WikiJournal Preprints/An overview of Lassa fever

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Article information

Author: Abdulmuttalib Musa Maibasira Orcid icon.png 

Musa Maibasira, A. 




Abstract

Lassa fever is a viral hemorrhagic fever caused by Lassa virus; the infection may be followed by a spectrum of diseases that varies from mild acute febrile illness of brief duration to a prolonged fatal disease with severe toxaemia, capillary leakage, hemorrhagic phenomena, shock and dysfunction of organ systems. Establishing a clinical diagnosis at an early stage is especially important because of the transmissibility of infection from person to person and the need for effective isolation of the patient and for containment of potentially infectious specimens during virological and clinico – pathological testing.[1]

Though first described in the 1950s, the virus causing Lassa disease was not identified until 1969 when two missionary Nurses in lassa town borno State, Northeastern Nigeria died from the infection. The virus is a single – stranded RNA virus belonging to “Arenaviridae” family. About 80% of infected persons are asymptomatic. The animal reservoir or host of lassa virus is a rodent of the genus Mastomys, commonly known as “Natal Multimammate rat” Mastomys rats infected with Lassa virus do not become ill but they can shed the virus in their urine and faeces thus infecting humans.[2]

Because of its similarities with other febrile diseases, (e.g. Malaria, typhoid etc.), early detection is difficult. Thus when patients have persistent fever not responding to normal conventional therapies, they should be screened for other possible causes (especially in endemic regions). When confirmed in a community, prompt isolation of affected patients, and screening, good infection protection and control practices and rigorous contact tracing can stop outbreaks

Pathophysiology[edit]

Lassa virus is a single stranded RNA virus that is acquired into the body through the respiratory system (as aerosols), gastrointestinal system, through broken skin and mucous membrane and sexual transmission (rare). High serum virus titres, combined with disseminated replication in tissues and absence of neutralizing antibodies (immuno - compromisation), lead to the development of Lassa fever. However the current knowledge on Lassa fever pathogenesis does not include the chains of event that take place during disease development.

One possible mechanism involved in Lassa fever pathogenesis could be infection – triggered induction of uncontrolled cytokine expression similar to what is seen in sepsis. Another possibility is that virus – induced immunosuppression may be involved in the pathogenesis of severe Lassa fever disease. Patients infected with Lassa virus produce IgM and IgG antibody isotypes. However since both immunoglobulin classes are detected in viremic patients, most likely the antibodies that are produced early in infection are not neutralizing.[3]

The main underlying feature of Lassa fever is that the vascular bed is attacked by the virus, with resultant micro - vascular damage and changes in vascular permeability. Secondary results of capillary leakage and reduced effective circulating blood volume may include increase in sympathetic tone, local tissue acidosis, anoxia and further reduction in tissue blood flow, thus generating the shock syndrome.

Pre – renal failure, lactic acidaemia, hyperkalaemia and reduced perfusion and oxygenation of vital tissue follows and progress to fatal outcome. The secondary effects of micro - vascular damage include alterations in pulmonary function due to several mechanisms.[4]

Frequency (Epidemiology)[edit]

Lassa fever frequently infects people in west Africa with about 80% being asymptomatic, studies show up to 300, 000 – 500, 000 cases annually and causes about 5,000 deaths. Lassa fever is endemic in parts of West Africa, including Sierra Leone, Liberia, Guinea, and Nigeria[5].

There also is evidence of endemicity in neighbouring countries; in 2016, 2 cases were reported in Togo[6], and 6 confirmed cases in Benin[7]. In the US on 25 May 2015, there was a confirmed case in a US returnee from Liberia[8]. In Europe, Specifically Sweden[9], Germany[10], The Netherlands[11] and United Kingdom[12], there have been previous reports of imported cases on Lassa fever in these countries, all of which where imported from west Africa.

Outbreak in Nigeria

In Nigeria, between August 2015 and 17 May 2016 there have been 273 confirmed cases of Lassa fever, including 149 Deaths in 23 states. Ten Health workers have been infected with Lassa fever of which two have died.[13]From 1 January through 25 February 2018, 1081 suspected cases and 90 deaths have been reported from 18 states in Nigeria. During this period, 317 cases have been confirmed and eight as probable, including 72 deaths (case fatality rate for confirmed and probable cases = 22%). A total of 2845 contacts have been identified in 18 states. Fourteen health care workers have been affected in six states with four deaths (case fatality rate= 29%). As of 18 February, four out of the 14 health care workers were confirmed positive for Lassa fever.

