Lujo virus

Lujo virus is an Old World arenavirus known from a single outbreak: a cluster of five cases of severe viral haemorrhagic fever in southern Africa in 2008, four of which were fatal. It takes its name from the geography of that outbreak, which began in Lusaka in Zambia and was carried to Johannesburg in South Africa, and its entire clinical description rests on those five patients. No reservoir has ever been found, no natural infection has been traced to its animal source, and no further case has been recorded, so the virus remains among the most enigmatic of the recognised haemorrhagic fever agents.

Its importance is out of proportion to that single event for two reasons. It is the only arenaviral haemorrhagic fever to have emerged within southern Africa, which places it firmly in the local differential diagnosis and biosafety planning, and its discovery was a landmark of a new diagnostic era, identified within days by unbiased deep sequencing when no conventional test could name it. For a virology reference in the region where it appeared, Lujo is a small but locally defining agent.

Discovery and historical significance

Lujo virus was discovered in 2008 during a rapidly fatal nosocomial outbreak. The index patient, a woman who fell critically ill in Lusaka, was medically evacuated by air to Johannesburg, where she died of an undiagnosed haemorrhagic illness. Over the following days the disease spread to those who had cared for or been in contact with her, including a paramedic who had accompanied the evacuation and hospital staff, producing a chain of five cases of which four died.

The outbreak is a landmark in diagnostic virology because of how the agent was found. With no conventional assay returning an answer, a collaboration between the National Institute for Communicable Diseases in South Africa and a metagenomics group used unbiased high-throughput pyrosequencing to identify a novel arenavirus within days, making Lujo one of the first human pathogens ever discovered by metagenomic sequencing rather than by culture or targeted testing. The new virus was named Lujo, a contraction of Lusaka and Johannesburg, for the two cities that bracketed its transmission.

Classification, structure, and genome

Classification

Lujo virus is the species Mammarenavirus lujoense in the genus Mammarenavirus, family Arenaviridae. It is broadly an Old World arenavirus, the group that contains Lassa and lymphocytic choriomeningitis viruses, but it is a marked phylogenetic outlier: its glycoprotein in particular is so divergent that the virus clusters cleanly with neither the Old World nor the New World complex, and it differs from Lassa across a large fraction of its genome. This deep divergence, alongside an almost identical clinical syndrome to Lassa, is a reminder that the disease an arenavirus causes cannot be read off its sequence.

Virion structure

The particle is a typical arenavirus: pleomorphic and enveloped, studded with glycoprotein spikes over a lipid envelope, and carrying host ribosomes incorporated during assembly that give the family its characteristic grainy appearance.

Genome organisation

The genome follows the standard arenavirus plan, a bisegmented, ambisense, negative-sense RNA in a small and a large segment. The small segment encodes the nucleoprotein and the glycoprotein precursor, and the large segment the RNA-dependent RNA polymerase and the Z matrix protein. The glycoprotein precursor is the most divergent part of the genome and underlies the virus’s unusual receptor use.

Replication cycle

Lujo virus is unusual among arenaviruses in the machinery it uses to enter cells. Rather than the alpha-dystroglycan of the Old World viruses or the transferrin receptor 1 of the pathogenic New World viruses, its glycoprotein binds neuropilin-2 at the cell surface, and then depends on the tetraspanin CD63 in the late endosome to trigger the low-pH membrane fusion that delivers the genome to the cytoplasm. This distinct entry pathway, independent of the usual arenavirus receptor genes, matches the virus’s outlier position in the family. Beyond entry, replication follows the familiar arenavirus pattern: cytoplasmic transcription and replication with cap-snatching, and budding from the plasma membrane driven by the Z protein.

Pathogenesis

The pathogenesis of Lujo fever has not been studied directly and is inferred from a small number of patients and from the biology of related arenaviruses. As with Lassa, the likely early targets are the antigen-presenting cells of the immune system, with suppression of the innate interferon response and a resulting failure to mount timely control. Severe disease appears to reflect vascular and platelet dysfunction with increased permeability, and the observation that neuropilin-2, the virus’s receptor, is well expressed on the microvascular endothelium offers a plausible, though unproven, link to the coagulopathy and capillary leak seen in the fatal cases.

Epidemiology

The epidemiology of Lujo virus is, in effect, the story of one outbreak. The 2008 cluster of five cases is the only recognised occurrence of the virus, and every case after the index patient arose from person-to-person, hospital-based transmission rather than from an independent animal exposure. Where the index patient acquired the infection is unknown, though the geography points to Zambia. Arenaviruses are typically maintained by a single rodent reservoir, and a rodent host for Lujo is presumed but has never been identified, so its natural range, its true incidence and its potential to re-emerge all remain unknown.

