Lassa fever – Information Sheet

1. Background and Context

a. Epidemiology

Lassa fever (LF) is a viral haemorrhagic fever, endemic to West Africa. The illness was discovered in the 1950s in Nigeria and Lassa Virus (LASV) was first identified in 19691. LASV a member of the virus family Arenaviridae is a single-stranded RNA virus and is zoonotic, or animal-borne2.

Lassa Virus is sustained in nature in chronically infected rats3. The predominant host of LASV is Mastomyces natalensis, the commonest rat in rural West Africa, frequently found in households3. The virus is shed in rat’s urine, faeces, and respiratory secretions and is found in blood3.

Lassa fever is known to be endemic in Benin (where it was diagnosed for the first time in November 2014), Ghana (diagnosed for the first time in October 2011), Guinea, Liberia, Mali (diagnosed for the first time in February 2009), Sierra Leone, and Nigeria, but probably exists in other West African countries as well1. It is estimated that 37.7 million people live in the area at risk of transmission in West Africa4. The prevalence of antibody to Lassa virus ranges from 7% in Guinea and 15–20% in Sierra Leone and Liberia; and to over 20% in Nigeria5. These regions are also endemic to other haemorrhagic fever viruses, including Ebola, complicating the differential diagnosis of suspected cases. LF has the potential to cause tens of thousands of deaths in humans6. Even after recovery, the virus remains in body fluids, including semen3.

Transmission

Humans usually become infected with Lassa virus from exposure to urine or faeces of infected rats. Humans can also become infected by inhaling dust contaminated with the virus, or by eating the rat3. There is no epidemiological evidence supporting airborne spread between humans1,3. Lassa virus may be spread between humans through direct contact with the saliva, blood, urine, or pharyngeal secretions of a person infected with Lassa fever (during the acute febrile phase)1. The risk of transmission begins with symptom onset and increases with disease severity, consistent with increasing viral load3. Person-to-person transmission occurs in both community and health-care settings, where the virus may be spread by contaminated medical equipment, such as re-used needles1. The virus is shed in the urine for 3–6 weeks, and up to 3 months in semen3, with sexual transmission reported1.

Lassa fever occurs in all age groups and both sexes1. Persons at greatest risk are those living in rural areas where Mastomys are usually found, especially in communities with poor sanitation or crowded living conditions1. Health workers are at risk if caring for Lassa fever patients in the absence of proper barrier nursing and inadequate infection prevention and control practices1.

Groups at high risk of infection1,3
  • Healthcare Workers(HCW)
  • Family members handling infected patients/ secretions/ excretions
  • Laboratory workers processing specimens/ working in research facilities
  • People in contact with or working with rodent reservoirs in endemic areas

b. Pathophysiology

The pathogenesis is not clearly understood and is related to immune suppression, uninhibited viral proliferation and host responses3,7. Microvascular instability and impaired haemostasis are the pathophysiologic hallmarks of LF and the VHFs7. However, unlike other VHFs, LF does not present with a marked increase in cytokine production/response also called a “cytokine storm”3.

Host immune responses to infection have a profound and direct influence on the disease course and outcomes and are not well understood8. LASV inhibits host immune responses by directly suppressing interferon production3.Cellular immunity is considered to be an important feature of pathogenesis, with strong T cell responses in survivors3,7.

Sensorineural hearing loss is a frequent complication of LF and the suggested pathologic mechanism for hearing loss is damage to the inner ear hair cells and auditory nerve9.

c. Virology

Phylogenetic studies point to LASV being a very old virus10, which is highly heterogeneous and constantly evolving10. The genetic diversity of LASV is not completely understood. Over the years LASV has spread across West Africa and this migration has been accompanied by mutations in the genome and associated changes in fatality rates10.

d. Clinical Presentation

Incubation period

The incubation period is usually 7–10 days, with a reported range of 3–21 days3.

Case fatality rate

Twenty percent of cases have a severe disease, requiring hospitalisation, while 80% have a mild or asymptomatic infection3. The general case fatality rate is estimated at 1–2 %3. In Africa, amongst those who develop severe disease (hospitalised patients), the case fatality rate is 15 - 20%3,11. Reported case fatality rates may be higher during outbreaks - in 2016 the WHO reported a higher CFR11.

