Khare et al Asian Journal of Dental and Health Sciences.

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Asian Journal of Dental and Health Sciences

Open Access to Pharmaceutical and Medical Research
Copyright © 2022 The Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0
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original author and source are credited

Open Access Review Article

An Overview of Lassa fever, an Rising Old World Haemorrhagic Viral

Disease
Basant Khare1, Dolly Jain1, Sameeksha Jain1, Monika Jain1, Pushpendra Kumar Khangar2, Deepak Kumar
Jain3*
1 Adina College of Pharmacy, ADINA Campus Rd, Lahdara, Sagar, MP, 470001
2 Adina Institute of Pharmaceutical Sciences, NH86A, Lahdara, Sagar, MP, 470001
3 Sun Institute of Pharmaceutical Education & Research (SIPER), Bhatpura Road, Lahar, Bhind, MP, 477445

Article Info: Abstract

_________________________________________ ___________________________________________________________________________________________________________________
Article History:
Lassa fever is an acute immunosuppressive illness of increasing public health concern causing severe
Received 10 Jan 2022 morbidity and significant mortality especially in epidemic cases. Lassa fever is an acute viral zoonotic
Reviewed 22 Feb 2022
illness caused by Lassa virus, an arenavirus known to be responsible for a severe haemorrhagic fever
Accepted 06 March 2022
Published 15 March 2022 characterised by fever, muscle aches, sore throat, nausea, vomiting, chest and abdominal pain. The
virus exhibits persistent, asymptomatic infection with profuse urinary virus excretion in the
_________________________________________ ubiquitous rodent vector, Mastomys natalensis. Lassa fever is endemic in West Africa and has been
Cite this article as: reported from Sierra Leone, Guinea, Liberia, and Nigeria. The virus replicates through a strategy
Khare B, Jain D, Jain S, Jain M, Khangar PK, Jain DK, known as the Ambisense, where two RNA strands code for genes in both the sense and antisense
An Overview of Lassa fever, an Rising Old World direction that is rapid and demonstrate temporal control in replication. Different diagnostic tests for
Haemorrhagic Viral Disease, Asian Journal of the virus are available, which range from viral culture to serological and molecular diagnostic tests.
Dental and Health Sciences. 2022; 2(1):20-26 There is an urgent need to develop drugs and vaccines against the virus because the World Health
DOI: http://dx.doi.org/10.22270/ajdhs.v2i1.12 Organization (WHO) has identified Lassa virus as one of the viruses that is likely to cause a future
epidemic, although a research is ongoing to evaluate Lassa virus vaccine immunogenicity in the
_________________________________________ CBA/J-ML29 mouse model. This review gives an overview on the structure, replication cycle,
*Address for Correspondence: pathogenesis and diagnosis of the virus.
Deepak Kumar Jain, Sun Institute of
Keywords: Lassa fever, Lassa virus, Arenavirus, Replication, Pathogenesis, Diagnosis
Pharmaceutical Education & Research (SIPER),
Bhatpura Road, Lahar, Bhind, MP, 477445

Email: jaindeepak2022@gmail.com

Introduction reported the presence of the virus in seminal fluids up to 3

months after infection of the virus. Research to show that
Lassa virus (LASV) is first described in the 1950s1 but not Lassa virus can be gotten via sexual intercourse has not been
identified until 1969 in Jos, Nigeria2, 3. The virus causes Lassa reported but there are speculations that LASV might possibly
fever that is hemorrhagic in nature, which is severe and fatal. be used for bioterrorism, so it is now being studied at greater
It affects 2-3 million people annually4,5 and has been known to lengths13,14. Due to the variability of the clinical course of the
be endemic in Benin Republic in 2014, Ghana in 2011, Guinea, disease, detection of the disease in affected patients has been
Liberia, and Mali in 2009, Sierra Leone, and Nigeria3,4,6, but challenging. When presence of the virus is confirmed in a
probably exists in other West African countries as well4. It is a locality, quick isolation of infected patients, good infection
reemerging virus with a select agent, which requires Biosafety prevention and control practices, and rigorous contact tracing
Level 4-equivalent containment7. It is endemic in West African can help halt epidemicity15.
countries including Sierra Leone, the Republic of Guinea,
Nigeria, and Liberia, where cases of the infection is between Epidemiology
300,000 and 500,000 yearly resulting in 5000 deaths
LASV is a single-stranded RNA virus of the Arenaviridae family.
annually4,8,9. About 80% infected with the virus are
First identified in 1969 in Nigeria, Lassa fever is now endemic
asymptomatic and 1 in 5 infection results in severe disease,
in West Africa including Nigeria, Sierra Leone, Guinea, Liberia,
where the virus affects several organs such as the liver, spleen,
Benin, Ghana and Mali and has spread to neighboring
and kidneys10. The virus is harbored by the multimammate
countries (Figure 1). In some areas, 10%-16% of people
rats of the genus Mastomys and transmitted to Mans through
primary aerosols of the rat’s urine, close contact with urine, admitted to hospitals every year have LASV. Cases have also
been identified in Germany, the Netherlands, Sweden, the USA,
feces, saliva, or ingestion of contaminated foods of the rat11.
the UK and Japan, largely imported after travel in West Africa.
LASV is also spread through contaminated hospital equipment
The long incubation period of LASV (~7–10 days) makes it one
but interestingly, it cannot be contracted by humans to
of the most commonly exported VHFs to countries outside its
humans only via bodily fluids contacts12. Findings have
endemic range16.