Natural history

After an estimated incubation of about 7 to 13 days, the illness in the 2008 patients began without specific features and then deteriorated over roughly a week. From a nonspecific febrile start it progressed through worsening systemic illness to multiorgan failure and, in four of the five, death in the second week. The one patient who survived was treated with ribavirin early in the course, and the natural, untreated history beyond this single fatal cluster is simply not known.

Clinical presentations and complications

The clinical picture of Lujo fever is drawn entirely from the five patients of the 2008 outbreak and closely resembles severe Lassa fever. Illness began with fever, headache, malaise, myalgia, sore throat and retrosternal pain, followed within days by diarrhoea, a morbilliform rash and swelling of the face. As the disease advanced, patients developed worsening bleeding, most often gingival bleeding, petechiae and oozing from injection sites rather than torrential haemorrhage, together with respiratory failure and the acute respiratory distress syndrome, neurological deterioration with cerebral oedema, renal failure and circulatory collapse. Laboratory features included thrombocytopenia and raised transaminases, in keeping with the wider arenavirus pattern. The very high case fatality of this cluster must be read against its tiny size and its entirely nosocomial, severely exposed group of patients.

Diagnosis

Because Lujo is a maximum-containment pathogen and no commercial assay exists, diagnosis rests on reverse transcription polymerase chain reaction performed under biosafety level 4 conditions at a reference laboratory, using primers informed by the sequence recovered in 2008. Historically, the virus’s defining diagnostic feature is that it was found at all: it was identified by unbiased metagenomic sequencing when targeted testing had failed, a route that remains relevant for any future undiagnosed haemorrhagic fever. As with the other haemorrhagic fevers, malaria and the common causes of severe febrile illness must be excluded in parallel.

Management

Treatment is principally intensive supportive care, with the same cautions that apply across the arenaviral haemorrhagic fevers, including careful fluid management and attention to bleeding and organ support. The specific antiviral is ribavirin, used by direct analogy with Lassa fever; the single survivor of the 2008 cluster received it early, which is consistent with, though it cannot prove, a benefit from early treatment. No Lujo-specific therapy exists.

Prevention and public health

Vaccination

There is no vaccine against Lujo virus and none in development, which reflects the virus’s extreme rarity rather than any specific obstacle: a single historical cluster does not support a vaccine programme.

Infection prevention and control

Infection prevention and control is the central public-health lesson of Lujo, because every case after the index patient was acquired in hospital. The virus is managed under strict viral haemorrhagic fever precautions: early isolation of a suspected case, appropriate personal protective equipment, safe handling of blood and body fluids, and safe management of sharps and waste. The 2008 outbreak, in which transmission reached a paramedic and hospital staff, is the standing illustration of what happens when a haemorrhagic fever is not recognised early and these measures are not yet in place.

Post-exposure prophylaxis

By analogy with Lassa fever, oral ribavirin may be considered for a defined high-risk exposure to a confirmed case, alongside active monitoring of contacts for fever through the incubation period.

Surveillance and notification

A suspected case is a notifiable event that triggers contact tracing and monitoring. Because the reservoir and natural range of the virus are unknown, any recurrence would be an important sentinel event, and Lujo remains on the list of high-consequence pathogens for which the region maintains preparedness.

South African context

Lujo virus holds a specific place in South African virology as the only arenaviral haemorrhagic fever to have emerged within the region. Although its origin lies to the north and it has not reappeared since 2008, the Johannesburg outbreak is the reason arenaviral haemorrhagic fever belongs in the local differential diagnosis of a severe, unexplained febrile illness and in national biosafety planning. It also showcased the diagnostic capability of the country’s reference system, since the virus was characterised through the National Institute for Communicable Diseases.

A suspected case would be handled exactly as for the other viral haemorrhagic fevers, through the national viral haemorrhagic fever pathway of early recognition, strict isolation, safe specimen transport and confirmatory testing at maximum containment. Lujo haemorrhagic fever is a notifiable medical condition requiring immediate reporting on suspicion, and its management is centralised through the same referral and reference-laboratory channels used for Lassa, Marburg and the other high-consequence agents.

References and recommended reading

• Bausch DG. Arenaviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. Washington: ASM Press; 2016. The source for the 2008 outbreak, the clinical syndrome and the place of Lujo among the arenaviral haemorrhagic fevers.
• Radoshitzky SR, Buchmeier MJ, de la Torre JC. Arenaviridae: The Viruses and Their Replication. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2022. The reference for arenavirus classification, genome organisation and the neuropilin-2 and CD63 entry pathway.
• Hewson R. Understanding Viral Haemorrhagic Fevers: Virus Diversity, Vector Ecology, and Public Health Strategies. Pathogens. 2024;13(10):909. Current placement of Lujo within the haemorrhagic fever viruses and its emergence in southern Africa.