Groups at high risk of death3,12
  • Female gender
  • Pregnancy, especially in the third trimester
  • Elderly
  • Children <18years

Reasons for the heterogeneity in severity are largely unknown, although differences in route and dose of infection, underlying comorbid illnesses, and genetic predisposition have been postulated.

Clinical Manifestations

Table 1 summarises the features of Lassa fever at different stages of the disease.

Table 1: Clinical stages of Lassa fever adapted from WHO 201613 and McCarthy 200214.
Stage / Symptoms and Signs
1 (days 1-3) / General weakness and malaise
high fever >39°C, constant with peaks of 40-41°C
2 (days 4-7) / Sore throat (with exudative white patches) very common
Exudative pharyngitis3
Throat pain3
Headache
Myalgia
Abdominal pain
Retrosternal chest pain
Productive cough
Diarrhoea
Nausea and vomiting
Hypotension (systolic <100mmhg)
Lymphadenopathy3
Conjunctivitis
Anaemia
Maculopapular rash3
3 (after 7 days) in patients who progress to severe disease / Facial oedema
Hypovolemic shock3
Pulmonary oedema3
Pleural effusion3
Ascites3
Renal failure
Haemorrhage (found in 17 % of cases only3) - mucosal bleeding (mouth, nose, eyes) and internal bleeding
Neurological signs such as confusion, disorientation and seizures
4 (after 14 days) / Coma and death
Post-Acute Complications3 / Sensorineural deafness (13.5 % of acute cases and predicting a worse outcome, after recovery, a third of patients will have SNHL, irreversible in two-thirds of them3)
Pericarditis
Arrhythmia
Pancytopenia
Renal failure
Meningitis
Encephalitis
Encephalopathy
Cerebellar ataxia.
Clinical predictors for death3,7
  • age of <18 years or elderly
  • neurological involvement
  • pharyngitis
  • vomiting
  • aspartate transaminase (AST) level above 110 IU
  • haemorrhagic signs
  • Plasma viral load of more than 103.6 TCID50 (50% tissue culture infective dose).

LF tends to be more severe during pregnancy, mainly in its late stages, with fatality rates of up to 50% and foetal loss in 75–100 % of cases. Uterine evacuation can lead to dramatic improvement.

Clinical Laboratory findings

These include transaminitis, early leukopenia followed by neutrophilia, anaemia and depression in platelet numbers and function3. Coagulation studies are usually normal3. Urine analysis may demonstrate proteinuria. High AST and viral load are predictors of mortality.

Laboratory Diagnosis

Testing is available only in reference laboratories1, found in the following locations for the Western African region.

Lassa fever is most often diagnosed by using enzyme-linked immunosorbent serologic assays (ELISA), which detect IgM and IgG antibodies as well as Lassa antigen2. Reverse transcription-polymerase chain reaction (RT-PCR) can be used in the early stage of disease2. The virus itself may be cultured in 7 to 10 days, but this procedure should only be done in a high containment laboratory with good laboratory practices2. Immunohistochemistry, performed on formalin-fixed tissue specimens, can be used to make a post-mortem diagnosis2. Antigen detection tests can also be used to diagnose LF1.

Differential diagnosis

The clinical presentation of LF is very similar to other common and endemic African diseases, such as malaria, typhoid fever, rickettsial infections and influenza3. It should also be differentiated from other diseases like Ebola and Marburg haemorrhagic fevers, diphtheria, legionella, yellow fever, Crimean-Congo haemorrhagic fever and many more5.

e. Current Management of LF

Clinical Management

The mainstay of treatment for LF is supportive treatment and Ribarivin1,2.

  • Specific treatment: Ribavirin within 6 days of onset of illness given IV for 10 days13
  • Supportive treatment: fluid management, temperature control etc13.
Prevention and Control
  • No vaccine currently available1.

General:

  • Rodent control1,2.
  • Good community hygiene to discourage rodents from entering homes1.
  • Effective measures include storing grain and other foodstuffs in rodent-proof containers, disposing of garbage far from the home, maintaining clean households and keeping cats1.
  • Family members should always be careful to avoid contact with blood and body fluids while caring for sick persons1.
  • Condom use/ protected sexual intercourse until 3months post infection or until virus cleared from semen3.

