Lassa fever

Lassa fever, also known as Lassa hemorrhagic fever (LHF), is a type of viral hemorrhagic fever caused by the Lassa virus.[1] Many of those infected by the virus do not develop symptoms.[1] When symptoms occur they typically include fever, weakness, headaches, vomiting, and muscle pains.[1] Less commonly there may be bleeding from the mouth or gastrointestinal tract.[1] The risk of death once infected is about one percent and frequently occurs within two weeks of the onset of symptoms.[1] Of those who survive, about a quarter have hearing loss, which improves within three months in about half of these cases.[1]

Lassa fever
Other namesLassa hemorrhagic fever
Community education material for Lassa fever
SpecialtyInfectious disease
SymptomsFever, headaches, bleeding[1]
ComplicationsDeafness[1]
Usual onset1–3 weeks following exposure[1]
CausesLassa virus[1]
Risk factorsExposure to rodents in West Africa[1]
Diagnostic methodLaboratory testing[1]
Differential diagnosisEbola, malaria, typhoid fever[1]
TreatmentSupportive[1]
Prognosis1% risk of death[1]
Frequency400,000 cases per year[2]
Deaths5,000 deaths per year[2]

The disease is usually initially spread to people via contact with the urine or feces of an infected multimammate mouse.[1] Spread can then occur via direct contact between people.[1] Diagnosis based on symptoms is difficult.[1] Confirmation is by laboratory testing to detect the virus's RNA, antibodies for the virus, or the virus itself in cell culture.[1] Other conditions that may present similarly include Ebola, malaria, typhoid fever, and yellow fever.[1] The Lassa virus is a member of the Arenaviridae family of viruses.[1]

There is no vaccine.[3] Prevention requires isolating those who are infected and decreasing contact with the mice.[1] Other efforts to control the spread of disease include having a cat to hunt vermin, and storing food in sealed containers.[1] Treatment is directed at addressing dehydration and improving symptoms.[1] The antiviral medication ribavirin has been recommended,[1] but evidence to support its use is weak.[4]

Descriptions of the disease date from the 1950s.[1] The virus was first described in 1969 from a case in the town of Lassa, in Borno State, Nigeria.[1][5] Lassa fever is relatively common in West Africa including the countries of Nigeria, Liberia, Sierra Leone, Guinea, and Ghana.[1][2] There are about 300,000 to 500,000 cases which result in 5,000 deaths a year.[2][6]

Signs and symptoms

Onset of symptoms is typically 7 to 21 days after exposure.[7] In 80% of those who are infected few or no symptoms occur.[7][8] These mild symptoms may include fever, tiredness, weakness, and headache.[7] In 20% of people more severe symptoms such as bleeding gums, breathing problems, vomiting, chest pain, or dangerously low blood pressure may occur.[7] Long term complications may include hearing loss.[7] In those who are pregnant, miscarriage may occur in 95%.[7] Lassa fever can be difficult to distinguish clinically from other viral hemorrhagic fevers, such as Ebola virus disease.[1] A combination of pharyngitis, pain behind the sternum, presence of excess protein in the urine and fever can indicate Lassa fever with higher specificity.[9]

In cases in which death occurs, this typically occurs within 14 days of onset.[7] About 1% of all Lassa virus infections result in death.[7] Approximately 15%-20% of those who have required hospitalization for Lassa fever die.[7] The risk of death is greater in those who are pregnant.[7] A "Swollen baby syndrome" may occur in newborns, infants and toddlers with pitting edema, abdominal distension and bleeding.[10]

Cause

Virology
A transmission electron micrograph (TEM) of a number of Lassa virus virions adjacent to some cell debris.

Lassa virus is a member of the Arenaviridae, a family of negative-sense, single-stranded RNA viruses.[11] Specifically it is an old world arenavirus, which is enveloped, single-stranded, and bi-segmented RNA. This virus has both a large and a small genome section, with four lineages identified to date: Josiah (Sierra Leone), GA391 (Nigeria), LP (Nigeria) and strain AV.[12]

Spread
Mastomys natalensis, the natural reservoir of the Lassa fever virus

Lassa virus commonly spreads to humans from other animals, specifically the natal multimammate mouse or African rat, also called the natal multimammate rat (Mastomys natalensis).[13] This is probably the most common mouse in equatorial Africa, common in human households and eaten as a delicacy in some areas.[13][14]

The multimammate mouse can quickly produce a large number of offspring, tends to colonize human settlements increasing the risk of rodent-human contact, and is found throughout the west, central and eastern parts of the African continent.[15]