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Khare et al Asian Journal of Dental and Health Sciences. 2022; 2(1):20-26

Figure 1 Geographic distribution of Lassa fever in West Africa, Adapted from Emergencies-Lassa fever, WHO, Geographic
distribution of Lassa fever in West African affected countries, 1969-2018

Lassa virus structure arenavirus genome consists of a small (s) and a large (l) RNA
fragment, sizes 3.4 and 7 kb, respectively and the sRNA
Lassa virus is an envelope, single-stranded, bisegmented RNA encodes the viral glycoprotein precursor protein (GPC) and
virus belonging to the Arenaviridae family. Like other the nucleoprotein (NP), while the lRNA encodes the viral
arenaviruses, Lassa virus lacks a conventional negative-strand polymerase and a small, zinc-binding (Z) protein25. New
coding arrangement and the isolates of the virus differ in their methods for full-length sRNA amplification are facilitating
genetic, serologic and pathogenic characteristics17-19. Lassa research efforts on the identification and molecular analysis of
virus is spherical in shape and measures between 70 and 150 new arenaviruses or arenavirus strains26. The sequencing of
nm in diameter (Figure. 2). It has a smooth surface envelope Lassa virus sRNA has enabled the identification and molecular
with T-shaped spikes measuring 7-10 nm and built with characterization of four Lassa virus strains. These include: the
glycoprotein. The envelope encloses the genome which has strain Josiah, originating from Sierra Leone, the strain Nigeria
helical nucleocapsid measuring between 400 and 1300 nm in and strain LP27,28, both from Nigeria and the strain AV
length20,21. Often the interior contains electron dense granule imported into Germany by a traveler who had visited Ghana,
identified as the host cell ribosome from where the name Côte D’Ivoire, and Burkina Faso. Sequencing of sRNA of Lassa
“arena” was derived meaning sandy22. Lassa virus can be virus indicated a considerable genetic variation among the
inactivated in ultraviolet, gamma irradiation, heating from 56- strains of the virus, however, phylogenetically, strain AV
100oC and pH range between 5.5 and 8.5. Chemical agents like appears to be the most closely related to strain Josiah from
0.5% sodium hypocorite, 0.5% phenol and 10% formalin are Sierra Leone.
good inactivants against the virus23,24. The single-stranded