Hospital related – Infection Prevention and Control (IPC):

  • Isolation of the patients1.
  • Basic hand hygiene, respiratory hygiene1.
  • Use of personal protective equipment (to block splashes or other contact with infected materials)1.
  • Safe injection practices and safe burial practices1.
  • When in close contact (within 1 metre) of patients with Lassa fever, health-care workers should wear face protection (a face shield or a medical mask and goggles), a clean, non-sterile long-sleeved gown, and gloves (sterile gloves for some procedures)1.
  • Samples taken from humans and animals for investigation of Lassa virus infection should be handled by trained staff and processed in suitably equipped laboratories under maximum biological containment conditions1.

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2. Summary of previous studies/trials and Details of possible treatments/therapies

Drug / Drug type / Mode of action / In vitro efficacy for Lassa / Animal efficacy for Lassa / Non-human Primate efficacy for Lassa / Drug tested in humans / Drug tested in Lassa infected humans / CI or precautions / Adverse events / Approval status / Comments
Ribavirin / guanosine analogue15 / Broad-spectrum of antiviral activity.
Mechanism of action differs depending on virus15. / Yes / Yes. 160 mg/kg per day from days 4 to 11 postinfection, significantly prolonged survival in 20% of LASV infected mice16. / - / Yes
Tested on different viruses such as HCV, VHFs etc. / Yes
Most effective if begun within 6 days of illness onset17,32 / Pregnancy Lactation (teratogenic and embryotoxic in rodents15). / Dose dependent haemolysis, appearing in approximately 20 % of patients, usually resulting in a modest decrease in haematocrit17. / Approved for VHFs18. / Ribavirin was found to have a cell-protective effect in mice compared to Favipiravir16.
There is no evidence to support the role of ribavirin as post-exposure prophylactic treatment for LF19.
the drug has not demonstrated great efficacy in treating advanced LF19
Favipiravir / purine nucleoside analogue20,
broad spectrum activity against RNA viruses / inhibiting the viral RNA-dependent RNA polymerase (RdRp)20 / Yes / Yes. 300 mg/kg per day from days 4 to 11 postinfection,
prevented death in 100% of LASV infected mice16.
Effective even when started 9days post infection in guinea pigs21 / - / Phase-2 completed (influenza) and phase-3 ongoing (influenza22 / No / Pregnancy Lactation
Contraception is required at the end of treatment in women of childbearing age23. / - / Approved in Japan for novel and re- emerging influenza viruses22 / synergistic interaction between Favipiravir and Ribavirin in vitro, increased survival rate and extended survival time when combining suboptimal doses in vivo16.
Convalescent Plasma (CP) / Blood Products / Stimulation of passive immunisation / Yes
In vitro studies in monkeys shows protect-tion24,25. / Yes. In guinea pig model also provided protection if given early26. / Human convalescent plasma protected recipient monkeys24,25 / Yes / Yes
Conflicting reports. No effect17
Limited efficacy however geo-graphically matched plasma seems to be more effective24. / Risk of transfusion-transmitted infections27
Requires convalescent patients for donation / Transfusion reactions. Blood borne viruses / N/A / Lack of high-quality studies (i.e. randomised clinical trials)
short window of efficacy19
in combination with ribavirin, has been shown to be protective in nonhuman primates infected with LASV24,25.
Interferon
IFN alfacon-1 / Non-naturally occurring bio-engineered alpha interferon28 / modulation of host innate immune responses20 / No / No. In a hamster model of Pichinde virus (PCV) infection, treatment significantly protected animals from death, prolonged the survival of those that eventually died, reduced virus titers28 / Yes. In LASV infected monkeys, early and strong immune responses and control of viral replication were associated with recovery, whereas fatal infection was characterised by weak immune responses and uncontrolled viral replication29. / Yes for HCV / No / ?Pregnancy / Systemic toxicity when given as bolus20
Leucopaenia30
Thrombocyto-paenia30
Drop in haemoglobin
Psychiatric adverse events30 / Approved for treatment of chronic hepatitis C 28 / Combining suboptimal doses of ribavirin (5-10 mg/kg/day) with IFN alfacon-1 (5-10 µg/kg/day) was found to have both additive and synergistic effects when administered within 24 hours after virus challenge with Pichinde virus (an arenavirus) in hamsters31.
IFN alfacon-1 treatment was more effective when delivered intranasal compared to delivery by i.p. injection20

