, Reston is non-pathogenic in humans, and Bombali is known only from bats.

Bombali virus was identified in insectivorous bats in Sierra Leone in 2018, the first ebolavirus described from its animal host before any human infection was known.

Reston, Sudan, Zaire and Taï Forest viruses were each first recognised through disease in humans or non-human primates.

Marburg outbreaks classically follow entry into caves or mines harbouring Egyptian rousette fruit bats, the exposure shared by affected miners and by cave-visiting tourists.

It is not acquired from mosquito or tick bites, undercooked pork, or freshwater exposure.

Unlike the Old World arenaviruses, Junin and Machupo cause disease in their Calomys rodent hosts, including haemolytic anaemia and reduced fertility, which helps regulate the shedding population.

Arenaviruses are rodent-borne rather than tick-borne, are shed in urine, establish persistent infection, and use rodents rather than bats as reservoirs.

The RVFV small (S) segment is ambisense, encoding the nucleocapsid protein in one orientation and the non-structural NSs from the opposite-sense strand.

The genome is otherwise negative-sense, tripartite RNA, not DNA, positive-sense, circular or unsegmented.

A raised aspartate aminotransferase (AST) above about 150 IU/L, together with a high viral load, marks a high risk of death in Lassa fever.

The other findings are not recognised markers of severity.

A history of maternal contact with wild or pet rodents in pregnancy should prompt consideration of congenital LCMV when the standard congenital-infection screen is negative in an infant with hydrocephalus and chorioretinitis.

The other exposures point elsewhere or are irrelevant.

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.

Lassa virus, like the other Old World arenaviruses, enters cells by binding alpha-dystroglycan.

Transferrin receptor 1 is the receptor for the pathogenic New World arenaviruses, not Lassa; the remaining options serve unrelated viruses.

A failure to mount an early type I interferon response is linked to severe and fatal disease, and those who die often fail to make RVFV-specific antibody.

A brisk innate response followed by neutralising antibody is the correlate of protection.

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.

Late complications reflect viral persistence in immune-privileged sites and include orchitis, uveitis, and rare relapse as meningoencephalitis, alongside a broader convalescent syndrome.

Chronic hepatitis, progressive dementia, nephrotic syndrome and pulmonary fibrosis are not characteristic.

Zabdeno (Ad26.ZEBOV) followed by Mvabea (MVA-BN-Filo) is a two-dose prophylactic regimen, suited to preventive protection of at-risk groups, in contrast to the single-dose rVSV vaccine Ervebo used reactively in outbreaks.

There is no licensed inactivated, mRNA or live-attenuated whole-virus Ebola vaccine.

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.

Negative-pressure ventilation is not required: South African experience across more than two hundred patients shows that standard isolation without it is adequate.

An ante-room, contact observation, chlorine decontamination and barrier nursing are all part of safe management.

Crimean-Congo haemorrhagic fever is the commonest indigenous VHF in South Africa, with fewer than 10 cases a year, chiefly in the Northern Cape and Free State.

Lassa, Marburg and Ebola are imported rather than indigenous, and Rift Valley fever appears only in epidemic years.

The admission or peak viral load is the most consistent predictor of death, with acute kidney injury and central-nervous-system involvement also marking a poor prognosis.

Age, rash, fever height and sex are far weaker predictors of outcome.

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.

The most direct primary-prevention measure is avoiding entry to caves and mines that harbour rousette fruit-bat colonies, or using protection when entry is unavoidable, because these are the sites of spillover.

Bed nets, water chlorination, household rodent control and vaccination do not address the bat-cave route.

Marburg virus uses VP40 to block the JAK-STAT pathway, disabling the cell’s response to interferon, whereas the ebolaviruses use VP24 to block STAT1 nuclear import; both genera use VP35 to prevent interferon being made.

VP35, VP24, VP30 and NP do not carry out Marburg’s JAK-STAT block.

Like other bunyavirals, CCHFV has no matrix protein. Inside the envelope the three genome segments exist as ribonucleoproteins, each coated by nucleocapsid protein and bound to the L polymerase.

Gn and Gc form the surface spikes, so all four of the other proteins are present.

Overt haemorrhage occurs in only a minority of patients and is usually a late sign, reflecting consumptive coagulopathy and thrombocytopenia; death is driven by fluid loss, shock and multi-organ failure.

