Lassa fever

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Ammu Susheela, M.D. [2]; Yazan Daaboul, M.D.; Serge Korjian M.D.

Lassa fever is an acute viral hemorrhagic fever caused by Lassa virus, a zoonotic, single-stranded RNA virus that is transmitted to humans by the Mastomys natalensis rodent. Lassa fever is endemic to West Africa with an annual incidence of 300,000 to 500,000 cases and a case fatality rate of approximately 5%-15%.^[1] Risk factors in the development of Lassa fever include travel to endemic regions (West Africa), exposure to infected individuals or rodents, and occupational exposure in healthcare settings. Pregnant women, immunosuppressed patients, and young patients are at high risk of developing Lassa fever-associated complications. Following exposure, infected patients remain asymptomatic for approximately 3 to 21 days. The majority of patients experience no or mild clinical manifestations. Typically, patients first develop persistent high-grade fever and other non-specific signs and symptoms. If left untreated, the majority of cases self-resolve. However, clinical manifestations may progress, and patients may experience hemorrhage, deafness, edema, seizures, coma, and death. Lassa fever is usually diagnosed by detection of Lassa antibodies in the patient’s serum using ELISA. The mainstay of therapy of Lassa fever is antiviral therapy with ribavirin. Ribavirin has been demonstrated to be most effective when administered intravenously early in the course of the disease (optimal efficacy when administered early within the first 6 days of symptom-onset).^[2] In addition to antiviral therapy, patients should receive supportive care to adequately maintain respiratory status and fluid and electrolyte balance. While there is no vaccine against Lassa fever, avoiding infected individuals or rodents and proper handling of infected waste products are recommended for the primary prevention of Lassa fever.

The first case of documented Lassa fever was reported in 1969 following the death of 2 nurses in Lassa, Nigeria.

Lassa fever may be transmitted from either infected animals (typically rodents) or humans following exposure to body fluids and excretions/secretions from the respiratory tract or GI tract. Following transmission, Lassa virus infects the endothelium and replicates intracellularly using an L-polymerase enzyme and nucleocapsid protein NP, which synthesize ribonucleoprotein (RNP) that produces mRNA and antigenomic RNA required for transcription. NP protein helps the virus evade the host immune system. Following transcription, vascular dysfunction ensues, resulting in the development of clinical manifestations of the disease. Although all organs may potentially be infected, the liver is a common target organ, and hepatitis/hepatic necrosis is typical following Lassa fever infection.

Lassa fever is caused by the Lassa virus, a member of the zoonotic Arenaviridae family. It is an enveloped, single-stranded, bisegmented RNA virus. The natural reservoir of Lassa virus is the Mastomys natalensis rodent (multimammate rat/mouse) that sheds the virus in urine and fecal droppings.

Lassa fever must be differentiated from other diseases that cause hemorrhagic fever, diarrhea, muscle fatigue, such as Ebola infection, Typhoid fever, Malaria, Diphtheria, Legionellosis, Congo-hemorrhagic fever, yellow fever, and Shigellosis.

Lassa fever is endemic in West Africa and is rare in developed countries. The annual incidence of Lassa virus is 100,000-300,000 individuals with a case fatality rate typically reaching 1-5% but may be as high as 65% during outbreaks.^[3] There is no predilection to specific age groups, gender, or race. However, young age and pregnancy are associated with increased risk of Lassa fever-associated

Risk factors for Lassa fever include travel to endemic regions (West Africa), exposure to infected individuals or rodents, and occupational exposure in healthcare settings. Pregnant women, immunosuppressed patients, and young patients are at high risk of developing Lassa fever-associated complications.

Following exposure, infected patients remain asymptomatic for approximately 3 to 21 days. The majority of patients experience no or mild clinical manifestations. Typically, patients first develop persistent high-grade fever and other non-specific signs and symptoms. If left untreated, the majority of cases self-resolve without intervention. However, in the minority of cases, clinical manifestations may progress to hemorrhage, deafness, abdominal/chest pain, pleural/pericardial effusions and ascites, and facial edema. Eventually, manifestations progress to include convulsions, hypovolemic shock, coma, and eventually death. The most common complications of Lassa fever are neurosensory deafness and hepatic injury, which may be a mild hepatitis or fulminant hepatic necrosis. Although prognosis of Lassa fever is generally good but development of complications, pregnancy, infancy, and immunosuppression are associated with poorer prognosis and increased risk of death.

Common symptoms of Lassa fever typically include persistent, high-grade fever and other non-specific symptoms, such as headache, myalgia/arthralgia, cough, conjunctival injection, and vomiting. Less commonly, patients may present with more severe symptoms, such as GI bleeding, deafness, confusion, seizures, and coma.

