Disease information on Lassa fever

Factsheet

Case definition

Lassa fever in humans is a notifiable disease in the European Union/European Economic Area (EU/EEA) in accordance with the case definition for viral haemorrhagic fevers defined in the Commission Implementing Decision (EU) 2018/945 of 22 June 2018 [1].

The pathogen 

Lassa mammarenavirus (Mammarenavirus lassaense) or Lassa virus (LASV) is a member of the Mammarenavirus genus, and the Arenaviridae family, which is a family of enveloped viruses with single-stranded, ambisense RNA genome. The LASV genome consists of two RNA segments (small and large) that each code for two proteins[2].

To date, seven lineages of LASV have been identified; Lineages I, II, and III from Nigeria, Lineage IV from Sierra Leone, Guinea, and Liberia, Lineage V from Cote D’Ivoire and Mali, Lineage VI from Togo, and Lineage VII from Benin [3,4]. 

LASV is a Risk Group 4 (RG-4) pathogen [5]. 

Clinical features and sequelae 

The incubation period of Lassa fever is typically six to 10 days (range 2−21 days). It has been suggested that those infected can shed infectious LASV in bodily fluids for up to three months (females), and up to one year (males) [6,7].

The spectrum of possible clinical features of Lassa fever is broad. Following infection with LASV, outcomes range from asymptomatic to fatal. The majority of infections are believed to be subclinical/mild with complete recovery and often no actual diagnosis is made. Only a minority of infections (approximately 20% of those who become infected with LASV) result in severe disease or death [8-13]. The predetermining factors for severe disease are currently not well understood. With severe infection and among hospitalised patients, the case fatality rate is high, ranging from 15−25% [14-16].

Patients affected by Lassa fever often present with an flu-like illness with fever, headache, myalgia, and gastrointestinal complaints. The clinical manifestations mostly associated with severe disease (including haemorrhagic fever) and fatal outcome are acute kidney injury and encephalitis [14-16].  Laboratory studies typically show elevated transaminases, indicating hepatitis, although acute liver failure is relatively rare [13-17]. 

The exact underlying pathology of these manifestations is unclear. Acute kidney damage is especially difficult to manage, as dialysis is often not available in LASV-endemic areas where resources are limited and/or in isolation ward settings. Encephalopathy can be both a result of metabolic causes (notably acute kidney injury and acute liver failure), and the result of direct infection of the central nervous system. In fact, some reports have suggested that LASV  isa neurotropic virus as it has been isolated from the cerebrospinal fluid of patients with neurological symptoms [18]. 

Severely ill patients exhibit a vascular leak syndrome, with pleural effusions resulting in respiratory failure, pericardial effusions and ascites, a possible cause of secondary bacterial peritonitis. These patients are at serious risk of secondary bacterial sepsis and multiple organ dysfunction syndrome (MODS). They have a high risk of death due to overwhelming inflammation and irreversible shock [19]. 

Recovery begins approximately 2−4 weeks after onset of illness. Patients can remain generally weak for extended periods, although no large formal studies have been conducted on long-term sequelae. Neurological symptoms, such as sensorineural deafness and ataxia, are frequently documented as complications [17]. 

Pregnant women are particularly vulnerable. Meta-analysis performed in 2020 estimated the absolute risk of maternal death associated with Lassa fever to be 33.73%, and adverse pregnancy outcomes are often observed [20]. Infection of the foetus may lead to intrauterine death and stillbirths [21]. 

Epidemiology 

LASV is a zoonotic virus which circulates in animal reservoirs but is capable of infecting humans. The main reservoir for LASV is the Natal multimammate mouse (Mastomys natalensis), a peri-domestic rodent [22,23]. Although M. natalensis is widely distributed across Sub-Saharan Africa, LASV has only been detected in M. natalensis trapped in West Africa. In addition, LASV has been isolated in Mus baoulei (African pigmy mouse), a species found in the West African countries of Benin and Ghana, in Hylomyscus pamfi (African wood mouse) and M. erythroleucus (Guinea multimammate mouse) which occurs in both Nigeria and Guinea [24-27]. Anti-LASV antibodies have been detected in Rattus rattus (black rat) and recently in lizards and domestic animals [18-22] in Nigeria.

It is important to note that the main LASV reservoir is absent from Europe and there is minimal information on the reservoir capacities of rodents in Europe.

Lassa fever was first documented following the death of two missionary-nurses in the village of Lassa in north-eastern Nigeria, 1969 [28]. Since its initial detection, LASV has caused sporadic outbreaks across the West African region, often showing a seasonal pattern [29]. These outbreaks are difficult to quantify due to diagnostic and surveillance systems not being fully implemented across the region, and other infections with similar symptoms being present. The largest outbreak (in Nigeria, 2018) had about 400 cases reported [29].