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References

1. World Health Organization (WHO). WHO | Lassa fever [Internet]. WHO. World Health Organization; 2017 [cited 2017 Feb 9]. Available from:

2. US Centers for Disease Control and Prevention. Lassa Fever | CDC [Internet]. CDC. 2015 [cited 2017 Feb 10]. Available from: https://www.cdc.gov/vhf/lassa/index.html

3. Brosh-Nissimov T. Lassa fever: another threat from West Africa. Disaster Mil Med [Internet]. 2016;2(1):8. Available from:

4. Mylne AQN, Pigott DM, Longbottom J, Shearer F, Duda KA, Messina JP, et al. Mapping the zoonotic niche of Lassa fever in Africa. Trans R Soc Trop Med Hyg [Internet]. 2015 Aug [cited 2017 Feb 10];109(8):483–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26085474

5. Ogbu O, Ajuluchukwu E, Uneke CJ. Lassa fever in West African sub-region: An overview. J Vector Borne Dis. 2007;44(1):1–11.

6. Richmond JK, Baglole DJ. Lassa fever: epidemiology, clinical features, and social consequences. BMJ Br Med J [Internet]. 2003;327(7426):1271–5. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC286250/

7. Khan SH, Goba A, Chu M, Roth C, Healing T, Marx A, et al. New opportunities for field research on the pathogenesis and treatment of Lassa fever. Antiviral Res. 2008;78(1):103–15.

8. Shao J, Liang Y, Ly H. Human hemorrhagic Fever causing arenaviruses: molecular mechanisms contributing to virus virulence and disease pathogenesis. Pathog (Basel, Switzerland) [Internet]. 2015 May 21 [cited 2017 Feb 9];4(2):283–306. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26011826

9. Yun NE, Ronca S, Tamura A, Koma T, Seregin A V, Dineley KT, et al. Animal Model of Sensorineural Hearing Loss Associated with Lassa Virus Infection. J Virol [Internet]. 2015 Dec 30 [cited 2017 Feb 9];90(6):2920–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26719273

10. Andersen KG, Shapiro BJ, Matranga CB, Sealfon R, Lin AE, Moses LM, et al. Clinical Sequencing Uncovers Origins and Evolution of Lassa Virus. Cell [Internet]. 2015 Aug 13 [cited 2017 Feb 10];162(4):738–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26276630

11. World Health Organization (WHO). Weekly epidemiological record Relevé épidémiologique hebdomadaire. 2016 [cited 2017 Feb 9];21(91):265–84. Available from:

12. Bello OO, Akinajo OR, Odubamowo KH, Oluwasola TAO. Lassa Fever in Pregnancy: Report of 2 Cases Seen at the University College Hospital, Ibadan. Case Rep Obstet Gynecol [Internet]. 2016;2016(9673683):1–3. Available from:

13. World Health Organization [WHO]. Clinical management of patients with viral haemorrhagic fever A pocket guide for the front-line health worker [Internet]. February 2. 2016. 1-203 p. Available from:

14. Michael McCarthy. USA moves quickly to push biodefence research. Lancet [Internet]. 2002 [cited 2017 Feb 9];360:732. Available from:

15. Beaucourt S, Vignuzzi M. Ribavirin: a drug active against many viruses with multiple effects on virus replication and propagation. Molecular basis of ribavirin resistance. Curr Opin Virol. 2014;8:10–5.

16. Oestereich L, Rieger T, Lüdtke A, Ruibal P, Wurr S, Pallasch E, et al. Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever. J Infect Dis [Internet]. 2016 Mar 15 [cited 2017 Feb 9];213(6):934–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26531247

17. McCormick J, King I, Webb P, Scribner C, Craven R, Johnson K, et al. Lassa fever. Effective therapy with ribavirin. N Engl J Med. 1986;314(1):20–6.

