Lassa virus: Questions

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.

When the human R0 is near zero the virus cannot sustain human chains, so every case depends on fresh spillover from the reservoir, the pattern seen with Lassa fever in West Africa. Only once R0 approaches and passes one can sustained human transmission occur.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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 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.

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.

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.