Persistent, high-grade fever is the most common sign on physical examination. Other common signs on physical examination include tachycardia, tachypnea, conjunctival injection, abdominal/chest tenderness, pharyngitis with tonsillar exudates, and hepatosplenomegaly.

Acute Lassa fever is usually diagnosed by detection of IgG Lassa antibodies in the patient’s serum using ELISA. Additional investigations are also required following diagnosis to monitor the course of the disease for development of complications and target organ damage.

Other diagnostic tests to confirm the diagnosis of lassa fever include reverse transcription–polymerase chain reaction (RT-PCR) and immunohistochemistry using either skin, tissue or liver tissue.

Management of Lassa fever includes supportive care and administration of intravenous (IV) ribavirin. Data on the efficacy of antiviral agents in Lassa fever are scarce. IV ribavirin was previously evaluated for treatment of Lassa fever and demonstrated a reduction in mortality when administered anytime during the course of the disease, especially early within the first 6 days of symptom-onset. Ribavirin is administered intravenously for a total of 10 days using the following regimen: first, loading dose of 30 mg/kg (max. 2g) followed by a dose of 16 mg/kg (max. 1g) IV q6h for 4 days, followed by a dose of 8 mg/kg (max. 500mg) IV q8h for 6 days.^[2] In addition to antiviral therapy, management includes supportive care to adequately maintain respiratory status, as well as fluid and electrolyte balance.

There is no vaccine for Lassa fever. Primary transmission of the Lassa virus can be prevented by avoiding contact with Mastomys rodents, especially in the geographic regions where outbreaks occur. When caring for patients with Lassa fever, further transmission of the disease through person-to-person contact or via nosocomial routes can be avoided by taking preventive precautions against contact with patient secretions.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

The first case of documented Lassa fever was reported in 1969 following the death of 2 nurses in Lassa, Nigeria.

• In 1955-1956, epidemics with clinical and epidemiological resemblance to Lassa fever were reported in Eastern Province and Sierra Leone.
• The first case of documented Lassa fever was reported in 1969 following the death of 2 nurses in Lassa, Nigeria.^[1] Prior to that, similar cases in West Africa were reported and thought to be caused by Lassa fever given the clinical and epidemiological resemblance of the presentation to Lassa fever.

• Administration of ribavirin for the treatment of Lassa fever was first introduced by Joe McCormick in 1979.
• Lassa fever is uncommon outside West Africa. Only 6 patients with Lassa fever have historically been hospitalized in USA (all 6 patients had recently traveled to West Africa). The most recent case of Lassa fever in USA was reported in May 2015.
  

Data from the Center of Disease Control and Prevention, as of May 2015

^{A physician examining a patient with Lassa fever patient in West Africa in 1977. Image retrieved from the Centers for Disease Control and Prevention (CDC) – Lassa Fever History[2]}

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Lassa fever may be transmitted from either infected animals (typically rodents) or humans following exposure to body fluids and excretions/secretions from the respiratory tract or GI tract. Following transmission, Lassa virus infects the endothelium and replicates intracellularly using an L-polymerase enzyme and nucleocapsid protein NP, which synthesize ribonucleoprotein (RNP) that produces mRNA and antigenomic RNA required for transcription. NP protein helps the virus evade the host immune system. Following transcription, vascular dysfunction ensues, resulting in the development of clinical manifestations of the disease. Although all organs may potentially be infected, the liver is a common target organ, and hepatitis/hepatic necrosis is typical following Lassa fever infection.

• Infection in humans typically occurs via exposure to animal (typically rodent) excrement through the respiratory or gastrointestinal tracts.
• Inhalation of tiny particles of infected aerosol is thought to be the most significant means of exposure, but transmission through direct exposure of infection to skin wounds or mucous membranes.
• Handling of dead infected animals has also been associated with the transmission of Lassa virus.

• Lassa virus may be transmitted following exposure to blood, tissue, secretions (including breast milk), or excretions of an infected individual.
• The virus cannot be transmitted without the exchange of body fluids.

• Following transmission, Lassa virus primarily infects the endothelial cells.
• The Lassa virus gains entry into the host cell by means of the cell-surface receptor the alpha-dystroglycan (alpha-DG),^[1] a versatile receptor for proteins of the extracellular matrix.
• Unlike most enveloped viruses which use clathrin-coated pits for cellular entry and bind to their receptors in a pH dependent fashion, Lassa virus instead undergoes cellular entry via endocytosis using alpha-dystroglycan receptor (ubiquitously expressed cell surface receptor), independent of either clathrin, caveolin, dynamin or actin.
• Once within the cell, the viruses are rapidly delivered to endosomes via vesicular trafficking. Once in contact with the endosome, Lassa virus evades endosomal degradation using envelope glycoproteins, which mediate a pH-dependent binding and membrane fusion.

