Approach

Lassa fever is a notifiable disease. Diagnosis is based on clinical suspicion, history, and physical examination, with laboratory testing to confirm diagnosis. Early suspicion and recognition of exposure, and rapid identification of Lassa fever are critical to the management and prevention of infection.

Isolation and personal protective equipment (PPE)

If infection is suspected, the patient should be isolated and all healthcare workers in contact with the patient should wear PPE.

The World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), and UK Department of Health (DoH) have produced detailed guidance on PPE for viral haemorrhagic fevers, including Ebola, and these should be followed for Lassa fever:

History

A detailed history, including a comprehensive travel history, should be taken to determine the risk of Lassa fever. This is particularly important in order to establish the level of protection required for healthcare workers and laboratory staff.

Lassa fever is endemic in parts of West Africa, particularly Nigeria, Sierra Leone, Liberia, and Guinea. Cases have also been reported in Ghana, Benin, Togo, Burkina Faso, and the Democratic Republic of the Congo. People living or working in endemic areas are at high risk of infection; however, recent arrival (within 21 days) from endemic areas is also an important risk factor. In non-endemic countries, cases are likely to be in people returning from travel or work in endemic areas. Attention should be paid to the seasonality of transmission. In Nigeria, there are outbreaks nearly every year throughout the country, with peaks between December and February (dry season). In Sierra Leone, the peak season is the height of the dry season (i.e., February to March) with a smaller peak in December.[12]

Direct exposure to blood or body fluids from infected rats or infected humans is the primary method of human transmission. A history of having resided in a house with evidence of rodent infestation, or where individuals have been infected previously, should be considered a risk factor for Lassa fever. The patient should also be asked about the possibility of rodent consumption.[22]

Lassa virus has been detected in the blood, urine, throat swabs, and cerebrospinal fluid (CSF) of patients, and sexual transmission has been suggested.[2][20][25] Nosocomial infections have, therefore, been described in both endemic and non-endemic settings.[26][27][28] Simple infection control measures dramatically reduce the risk of nosocomial transmission.[29] Household contacts of infected patients are at a higher risk of infection if there is active diarrhoea, vomiting, or bleeding. 

Malaria and typhoid are usually endemic in areas where Lassa fever is found, and the history should include an assessment for malaria and typhoid risk.

Clinical presentation

The incubation period for Lassa fever in humans is 3 to 21 days with a median of approximately 10 days.[4][17][18] It can present in multiple ways, but is asymptomatic or produces only mild symptoms in approximately 80% of cases.[2] Initial signs and symptoms include: 

  • Fever

  • Malaise

  • Generalised weakness

  • Headache

  • Sore throat

  • Myalgia

  • Nausea

  • Vomiting

  • Diarrhoea

  • Cough

  • Abdominal pain

  • Chest pain.

Fever was noted in all of 441 patients admitted with Lassa fever to one hospital in Sierra Leone.[4] Over 70% of these patients also experienced chest pain, diarrhoea, vomiting, and headache.

Owing to the variation and non-specific nature of signs and symptoms associated with Lassa fever, clinical diagnosis may be difficult. Less common symptoms that can differentiate Lassa fever from other causes of fever (e.g., malaria, leptospirosis, yellow fever) include a dry non-productive cough and sore throat (experienced by around 66% of patients).[4] Neurological signs such as confusion and reduced Glasgow Coma Scale (GCS) score have also been reported.[7][30]

Severe disease develops in approximately 20% of patients. Severe symptoms include haemorrhage (e.g., gums, eyes, nose, rectum, and vagina [particularly in pregnant women]); respiratory distress; repeated vomiting; facial swelling; pain in the chest, back, and abdomen; and shock. Organs such as the liver, spleen, and kidneys, can also be affected in severe disease.

Physical examination

Physical examination should be performed to identify alternative diagnoses for fever.

The following signs should be looked for:

  • Fever ≥37.5°C

  • Elevated respiratory rate

  • Low systolic blood pressure

  • Conjunctival injection

  • Inflamed swollen posterior pharynx and tonsils.

Fever is present in virtually all patients with Lassa fever. However, it may not be continuous; therefore, being afebrile on presentation does not rule out Lassa fever.

Fever, elevated respiratory rate, and low systolic blood pressure can be seen in a multitude of infectious diseases and make the diagnosis of Lassa fever challenging. The combination of known exposure and having a fever >38°C for less than 3 weeks with absence of local inflammation is required for admission to the Lassa ward in the endemic region of Sierra Leone. The absence of local inflammation is key in ruling out more common bacterial infections, for example.