Bleeding is not universal, does not arise from a single organ, and is not due to direct endothelial lysis.

Patients are not infectious during the incubation period, and infectiousness rises with the viral load, so the sickest patients and freshly deceased bodies are the most dangerous sources.

Asymptomatic carriage does not drive transmission, infectivity is not constant, and the corpse remains highly infectious after death, which is why safe burial matters.

There is no licensed Lassa vaccine, but a recombinant vesicular stomatitis virus candidate (rVSVdeltaG-LASV-GPC) has reached advanced clinical trials in West Africa.

Candid #1 is the Junin (Argentine haemorrhagic fever) vaccine, not a Lassa vaccine, and no Lassa subunit vaccine has been licensed.

LCMV is an Old World arenavirus, but unlike its relatives Lassa and Lujo it is not a haemorrhagic fever agent, and it is distributed worldwide rather than confined to Africa.

It is neither a New World virus nor a flavivirus, and it does not cause haemorrhagic fever.

LCMV is managed supportively, and although ribavirin has been used in severe and transplant-associated disease its benefit is not established.

There is no vaccine, aciclovir has no role, LCMV is generally handled at moderate rather than maximum containment, and the congenital injury is fixed by birth.

Treatment is supportive; unlike for Crimean-Congo haemorrhagic fever, ribavirin is not recommended for RVF, having been linked to late-onset encephalitis in animal studies, and corticosteroids are not recommended either.

No antiviral is approved for the disease.

The 2013 to 2016 West African epidemic of Zaire ebolavirus was by far the largest ever recorded, causing more than eleven thousand deaths across Guinea, Liberia and Sierra Leone.

The other outbreaks listed were far smaller.

Junin virus, the cause of Argentine haemorrhagic fever, was the first of the group identified, in the late 1950s.

Machupo followed in 1963, and Guanarito, Sabia and Chapare emerged later.

The Angolan outbreak of 2004 to 2005 was the largest and most lethal recorded, with about 252 cases and a case fatality near 90%.

The 1967 European, 2008 Ugandan tourist, Durba mining and 2024 Rwandan outbreaks were all smaller.

A clade B virus can infect people when its GP1 subunit engages the human form of transferrin receptor 1, not only its rodent host’s version.

This fit to the human receptor, rather than any of the other mechanisms, determines the capacity to spill over.

The basic reproduction number is modest, around 1.5 to 2, and transmission requires direct contact with infected fluids, so interrupting those contacts through isolation, safe burial and contact tracing halts spread.

Patients are not infectious before symptoms, herd immunity is not reached quickly, environmental stability is not the decisive factor, and most infections are symptomatic.

Lujo is the only arenaviral haemorrhagic fever to have emerged within southern Africa, in the 2008 Johannesburg outbreak, which places arenaviral haemorrhagic fever in the local differential and biosafety planning.

It is not endemic, tick-borne, vaccine-preventable or a routine cause of fever.

Immunoglobulin M can persist for months after Lassa fever, so its presence does not confirm acute infection, which is better shown by antigen detection or reverse transcription polymerase chain reaction.

IgM does develop, the virus is immunogenic, molecular testing does not require maximum containment, and malaria cross-reaction is not the issue.

Lujo virus is broadly an Old World arenavirus but a marked phylogenetic outlier, its glycoprotein so divergent that it clusters with neither the Old World nor the New World complex.

It is not a New World, reptile or Tacaribe-complex virus, and despite an almost identical syndrome it is genetically distant from Lassa.

Using LCMV, Zinkernagel and Doherty showed that cytotoxic T cells recognise viral antigen only alongside self-MHC molecules, the principle of MHC restriction, for which they received the Nobel Prize.

The other concepts were established in different systems.

• Marburg virus was recognised first, in 1967, when laboratory workers in Marburg and Belgrade were infected by imported African monkeys.
• The ebolaviruses were recognised in 1976, in simultaneous outbreaks of the Zaire and Sudan species in central Africa.
• Distribution: both are confined to sub-Saharan Africa; Marburg spillover clusters around cave and mine exposure, while the ebolaviruses occur across the forest zones of central and West Africa, the Zaire species causing the largest outbreaks.
• Marburg virus disease and Ebola disease are otherwise clinically very similar.

Definition: ring vaccination immunises the contacts of a confirmed case, and their contacts in turn, forming a protective ring around each case rather than vaccinating the whole population.