Lassa fever cases have been imported to Europe, both in returning travellers and repatriated cases, although to date, there have been no locally-acquired cases reported. A map of the geographical distribution of Lassa fever in West Africa is maintained on the World Health Organization (WHO) Lassa fever page [30].

Transmission

Spill-over of LASV from rodents to humans occurs as a result of exposure to the excretions of infected Mastomys, or unknown intermediate hosts. There are different transmission modes for LASV:

  • Ingestion: consuming food or drinking water contaminated with the urine or faeces of infected rodents or consuming undercooked rodent meat.
  • Inhalation: breathing in particles of contaminated rodent urine or faeces suspended in the air, especially in areas with poor ventilation.
  • Mucocutaneous transmission: inoculation through injured skin or mucosal surfaces (e.g. through contaminated needles or other sharp devices, or the bites of infected rodents).
  • Sexual transmission: there is evidence that LASV can be transmitted sexually, although this is not the primary route of transmission [31].
  • Mother-to-child transmission: pregnant women can pass the virus to their unborn babies, which often results in severe complications [32].

The main risk situations for LASV infection are:

  • Direct contact with rodents: handling infected rodents or coming into contact with their blood, urine, or faeces (including preparation of rodents for human consumption).
  • Direct contact with bodily fluids of infected persons: exposure to the blood, tissue, urine, faeces, or other bodily fluids of an infected person, particularly in the late stages of the illness.
  • Contaminated medical/laboratory equipment: using needles, syringes, or other medical instruments that have not been properly sterilised and have been in contact with the virus.
  • Caring for infected individuals: healthcare workers and family members who provide care for Lassa fever patients without applying proper protective measures are at increased risk.

LASV transmission through sexual contact has been documented, and LASV has been detected in the seminal fluid of survivors [31]. The most comprehensive study to date shows the persistence of infectious LASV in seminal fluid, which implies a risk of LASV being sexually transmitted. Safe sex practices (one year for male survivors and three months for female survivors) after discharge from the hospital can reduce the risk of sexual transmission [7]. Further research on the potential sexual transmission of LASV is needed [31]. 

LASV shows shorter persistence on surfaces than previously assessed enveloped virus surrogates and priority pathogens, and longer persistence in some aqueous solutions. A study from 2007 suggests LASV in biological samples can remain viable for over 30 days [33,34]. However, a similar study from 2020 showed that, when incubated (19−22oC) in rat blood in a closed tube, LASV was only viable for 48 hours (possibly longer) [35]. LASV is susceptible to various methods of disinfection, including 0.5% sodium hypochlorite, phenolic compounds with detergent (0.5% phenol), 10% formalin, and 3% acetic acid (15-minute exposure time) [6,34]. 

LASV can be inactivated using a variety of protocols and inactivation buffers [6,34,36-39].

Diagnostics

Given the similarity of Lassa fever symptoms to symptoms caused by other infectious diseases, differential diagnosis is essential. Healthcare providers should consider and rule out other diseases, such as malaria, dengue, typhoid fever, and other viral haemorrhagic fevers (e.g. Ebola virus disease, Marburg virus disease). A thorough patient history, including travel history and exposure risk factors, is critical in guiding the diagnostic process.

LASV is a risk-group 4 pathogen and patient samples and the virus (e.g. virus isolation, propagation) should be handled with strict adherence to the appropriate biosafety protocols to prevent infection [5].

Reverse-transcription polymerase chain reaction (RT-PCR) is typically the first option for diagnosis of an LASV infection and both laboratory-developed tests (LDTs) and commercially available assays are available [40-42]. LASV can be detected in blood, saliva (including throat swabs), urine, cerebrospinal fluid (CSF), or pleural fluid. LASV can be propagated in cell culture (typically Vero E6 cells). Viral culture from organ samples (liver, spleen, lung, kidney, heart, and placenta) of fatal cases may be positive [43]. 

Antibodies and virus antigens can be detected using different assays. The routine method is LASV antigen detection, or IgM and IgG antibody detection, along with clinical symptoms. Most current serology tests for LASV target the nucleoprotein (NP) or glycoprotein (GP) antigens [44]. 

Laboratory diagnosis of LASV infection encompasses a wide range of assay complexity, quality/reliability, and infrastructure requirements. Mazzola and Kelly-Cirino summarise the different diagnostic infrastructure requirements for different types of LASV diagnostic tests, as well as information on LDTs (both NAATs and serological and antigen tests for LASV) [42]. 

LASV has a large amount of lineage diversity linked to its geographical distribution, and this diversity must be considered in the choice of PCR primers/probes and serology antigens. Continued (re)-evaluation of assays is important as new lineages are revealed and new mutations occur [40,41].

Case management and treatment

Managing Lassa fever cases requires not only effective clinical treatment but also coordinated public health efforts to contain the disease, prevent transmission, and mitigate the impact of outbreaks[45,46].