Hearing loss or impairment is a unique sign that may be useful for diagnosis. It was shown to occur in around 29% of 49 acutely febrile patients with confirmed Lassa fever in Sierra Leone.[6] It has also been seen as a late consequence in survivors.[4]

Prior to the epidemic of Ebola in Sierra Leone, one large cohort study found that the combination of sore throat and vomiting selected around 90% of admitted cases, and the combination of bleeding and sore throat was the best predictor of death.[4]

There is no classical skin rash in patients with Lassa fever, and subcutaneous bleeding (ecchymosis or petechiae) is not commonly seen, but oedema of the face, neck, and jaw have been described.[4]

Reduced GCS score or seizures may indicate Lassa fever encephalopathy.[30]

One case series described the identification of Lassa fever in 7 patients who underwent abdominal surgery following presentation with abdominal tenderness with guarding or rebound, and acute surgical abdomen.[31]

In late presentation or deterioration, bleeding (17%) and effusions (3%) have been reported, the latter being linked to proteinuria.[4]

Initial investigations

Individuals admitted with fever and recent (within 21 days) travel to an endemic or epidemic area for Lassa fever should be assessed according to national protocols.

If laboratory testing is indicated, blood sample collection, packaging, and transport should be carried out according to national protocols, whilst the patient remains isolated and PPE is used. Specimens should be sent to a laboratory that is suitably equipped to handle biosafety level 4 pathogens. Furthermore, specimens should only be sent once a full risk assessment has been carried out and following discussions with the laboratory (i.e., to alert them of potentially biohazardous material), in order to minimise risk of nosocomial transmission.

The initial investigation in all suspected patients should be reverse transcription-polymerase chain reaction (RT-PCR) for Lassa virus. The highest viraemia occurs 4 to 9 days after the onset of symptoms.[17] Serological testing using IgM ELISA should also be carried out. IgM ELISA has demonstrated 88% sensitivity and 90% specificity for acute infection.[32]

If the initial laboratory investigations are negative and clinical suspicion remains high, repeating the laboratory investigations after 24 hours could be considered.

RT-PCR and IgM ELISA may not be available in some endemic areas where resource is limited. To address this issue, the ReLASV® Antigen Rapid Test has been developed as a rapid diagnostic test for Lassa fever for bedside use in resource-limited regions.[1] The test is a dipstick-style lateral flow immunoassay, based on principles akin to ELISA, which can detect Lassa virus antibodies and antigens in blood from a single finger prick. Performance against gold standard RT-PCR has demonstrated sensitivity of 76% and specificity of 98.6%. If results from the rapid antigen test are negative, RT-PCR or serology should be performed for diagnostic confirmation.

Lassa fever is usually co-endemic with malaria and typhoid; therefore, a rapid diagnostic test for malaria should be carried out immediately, along with blood cultures for typhoid. There is no reliable rapid diagnostic test available for typhoid. Co-infection with either malaria or typhoid is unusual, though not impossible, and consideration should be given to testing samples for Lassa fever whilst treating for these infections.

Other investigations

  • Serum electrolytes and renal function

    • Serum electrolyte levels are especially useful in patients with diarrhoea and vomiting, and can be used to guide correction of electrolytes and fluid replacement. Moderately elevated creatinine has been seen, probably indicating dehydration or damage from elevated creatine kinase.[4]

  • Blood lactate/ABG

    • Blood lactate, arterial or venous pH, and bicarbonate can be used to determine tissue hypoperfusion and guide fluid management.

  • FBC

    • Elevated haematocrit is usually seen and is indicative of dehydration. Thrombocytopenia has been reported.[33]

  • Coagulation studies

    • Should be performed and abnormalities corrected as necessary.

  • Liver function tests

    • Elevated alanine aminotransferase has been noted and is associated with worse outcome.[34]

  • Chest x-ray

    • Should be performed to look for pleural or pericardial effusion.

  • Urinalysis

    • Should be performed to screen for proteinuria.

  • Blood cultures

    • May be helpful in the identification of other causes of sepsis (e.g., deep abdominal infection, upper urinary tract infection, endocarditis, or discitis).

  • Lumbar puncture

    • Encephalopathy is quite common among symptomatic patients who present after more than 6 days of symptoms; however, detection of Lassa virus RNA in CSF has been rarely reported, as lumbar puncture is rarely performed in these patients.[30]

    • Lumbar puncture is not routinely recommended due to risk of transmission to healthcare workers during the procedure. It can also be particularly difficult and dangerous in encephalopathic patients who are in a state of confusion.

  • Abdominal ultrasound

    • May be considered for the investigation of intraperitoneal fluid and pericardial effusion.[18]

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