Clinical Manifestations[edit]

The incubation period ranges from 6 – 21 days. The onset of the disease is non – specific when symptomatic and usually gradual, starting with fever, general weakness and malaise. After few days, headache, sore throat, muscle pain, chest pain, nausea, vomiting, diarrhea, cough, and abdominal pain may follow. In severe cases systemic involvements occurs with the following:

Causes/Transmission:[edit]

  • Lassa virus is Zoonotic, it spreads specifically from Multimammate mice (mastomys natalensis). It is the most common mouse in equatorial Africa, Ubiquitous in human households and eaten as a delicacy in some areas. Infection occurs by exposure to rat excrement directly or indirectly via contaminated food stuffs
  • Infection can also occur by inhalation of tiny particles (aerosols) of infected materials. (meanwhile there is no epidemiological evidence supporting airborne spread between humans)
  • It is possible to acquire infection through broken skin or mucous membrane that is directly exposed to infectious materials, and through rat bites
  • Via contaminated medical equipments, such as re – used needles and improper sterilization
  • Sexual transmission of Lassa virus has been reported but not frequent.

Diagnosis[edit]

Because the symptoms of Lassa fever are so varied and non – specific, clinical diagnosis is often difficult, especially in early course of the disease. Lassa fever is difficult distinguish from other febrile disease e.g. Malaria, typhoid, influenza, relapsing fever, leptospirosis. And hemorrhagic fevers e.g. yellow fever, dengue fever, Marburg and Ebola virus etc.[15]

It is important to state that the test for Lassa fever virus must be done only in a Bio-safety level 4 Laboratories where highest level of biosafety precautions are adhered to.

Lab studies[edit]

Currently, two National Laboratories in Nigeria are supporting the laboratory confirmation PCR tests. All the samples are also tested for Ebola, Dengue, yellow fever (which have so far tested negative) [17]

Management[edit]

Supportive (Symptomatic) management[edit]

  • Bed rest
  • Close observation and monitoring
  • Serial laboratory tests
  • Analgesics ( e.g. acetaminophen, and pentazocine) when necessary
  • Tepid sponging and antipyretic drugs to reduce fever
  • Antiemetic drugs (e.g. Metoclopramide and promethazine)
  • Diuretics (e.g. furusemide) for fluid retention
  • Prompt Fluid and electrolyte replacement
  • Oxygen therapy
  • Blood transfusion
  • Management of other complications.

Specific Management[edit]

Early aggressive treatment using Ribavirin is the most effective treatment. Intravenous interferon may also be given alongside ribavirin.

Drug Pharmacology[edit]

Generic name: Ribavirin

Brand Names: Virazole, virazole, virazid, virazide, rebetol, copegus Group: Broad – spectrum antiviral nucleoside (guanosine)

Mode of action[edit]

Although the mechanism of ribavirin remains unclear, ribavirin appears to be a non – specific antiviral agent with most of its efficacy due to incorporation of ribavirin into the viral genome. When cells are exposed to ribavirin, there is reduction in intracellular guanosine triphosphate(a requirement for translation, transcription and replication in viruses). Therefore ribavirin significantly inhibits viral replication and translation by inhibiting DNA and RNA synthesis.[18]

Adult intravenous dosage[edit]

Loading dose: 30mg/kg infused over 30mins (max of 2g per dose) Post loading regimen: 17mg/kg/d divided 6hourly from day1 – day4 (max of 1g per dose). Followed by 8mg/kg/d divided 8hourly from day5 – day 10 (max of 500mg per dose).[7][9]

Adult oral dosage[edit]

Loading dose: 2000mg

Maintenance dose: 1000mg 6hourly from day1 – day4. Followed by 500mg 8hourly, from day5 – day10.[16][19]

Pediatric Use[edit]

Pharmokinetic evaluations in pediatric patients have not been performed. Safety and effectiveness ribavirin have not been established in patients below the age of 5 years. Therapy should only be started when benefits outweigh the risks.[20]

Pediatric intravenous dosage[edit]

Loading dose: 17mg/kg infused over 30mins (max of 2g per dose)

Post loading regimen: 17mg/kg/d divided 6hourly from day1 – day4 (max of 1g per dose) Followed by 8mg/kg/d divided 8hourly from day5 – day 10 (max of 500mg per dose).[20][21]

Pediatric oral dosage[edit]

Loading dose: 30mg/kg

Maintenance dose: 15mg/kg 6hourly from day1 – day4, Followed by 7mg 6hourly, from day5 – day10.[16][19]

Contraindication[edit]

Documented or known hypersensitivity, compromised renal function, or renal failure (creatinine clearance <30 ml/min), pregnancy, hemoglobinopathies (e.g. Thelassemia major, sickle cell anemia (with hemoglobin level less than 8g/dl) etc.)