• It targets those at highest risk, the people most likely to have been exposed, concentrating protection where transmission occurs.
• It uses limited vaccine efficiently, achieving outbreak control without the supply needed for mass vaccination.

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.

• Composition: a live recombinant vesicular stomatitis virus engineered to carry the Zaire ebolavirus glycoprotein, given as a single dose.
• Route: intramuscular injection.
• Cold chain: it requires ultra-cold storage, at around minus 60 to minus 80 degrees Celsius, which complicates field deployment.

• 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.

• Moderate risk: a VHF-compatible febrile illness with a rural or tropical exposure, or contact with animals, ticks or mosquitoes, or an indirect link to a VHF case, but no direct contact with a case and no bleeding.
• High risk: a patient either severely ill with fever and haemorrhage, or with a definite VHF exposure, such as a health worker who falls ill within the incubation window of caring for a confirmed case, or a close contact of a known case.

• Healthcare workers: contact with a patient’s blood and body fluids without adequate infection control.
• Family carers and funeral attendees: contact with the body during care and traditional burial washing.
• Hunters and people handling wildlife: contact with infected bats, primates or forest antelope through the bushmeat trade.
• Sexual partners of survivors: exposure to virus persisting in semen after recovery.

• 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.

• Immediate first aid: wash a contaminated skin wound with soap and water, encouraging bleeding, and irrigate exposed mucous membranes with water or saline.
• Report and risk-assess: notify occupational health and the reference laboratory at once for a risk assessment.
• Post-exposure vaccination: for a genuine high-risk Zaire ebolavirus exposure, the rVSV-ZEBOV vaccine is offered as soon as possible, since its benefit depends on early administration.
• Monitoring: record temperature twice daily for 21 days from the exposure, isolating and managing as a suspected case if fever or symptoms develop.

Current WHO guidance recommends offering Ervebo to pregnant and breastfeeding women in areas with an active Ebola outbreak, with informed consent and after weighing the woman’s risk of exposure. This reverses the earlier practice of excluding them, which had been criticised for denying protection to a high-risk group.

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 covers the containment level, what may be done on site, and how specimens are handled and moved.

Containment. Confirmatory testing is done only at the national reference laboratory, the sole biosafety level 4 facility in Africa; live-virus work is confined there.

On-site testing. The managing laboratory may run the essential tests to exclude other diagnoses and monitor the patient, but any aerosol-generating step is done inside a biosafety cabinet, under enhanced personal protective equipment, by a small team of experienced staff, and clinically essential tests are never withheld.

Specimen handling and transport. Specimens are Category A infectious substances, triple-packaged to UN2814 under International Air Transport Association (IATA) packing instruction 620, kept cold and not frozen, and dispatched only after prior consultation with the reference laboratory.

Inactivation. Molecular assays run on chemically inactivated samples allow safe testing at lower containment.

A complete answer covers isolation, protective equipment, decontamination, and the handling of contacts and the deceased.

Isolation. Isolate the patient in a room with an ante-room for donning and doffing protective equipment; negative-pressure ventilation is not required, as standard isolation has proven adequate in South African practice.

Personal protective equipment. A gown or coverall, a plastic apron, an N95 respirator, eye protection, a double pair of gloves and boot covers, put on and removed with a trained partner watching.

Decontamination. Chlorine at 0.5% for spills, body fluids and surfaces, and 0.05% for skin and lightly soiled items, made up fresh daily.

Contacts and the deceased. Contacts are placed under active observation; a body is disinfected, double-bagged and refrigerated pending diagnosis; and staff exposures are logged and monitored.

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.

A complete answer covers the tests, where they are done, the biosafety level and notification.

Tests. Acute infection is confirmed by reverse transcription polymerase chain reaction for viral genome and by antigen detection, with serology (fluorescent antibody test and enzyme-linked immunosorbent assay) for antibody; an early negative is backed by a convalescent sample because culture can still turn positive later.

Where and at what biosafety level. Confirmatory testing is done only at the National Institute for Communicable Diseases (NICD) reference laboratory at biosafety level 4, after prior consultation; the referring laboratory sends one clotted and one EDTA tube with the case investigation form under Category A packaging.

Notification. Marburg is notified as a Category 1 Notifiable Medical Condition through the application, alongside the hotline call.