Once the mouse has become a carrier, it will excrete the virus throughout the rest of its lifetime through feces and urine creating ample opportunity for exposure.[15] The virus is probably transmitted by contact with the feces or urine of animals accessing grain stores in residences.[14] No study has proven presence in breast milk, but the high level of viremia suggests it may be possible.[10]

Individuals who are at a higher risk of contracting the infection are those who live in rural areas where Mastomys are discovered, and where sanitation is not prevalent. Infection typically occurs by direct or indirect exposure to animal excrement through the respiratory or gastrointestinal tracts. Inhalation of tiny particles of infectious material (aerosol) is believed to be the most significant means of exposure. It is possible to acquire the infection through broken skin or mucous membranes that are directly exposed to infectious material. Transmission from person to person has been established, presenting a disease risk for healthcare workers. The virus is present in urine for between three and nine weeks after infection, and it can be transmitted in semen for up to three months after becoming infected.[13][16][17]

Diagnosis
Liberian laboratory technicians in personal protective equipment preparing to test Lassa fever samples.

A range of laboratory investigations are performed, where possible, to diagnose the disease and assess its course and complications. The confidence of a diagnosis can be compromised if laboratory tests are not available. One comprising factor is the number of febrile illnesses present in Africa, such as malaria or typhoid fever that could potentially exhibit similar symptoms, particularly for non-specific manifestations of Lassa fever.[11] In cases with abdominal pain, in countries where Lassa is common, Lassa fever is often misdiagnosed as appendicitis and intussusception which delays treatment with the antiviral ribavirin.[18] In West Africa, where Lassa is most common, it is difficult to diagnose due to the absence of proper equipment to perform testing.[19]

The FDA has yet to approve a widely validated laboratory test for Lassa, but there are tests that have been able to provide definitive proof of the presence of the LASV virus.[11] These tests include cell cultures, PCR, ELISA antigen assays, plaque neutralization assays, and immunofluorescence essays. However, immunofluorescence essays provide less definitive proof of Lassa infection.[11] An ELISA test for antigen and Immunoglobulin M antibodies give 88% sensitivity and 90% specificity for the presence of the infection. Other laboratory findings in Lassa fever include lymphocytopenia (low white blood cell count), thrombocytopenia (low platelets), and elevated aspartate transaminase levels in the blood. Lassa fever virus can also be found in cerebrospinal fluid.[20]

Prevention
Main article: Prevention of viral hemorrhagic fever
Community education material for Lassa fever

Control of the Mastomys rodent population is impractical, 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. Gloves, masks, laboratory coats, and goggles are advised while in contact with an infected person, to avoid contact with blood and body fluids. These issues in many countries are monitored by a department of public health. In less developed countries, these types of organizations may not have the necessary means to effectively control outbreaks.

Vaccine

There is no vaccine for humans as of 2019.[21] Researchers at the United States Army Medical Research Institute of Infectious Diseases facility had a promising vaccine candidate in 2002.[22] They have developed a replication-competent vaccine against Lassa virus based on recombinant vesicular stomatitis virus vectors expressing the Lassa virus glycoprotein. After a single intramuscular injection, test primates have survived lethal challenge, while showing no clinical symptoms.[23]

Treatment

Treatment is directed at addressing dehydration and improving symptoms.[1] All persons suspected of Lassa fever infection should be admitted to isolation facilities and their body fluids and excreta properly disposed of.

Medications

The antiviral medication ribavirin has been recommended,[1] but evidence to support its use is weak.[4] Some evidence has found that it may worsen outcomes in certain cases.[4] Fluid replacement, blood transfusions, and medication for low blood pressure may be required. Intravenous interferon therapy has also been used.

Pregnancy

When Lassa fever infects pregnant women late in their third trimester, inducing delivery is necessary for the mother to have a good chance of survival.[24] This is because the virus has an affinity for the placenta and other highly vascular tissues. The fetus has only a one in ten chance of survival no matter what course of action is taken; hence, the focus is always on saving the life of the mother.[25] Following delivery, women should receive the same treatment as other people with Lassa fever.