Drug interaction

Ribavirin inhibits the phosphorulation of zidovudine and ostavudin.

Adverse effects[edit]

  • Hemolytic anemia: This may occur 1 – 2 weeks after initiation of therapy. It is recommended that hematocrit count (PCV) is obtained pre – treatment and at week 2 and week 4 of therapy or more frequently if clinically indicated.
  • Fatal and Non – fatal myocardial infarction have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of therapy. Patients with pre – existing cardiac disease should have electrocardiography done before treatments and should be appropriately monitored during therapy. If cardiovascular status deteriorates, discontinue therapy.
  • Hypersensitivity: e.g. uticaria, angioedema, bronchoconstriction and anaphylaxis.
  • Bone marrow suppression (Pancytopenia)
  • Unusual tiredness and weakness
  • Insomnia, depression, irritability and suicidal behavior have been reported with oral administration.
  • Ocular problems
  • Mild hepatic and renal impairment.[21]

Ribavirin in Pregnancy[edit]

Ribavirin may cause birth defects and/or death of exposed fetus. Ribavirin has demonstrated significant teratogenic and/or embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human doses of ribavirin.

Ribavirin therapy should not be started unless a report of pregnancy negative test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients (as ribavirin can be excreted via sperm). Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 Months after treatment has been stopped. Pregnancy testing should occur monthly during ribavirin therapy and for six months after therapy has stopped.

Precautions[edit]

Suspend therapy in patients with signs and symptoms of pancreatitis and discontinue in patients with confirmed pancreatitis. Perform complete and differential white blood cell count, platelet count, liver function test, TSH determination, and pregnancy test prior to beginning treatment and periodically Depression, psychosis, aggressive behavior and hallucinations may occur with oral administration, Caution should be taken in patients with history of psychiatric disorders.[16]

Note: In pregnancy the goal is to save the mother’s life, as ribavirin therapy cannot be started with pregnancy because of the risks it poses to the mother and fetus. In some cases labor must be induced to save the mother’s life after which ribavirin therapy can begin immediately especially in third trimesters.

Post Exposure Prophylaxis (PEP)[edit]

People, who come in contact with infected patients or equipment (i.e. via broken skin, mucous membrane or needle stick injuries) approximately within 2 days of exposure, are given 800mg of ribavirin daily or 400mg twice daily for 10 days. This was the proposal of (Vito et al, 2010) following their experimental research in Sierra Leone’s Lassa ward on only 25 people who were exposed to the all being negative from the virus after the prophylaxis. But there are no substantial evidences to support the effectiveness of immediate initiation of PEP.[22]

However CDC recommends placing high risk exposed individuals under medical surveillance for 21 days and treating presumptively with ribavirin if clinical evidence of viral hemorrhagic fever develops.

Prognosis[edit]

About 15 – 20% of hospitalized Lassa fever patient die from the illness. Deafness occurs in 25% of patients who survive the disease and in half of the cases hearing partially returns after 1 – 3 months. Mortality rate of pregnant women infected with Lassa fever is 80% and 95% fetal deaths. Mortality rate during epidemics can be as high as 50%.[23]

Prevention and Control[edit]

Prevention of Lassa fever relies on prompting good “Community hygiene” to discourage rodents from entering homes. Effective measures include storing grain and other foodstuffs in rodent – proof containers, disposing of garbage far from the home, maintaining clean households and keeping cats. Because mastomys rats are so abundant in endemic areas, it is not possible to completely eliminate them from the environment but it is possible to control contact with them. Family members should avoid contact with blood and body fluid while caring for sick persons and safe burial practices.

In health care settings, staffs should always apply standard infection prevention and control precautions when caring for patients, regardless of their presumed diagnosis. These include basic hand hygiene, respiratory hygiene, use of personal protective equipment (to block splashes or other contact with infected materials), Handling of laboratory samples with caution, and safe injection practices.

Proper isolation of suspected and confirmed cases of Lassa fever, good quarantine protocols, health education and rigorous contact tracing should be employed by the government and health care agencies. Drugs, equipments and appropriate expertise should also be readily available to control the spread in time.

Additional information[edit]

Competing interests[edit]

No competing interest.

References[edit]

[24] [16] [25] [20] [26] [21] [19] [18] [5]

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  2. Yun, Nadezhda E.; Walker, David H. (2012-10-09). "Pathogenesis of Lassa Fever". Viruses 4 (10): 2031–2048. doi:10.3390/v4102031. ISSN 1999-4915. PMID 23202452. PMC PMC3497040. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497040/. 
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