Figure 2 Structure of Lassa virus

Replication of Lassa virus infected host cytoplasm where both replication and
transcription take place. During the process, the cell nucleus
The first step in viral replication is adsorption on cell surface provides capped cellular mRNA for priming transcription, and
receptors that are found to be widely distributed and highly the nuclear membranes provide structural support. It has
conserved molecules29. The glycoprotein of the spikes is been observed that the 5’ end of the S derived subgenomic
responsible for the interactions with cell surface receptors30. mRNAs extend beyond the end of the genomic RNA template
The next step is the penetration of the virus, then and thelength of such an extension varies between 1 and 7
deproteinisation, and finally liberation of RNA genome into the nucleotides and terminate at 5’ cap structure31. The initiation
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Khare et al Asian Journal of Dental and Health Sciences. 2022; 2(1):20-26
of replication and transcription starts from the terminus of the the evasion of host immune responses. The recent
template. As the RNA polymerase rails on the template to add understanding of the pathogenesis of the viral fever does not
new nucleotides that will form polynucleotide of the new involve the chain of functions that take place during
strand, the first two slip back on the template to create development of the disease state and leads to mortality of
nontemplated nucleus, a process peculiar to arenaviruses. severed ill patients36. The high death and truly dramatic
After biosynthesis of macro-molecules, the virions are course of the disease state, the pathological findings do not
assembled through a process not yet understood. Matured give the bench that would explain the mechanism of disease
virions are released through budding from the plasma progression and the cause of mortality by the viral agent5,8.
membrane of acutely infected cells. Development of the cellular immune response failure, which
would control dissemination of LASV is indicated by high
Reservoir serum titers of the virus, together with dispersed replication
Mastomys natalensis multimammate rodents are the most in tissues and lack of neutralizing antibodies that could lead to
common rodent across the African continent, found the fatal Lassa fever development6,37. Patientscheck physically
predominantly in rural areas and human dwellings. These after fever onset usually depicts facial oedema, bilateral
rodents show persistent LASV infection but are largely conjunctival hemorrhages, purulent pharyngitis, and
unaffected by the disease and shed the virus in their abdominal disorders5. Pathological changes physically may
excrement. Seroprevalence has been reported to be as high as include pulmonary oedema, ascites, pleural effusions, and
60%-80% in M. natalensis populations. More recently, other hemorrhagic signs in the gastrointestinal mucosa while
rodent species including Hylomyscus pamfi and Mastomys examination under the microscope reveals splenic necrosis,
erythroleucus have been shown to host LASV. Transmission to hepatocellular necrosis, adrenocortical necrosis and
humans occurs primarily through contact with infected rodent apoptosis, mild mononuclear interstitial myocarditis without
urine or faeces; handling and consumption of infected rodents myocardial fiber necrosis, alveolar oedema with capillary
is also a pathway to infection. Airborne transmission may blockage and mild interstitial pneumonitis, lymph nodal sinus
occur from aerosolised rodent excretions (dust) during histiocytosis with mitoses, gastrointestinal mucosal petechiae,
cleaning activities. M. natalensis rodents readily colonise renal tubular injury, lymph nodal sinus histiocytosis with
human areas where food is stored, contributing a significant mitoses, and interstitial nephri. More often, lesions of Lassa
risk for spillover, especially in communities with poor fever in man happen in the hepatic cells5,8. There are four
sanitation or crowded living conditions. Human-to-human major characteristic hepatitis of LASV, which is derived:
transmission is less common, but LASV can be spread through i. Focal cytoplasmic degeneration of hepatocytes related to
direct contact with bodily secretions of persons infected with phagocytosed apoptotic fragments. ii. Distribution of