Prognosis

About 15–20% of hospitalized people with Lassa fever will die from the illness. The overall case fatality rate is estimated to be 1%, but during epidemics, mortality can climb as high as 50%. The mortality rate is greater than 80% when it occurs in pregnant women during their third trimester; fetal death also occurs in nearly all those cases. Abortion decreases the risk of death to the mother.[26] Some survivors experience lasting effects of the disease,[27] and can include partial or complete deafness.[1]

Because of treatment with ribavirin, fatality rates have declined.[28][29]

Epidemiology
Lassa fever distribution. Countries reporting continued spread of disease and outbreaks in blue. Countries reporting a few cases, periodic isolation of virus, or serological evidence of infection in green. Countries with unknown status in grey.[30]

There are about 300,000 to 500,000 cases which result in 5,000 deaths a year.[2][6] One estimate places the number as high as 3 million cases per year.[15]

Estimates of Lassa fever are complicated by the lack of easy-available diagnosis, limited public health surveillance infrastructure, and high clustering of incidence near high intensity sampling.[11]

The infection affects females 1.2 times more than males. The age group predominantly infected is 21–30 years.[31]

Geography

Lassa high risk areas are near the western and eastern extremes of West Africa. As of 2018, the Lassa belt includes Guinea, Nigeria, Sierra Leone and Liberia.[10] As of 2003, 10-16% of people in Sierra Leone and Liberia admitted to hospital had the virus.[13] The case fatality rate for those who are hospitalized for the disease is about 15-20%. Research showed a twofold increase risk of infection for those living in close proximity to someone with infection symptoms within the last year.

The high risk areas cannot be well defined by any known biogeographical or environmental breaks except for the multimammate rat, particularly Guinea (Kindia, Faranah and Nzerekore regions), Liberia (mostly in Lofa, Bong, and Nimba counties), Nigeria (in about 10 of 36 states) and Sierra Leone (typically from Kenema and Kailahun districts). It is less common in the Central African Republic, Mali, Senegal and other nearby countries, and less common yet in Ghana and the Democratic Republic of the Congo. Benin had its first confirmed cases in 2014, and Togo had its first confirmed cases in 2016.[16]

As of 2013, the spread of Lassa outside of West Africa had been very limited. Twenty to thirty cases had been described in Europe, as being caused by importation through infected individuals.[15] These cases found outside of West Africa were found to have a high fatality risk because of the delay of diagnosis and treatment due to being unaware of the risk associated with the symptoms.[15] Imported cases have not manifested in larger epidemics outside of Africa due to a lack of human to human transmission in hospital settings. An exception had occurred in 2003 when a healthcare worker became infected before the person showed clear symptoms.[15]

2018 outbreak

An outbreak of Lassa fever occurred in Nigeria during 2018 and spread to 18 of the country's states; it was the largest outbreak of Lassa recorded.[32][33][34] On 25 February 2018, there were 1081 suspected cases and 90 reported deaths; 317 of the cases and 72 deaths were confirmed as Lassa which increased to a total of 431 reported cases in 2018.[35]

2019 outbreak

The total cases in Nigeria in 2019 was 810 with 167 deaths, the largest case fatality rate(23.3%)till then.[36][37]

2020 outbreak

The epidemic started from the second week of the January. By the tenth week the total number of cases has risen to 855 and deaths to 144, the case fatality rate of 16.8%.[37]

Liberia

Lassa fever is endemic in Liberia. From 1 January 2017 through 23 January 2018, 91 suspected cases were reported from six counties: Bong, Grand Bassa, Grand Kru, Lofa, Margibi, and Nimba. Thirty-three of these cases were laboratory confirmed, including 15 deaths (case fatality rate for confirmed cases = 45.4%).[38]

In February 2020, a total of 24 confirmed cases with nine associated deaths has been reported from nine health districts in six counties.Grand Bossa and Bong counties account for 20 of the confirmed cases.[39]

History

The disease was identified in Nigeria in 1969.[15] It is named after the town of Lassa, where it was discovered.[15]

A prominent expert in the disease, Aniru Conteh, died from the disease.[40]

Research

The Lassa virus is one of several viruses identified by WHO as a likely cause of a future epidemic. They therefore list it for urgent research and development to develop new diagnostic tests, vaccines, and medicines.[41][42]

In 2007, SIGA Technologies, studied a medication in guinea pig with Lassa fever.[43] Work on a vaccine is continuing, with multiple approaches showing positive results in animal trials.[44]

In addition to animal models, Organ-on-a-chip models have been developed to study Lassa hemorrhagic syndrome. These microchips allow for high throughput modelling of hemorrhagic syndrome and candidate drug screening. The chip model has been used to show the therapeutic effects of FX-06 for Lassa virus disease.[45]

References
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