There is currently no vaccine that protects against Lassa fever, although there are trials ongoing [47]. Ribavirin (a broad-spectrum antiviral) is commonly used for treatment of Lassa fever and is currently a component of the standard care. However, the mechanisms, effects, and overall efficacy of Ribavirin in treating Lassa fever have not been studied in sufficient detail [48]. Patients should also receive supportive care (including, but not limited to, oral or intravenous fluid therapy, analgesics, oxygen, renal replacement therapy, mechanical ventilation and treatment of any other symptoms). Different regimens of ribavirin and support care can be used depending on age, pregnancy status, and health context/physicians decision [11]. 

Public health prevention and control measures (for the authorities)

Control of the Mastomys rodent population is inappropriate or inefficient in LASV endemic areas, so measures focus on keeping rodents out of homes and food supplies, encouraging effective personal hygiene, storing grain and other foodstuffs in rodent-proof containers, and disposing of garbage far from the home to help sustain clean households [33]. Stigma in regions where Lassa fever is endemic can discourage people from seeking treatment or reporting symptoms. Public health messaging should aim to reduce fear and promote supportive behaviour toward those affected by the disease. For effective outbreak control, public health authorities must engage with communities to provide accurate information on transmission risks and prevention to reduce fear and misinformation [49]. 

Lassa fever is a notifiable disease in most countries due to its potential for outbreaks. Healthcare providers must promptly report probable and confirmed cases to public health authorities to trigger an appropriate response. Early notification will make it possible to initiate timely contact tracing, assess the risk of further spread, and implement control measures. At population level, the most effective control measure is the dissemination of information to residents and visitors in LASV-endemic areas.

When carrying out work either in endemic or non-endemic countries that may involve contact with infectious material, protective clothing, a face mask and gloves must be worn.

An important goal of Lassa fever outbreak control in both endemic and non-endemic countries is to interrupt direct human-to-human transmission. Outbreak control activities are based on:

  • the early identification of infections through timely and comprehensive contact tracing;
  • systematic and rapid isolation of cases and contact monitoring;
  • appropriate infection prevention and control (IPC) measures.

IPC measures are to be applied both in healthcare facilities (as specified below) and in households. They include cleaning and disinfection of infectious materials (e.g. bedding and other fomites), use of personal protective equipment with cases and contacts, safe and dignified burial for Lassa fever cases, and preventive measures for cases (e.g. work restrictions and condom use during sex).

In previous outbreaks or for travel-related cases, isolation of infected patients, comprehensive contact monitoring (involving high- and low-risk contacts) and the implementation of appropriate IPC measures has been shown to effectively stop the spread of virus [50-52].

Early and culturally relevant community engagement and social mobilisation is essential for the support of outbreak response activities in endemic regions. Information given to the affected populations should focus on the risk factors of viral infection and the individual protective measures that they can adopt.

Infection control, personal protection and prevention (for health facilities)

Healthcare workers can be infected while treating patients with suspected or confirmed Lassa fever. This occurs through close contact with patients or fomites where IPC measures are not strictly implemented, or viral aetiology has not yet been recognised or diagnosed [14].

The appropriate use of IPC and the application of strict barrier nursing procedures are critical to preventing nosocomial transmission. Implementation of appropriate infection control measures in healthcare settings, including use of personal protective equipment, will minimise the risk of LASV transmission.

The risk of LASV transmission is particularly high in aerosols [53,54]. This must be taken into account when processing material in the laboratory and during medical procedures in which aerosols can be generated.

Advice to travellers

Travellers planning to visit areas with known circulation of LASV should consult a travel health specialist in order to be aware of the risk of infection and ways in which to mitigate exposure to the virus. Prevention of Lassa fever relies primarily on promotion of good ‘community hygiene’ which discourages rodents from entering homes or shelter.

All travellers to Lassa fever endemic areas should:

  • avoid contact with any person who appears to have Lassa fever symptoms;
  • avoid contact with blood and bodily fluids and/or items that might have been contaminated with blood and body fluids;
  • avoid areas where there is possible contamination from rodent urine or droppings;
  • avoid eating, cooking or preparing any meat from an unknown source;
  • store food in rodent-proof containers;
  • always wash and peel fruit and vegetables carefully;
  • follow good food, water and personal hygiene advice, including careful, regular hand washing with soap and water;
  • when attending funerals, avoid all contact with the deceased, including their body fluids and personal property.

Field and agricultural workers, aid workers and health professionals planning to undertake humanitarian work in areas where Lassa fever is endemic should seek advice and training, and obtain personal protective equipment from their employer/organisation prior to travel. Travellers to affected areas should be aware of the signs and symptoms of Lassa fever and consult a health specialist if they become ill, highlighting their travel history (and possible exposure to the virus).

Disclaimer: travel health physicians and travellers should always first consult national travel guidelines and recommendations as the primary source of information.

References

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