Lassa fever, presenting a higher risk for healthcare and multifocal hepatocellular necrosis randomly.
humanitarian personnel, who increases with progression of
disease and increasing viral load. There are suspected sexual iii. Monocytic reaction to necrotic hepatocytes.
transmission risks, as LASV can be detected in semen for 3 iv. Hepatocellular mitoses.
months past symptomatic infection16.
The physical impacts do not happen uniformly in all cases,
Pathogenesis rather in some instances can be observed simultaneously. The
virus fever is not associated with coagulation dysfunction, for
The Lassa virus is well-known to cause Lassa fever32. Its
example, decrease in the coagulation factors and disseminated
symptoms include flu-like illness characterized by fever,
intravascular coagulation (DIC) have been revealed in infected
general body weakness, cough, tonsillitis, headache and
subjects. More so, moderate thrombocytopenia with
gastrointestinal disorders. Hemorrhagic manifestations are
importantly damaged functionality of thrombocytes is
other features of Lassa fever, which include vascular
reported in severe Lassa fever subjects7,37. One significant
permeability10. The virus pathogenesis is still unclear, but it
mechanism involved in the pathogenesis of Lassa fever is
has been shown that the virus chiefly target the antigen-
infection-triggered induction of uncontrolled cytokine
presenting cells (mainly dendritic cells) and endothelial
expression, which looks like what is seen in sepsis9. In this
cells33. Lassa virus infects most tissues in the human body
subject that died from hemorrhagic shock and multi-organ
when gained entry. It starts with the mucosa, intestine, lungs,
failure, the proinflammatory cytokines, tumor necrosis factor
and urinary system, and then moves to the vascular system.
α (TNF-α), and interferon γ (IFN-γ) rises to extremely high
There are findings that the viral agent can prevent a host’s
level just before death. In a related study, no increase of both
innate immune system by NP activity34. Usually, when a
cytokine levels was reported in the checked fatal cases of the
microbe penetrates a host, the innate defense system detects
virus fever, and it is suggestive that the levels of IFN-γ and
the pathogen-associated molecular patterns (PAMPs) and
TNF-α are either elevated only in a fraction of patients or
aggravates the response of the immune system. One of
during a limited period that would involve frequent sampling
themechanisms identifies double-stranded RNA that is only
for assay12,35. Virus-induced immunosuppression may be
produced by negative-sense viral agents35. In the cytoplasm,
involved in a severe Lassa fever pathogenesis where the LASV
dsRNA receptors, such as melanoma differentiation-associated
infection fails to trigger macrophages (MP) and monocyte-
gene 5 (MDA-5) and retinoic acid-inducible gene I (RIG-I),
derived dendritic cells (DC) of human. Human-infected DC
detects dsRNAs and facilitates ignaling pathways that results
with the naturally nonpathogenic mopeia virus induces
in the translocation of interferon regulatory factor 3 (IRF-3)
stronger CD4 and CD8 T-cell responses when compared with
and other transcription factors to the nuclear material9.
those infected with LASV5,8. Infected DC fail to secrete
Translocated transcription factors enhance expression of
proinflammatory cytokines, do not upregulate costimulatory
interferons 𝛂 and 𝛃, and secreted interferons facilitate
molecules, such as CD40, CD80, and CD86, and poorly induce
antiviral responses including adaptive immunity. NP encoded
proliferation of T cells. Downregulation of immune responses
in the viral agent is important in the replication and
due to infection by LASV has been depicted in vitro, and it is
transcription of the virus, but it also stops host innate IFN
also in consonance with findings of clinical reports
response by inhibiting translocation of IRF-3. NP of the virus is
demonstrating that the virus fever fatal outcome relates with
reported to have an exonuclease activity to only dsRNAs12.
low levels interleukin (IL) 8 and IFN inducible protein 10 (IP-
Double-stranded RNA exonuclease activity of the NP leads to
10) in the system14.
counteract IFN responses by digesting the PAMP that leads to