18. World Health Organization (WHO). Annex 1 19th WHO Model List of Essential Medicines (April 2015) [Internet]. 2015 [cited 2017 Feb 9]. 51 p. Available from:

19. Bausch DG, Hadi CM, Khan SH, Lertora JJL. Review of the Literature and Proposed Guidelines for the Use of Oral Ribavirin as Postexposure Prophylaxis for Lassa Fever. Clin Infect Dis [Internet]. 2010 Dec 15 [cited 2017 Feb 9];51(12):1435–41. Available from:

20. Gowen BB, Bray M. Progress in the experimental therapy of severe arenaviral infections. Future Microbiol [Internet]. 2011 Dec [cited 2017 Feb 2];6(12):1429–41. Available from:

21. Safronetz D, Rosenke K, Westover JB, Martellaro C, Okumura A, Furuta Y, et al. The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset. Sci Rep [Internet]. 2015 Oct 12 [cited 2017 Feb 9];5:14775. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26456301

22. Goeijenbier M, van Kampen JJA, Reusken CBEM, Koopmans MPG, van Gorp ECM. Ebola virus disease: a review on epidemiology, symptoms, treatment and pathogenesis. Neth J Med [Internet]. 2014;72(9):442–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25387613

23. Nagata T, Lefor AK, Hasegawa M, Ishii M. Favipiravir: A New Medication for the Ebola Virus Disease Pandemic. Disaster Med Public Health Prep [Internet]. 2015 Feb [cited 2017 Feb 9];9(1):79–81. Available from:

24. Jahrling PB, Frame JD, Rhoderick JB, Monson MH. Endemic lassa fever in liberia. IV. Selection of optimally effective plasma for treatment by passive immunization. Trans R Soc Trop Med Hyg [Internet]. 1985 Jan [cited 2017 Feb 9];79(3):380–4. Available from:

25. Jahrling PB, Peters CJ. Passive antibody therapy of Lassa fever in cynomolgus monkeys: importance of neutralizing antibody and Lassa virus strain. Infect Immun [Internet]. 1984 May [cited 2017 Feb 9];44(2):528–33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6715049

26. Cross RW, Mire CE, Branco LM, Geisbert JB, Rowland MM, Heinrich ML, et al. Treatment of Lassa virus infection in outbred guinea pigs with first-in-class human monoclonal antibodies. Vol. 133, Antiviral Research. 2016.

27. Marano G, Vaglio S, Pupella S, Facco G, Catalano L, Liumbruno GM, et al. Convalescent plasma: New evidence for an old therapeutic tool? Blood Transfus. 2016;14(2):152–7.

28. Gowen BB, Barnard DL, Smee DF, Wong M-H, Pace AM, Jung K-H, et al. Interferon Alfacon-1 Protects Hamsters from Lethal Pichinde Virus Infection. Antimicrob Agents Chemother [Internet]. 2005 Jun 1 [cited 2017 Feb 9];49(6):2378–86. Available from:

29. Baize S, Marianneau P, Loth P, Reynard S, Journeaux A, Chevallier M, et al. Early and strong immune responses are associated with control of viral replication and recovery in lassa virus-infected cynomolgus monkeys. J Virol [Internet]. 2009 Jun [cited 2017 Feb 9];83(11):5890–903. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19297492

30. Melian EB, Plosker GL. Interferon Alfacon-1. Drugs [Internet]. 2001 [cited 2017 Feb 9];61(11):1661–91. Available from:

31. Gowen BB, Smee DF, Wong M-H, Pace AM, Jung K-H, Bailey KW, et al. Combinatorial ribavirin and interferon alfacon-1 therapy of acute arenaviral disease in hamsters. Antivir Chem Chemother [Internet]. 2006 [cited 2017 Feb 9];17(4):175–83. Available from: https://www.ncbi.nlm.nih.gov/labs/articles/17066896/

32. Shaffer JG, Grant DS, Schieffelin JS, Boisen ML, Goba A, Hartnett JN, et al. Lassa Fever in Post-Conflict Sierra Leone. PLoS Negl Trop Dis. 2014;8(3).

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