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Khare et al Asian Journal of Dental and Health Sciences. 2022; 2(1):20-26

Diagnosis the RT-PCR assays are very sensitive, their applicability in the
West African countries where Lassa fever is endemic is limited
The signs and symptoms of Lassa fever may be difficult to by issues of strain variation, cross contamination, lack of
distinguish from diseases that are common in the tropics such qualified personnel, inadequate facilities and expense50,51.
as severe malaria, typhoid fever, yellow fever and other viral Another valuable diagnostic tool is the rapid diagnostic
haemorrhagic fevers38-40, but diagnosis can be assisted with immunoblot assay (RDIA) for Lassa fever. Unfortunately, its
simple laboratory support but definitive diagnosis requires usefulness is limited by its low capacity to provide prognostic
testing that is available only in highly specialized information and also its low sensitivity.
laboratories42. As the symptoms of Lassa fever are so varied
and nonspecific, clinical diagnosis is often difficult especially Differential diagnosis: Lassa haemorrhagic fever must be
early in the course of infection. Hence, to make accurate differentiated from other febrile diseases like Ebola (Marburg)
diagnosis of Lassa fever, clinical manifestation, haemorrhagic fever, malaria, diphtheria, legionella, yellow
epidemiological data and result of laboratory findings should fever, Congo-haemorrhagic fever, etc. Lassa fever virus has a
be taken into consideration. peculiar natural reservoir rodent host (M. natalensis). It is very
imperative that clinical assessment be combined with specific
Laboratory investigation: Lassa fever is diagnosed by detection laboratory diagnosis to adequately identify the Lassa fever
of Lassa antigen, antibodies, or virus isolation techniques. In virus in order to commence early treatment which is
the laboratory, the virus can be isolated using laboratory paramount to the survival of infected individual52.
animals such as albino mice, guinea pigs, Vero cell or African
green mon keys. Albino mice inoculated intracerebrally die Useful prevention/control measures
between 3 and 5 days. Lassa fever virus causes conspicuous
Lassa fever transmission is enhanced by cohabitation of M.
cytopathic effect on confluent monolayer of Vero cell culture
natalensis species of rodent with humans in their residences in
within 96 h. The antigens to be used for viral isolation can be
the affected areas having access to water and food items in the
obtained from the patients blood, urine, pleural fluid, throat
household. These rats are also prepared and consumed as
swab and in case of death, pathological materials from liver,
delicacies by many inhabitants of West African region53,54.
kidney, spleen and heart41. The virus can be seen under
Therefore, any control/preventive measures to be adopted
electron microscope using specimens obtained from infected
must take cognizance of routes and mechanism of
persons. Although virus isolation remains the most sensitive,
transmission of Lassa fever. The following measures are
it is still uniquely a research tool. The classical method to
detect Lassa virus is inoculation of Vero cells with serum, imperative in curtailing the regular epidemic outbreak and
spread of Lassa fever in sub-Saharan region of Africa. These
cerebrospinal fluid (CSF), throat washing, pleural fluid or
include:
urine of the patient. Specimen for laboratory analysis should
be collected as soon as possible from the patient suspected of  Observance of general hygiene including personal and
having the infection. Lassa virus is infectious by aerosol and environmental hygiene by the populace.
the human and rodent specimens should be processed with
appropriate precautions in biosafety level IV laboratories 42.  Since Lassa fever transmission is associated with infected
The specific diagnosis is readily made by the isolation and mouse (M. natalensis), therefore, every household needs to
identification of the virus. This is usually done by the device all means geared towards preventing rats from
inoculation of blood from the patient into Vero cell cultures. having any contact with foods, water and utensils utilized
Virus antigen can be detected by enzymelinked by the household. This may be achieved by: -Covering of
immunosorbent assays (ELISA) using Lassa virus-specific foods and water meant for human consumption regularly. -
antibodies. These tests are easy to handle and rapid, and can Foods should be kept in tightly sealed containers. -Ready-
be performed with inactivated specimens, which is to-eat food item (such as gari) should not be spread in the
advantageous in the field if sophisticated equipment is not open or by the roadside where rats can have access to it.
available. Results should be mentioned as soon as they are  Public enlightenment campaign about Lassa fever should
ready to help in monitoring the prognosis of the disease. The be conducted regularly in areas where the disease is
indirect fluorescent-antibody (IFA) test has traditionally been prevalent.
employed in the laboratory diagnosis of acute Lassa virus
infection43,44. Although the interpretation of IFA results is  Every community should be counseled to avoid foods and
complicated by the presence of IFA during both acute and other items contaminated with rat’s excretions and
convalescent stages of infection and by the subjective nature secretions.
of the assay, the appearance of IFA antibody early in the  People should be admonished to kill and destroy rats in
course of Lassa infection may be useful in identifying patients and around the house, shops or market places.
with poor prognosis. However, due to lack of specificity in
populations in non-endemic areas45 the technique has been  Foods and water should be boiled adequately before
largely replaced by ELISA for Lassa virus antigen and Lassa consumption.
virus-specific immunoglobulin M (IgM) and G (IgG)
 Encourage members of the community to always attend
antibodies46-48. A thorough evaluation of the Lassa virus ELISA
healthcare centre nearest to them for medical attention
on field-collected samples to assess its true sensitivity and
when they are sick or have had contact with contaminated
specificity was performed in Sierra Leone and Guinea in West
environment.
Africa49. In the study, isolation of virus as detected by
immunofluorescent stains for viral antigen along with a  All persons suspected of Lassa virus infection should be
positive reverse transcription-PCR (RT-PCR) test on the admitted to isolation facilities and promptly attended to
isolate wasemployed as the “gold standard” test of Lassa virus with utmost care. -Hospital workers should take universal
infection. The results showed that the combined ELISA Ag/IgM precautions and protective measures when attending to
assay was highly sensitive and specific for the diagnosis of such patients. -Every body fluids and excreta produced
Lassa fever and the antigen detection assay offered a bysuch patients should be handled with care and properly
particular advantage in providing early diagnosis as well as disposed of.
prognostic information. From this research, the technique
appeared to be a better diagnostic tool for Lassa virus
infection compared to other serological techniques. Although
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Khare et al Asian Journal of Dental and Health Sciences. 2022; 2(1):20-26
 Early detection of the disease and aggressive treatment and speed up the process leading to production of effective
(such as the use of intravenous ribavirin) 55 is important vaccine to checkmate the menace of Lassa fever outbreak and
for the survival of infected patient. associated morbidity and mortality.
 Healthcare workers should be sensitized about the need to References
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