• Intracellular RNA synthesis is initiated within an L-polymerase enzyme, which utilizes viral RNA templates and nucleocapsid protein NP to synthesize viral ribonucleoprotein (RNP). Once synthesized, RNP is transmitted to the host cell cytoplasm, and transcription of mRNA and antigenomic RNA (agRNA).^[2]

• Lassa fever evades the host immune system by production of NP protein, which has an exonuclease activity and causes the inhibition of host type I IFN signaling.^[3]
• Endothelial dysfunction results in the release of pro-inflammatory cytokines and cell mediators^[2], which in turn cause platelet dysfunction, hepatic necrosis, suppression of cardiac function, and development of Lassa fever-associated clinical manifestations, including facial edema, pleural and pericardial effusions, and hypovolemic shock.
• Lassa fever may potentially infect all organs, but the liver and auditory sensorineural system are commonly involved.
• Failure of the host to mount an adequate cellular immune response to control viral dissemination, along with disseminated replication in tissues and absence of neutralizing antibodies, results in host death.^[4] Prompt host immune response is critical for host survival, and fatal Lassa fever is often characterized by impaired or delayed cellular immunity^[5].

• Replication for Lassa virus is very rapid and demonstrates a temporal control.^[6]
• The initial replication step is transcription of mRNA copies of the negative (minus-sense) genome. This process ensures an adequate supply of viral proteins for subsequent steps of replication, as the NP and L proteins are translated from the mRNA.
• Following the initial replication step, the positive (plus-sense) genome then synthesizes viral complementary RNA (vcRNA) copies of itself. The vcRNA copies are then used to synthesize more mRNA and to serve as templates for the production of more negative-sense progeny. The mRNA synthesized from vcRNA are then translated to produce GP and Z proteins.
• This temporal control allows the spike proteins to be produced last, and therefore, delay recognition by the host immune system.

Lassa virus commonly involves the liver and results in hepatocellular necrosis and apoptosis. Other organs may be involved, and Lassa fever infection may manifest with the following:^[7][8][9]

• Splenic necrosis
• Adrenocortical necrosis
• Mononuclear interstitial myocarditis
• Pulmonary alveolar edema with capillary congestion and mild interstitial pneumonitis
• Lymph nodal sinus histiocytosis
• Gastrointestinal mucosal petechiae
• Renal tubular injury
• Interstitial nephritis

Typical features of Lassa fever-associated hepatitis include the following:

• Acidophilic necrosis
• Apoptotic changes
• Ballooning degeneration
• Pycnotic nuclei
• Microvascular changes
• Councilman bodies (intracellular inclusion bodies)

The images below display key features of microscopic pathology of Lassa virus.

• 
  This photomicrograph demonstrates hepatitis caused by the Lassa virus, using toluidine-blue azure II stain. Retrieved from the Public Health Image Library (PHIL) of the Centers for Disease Control and Prevention.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[10]
• 
  This transmission electron micrograph (TEM) demonstrates the cytoarchitectural changes of a liver tissue specimen extracted from a patient with Lassa fever. The presence of a typical Councilman body, pycnotic nuclei in an area of acidophilic necrosis, and microvacuolar fatty changes are noted.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[10]
• 
  Scanning electron micrograph (SEM) demonstrates the cytoarchitectural changes of a liver tissue specimen extracted from a patient with Lassa fever. A zone of acidophilic necrosis, and numbers of pycnotic nuclei are noted.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[10]
• 
  Sudan III-stained photomicrograph demonstrates the cytoarchitectural changes of a liver tissue specimen extracted from a patient with Lassa fever. Microvacuolar fatty necrosis is noted.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[10]
• 
  This photomicrograph demonstrates hepatitis caused by the Lassa virus, using toluidine-blue azure II stain, magnified 500X.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Lassa fever is caused by the Lassa virus, a member of the zoonotic Arenaviridae family. It is an enveloped, single-stranded, bisegmented RNA virus. The natural reservoir of Lassa virus is the Mastomys natalensis rodent (multimammate rat/mouse) that sheds the virus in urine and fecal droppings.

• Viruses; ssRNA viruses; ssRNA negative-strand viruses; Arenaviridae; Mammarenavirus ^[1]

• Lassa virus belongs to Arenaviridae.^[2]
• The Arenaviridae are a family of viruses whose members are generally associated with rodent-transmitted diseases in humans (zoonotic). Each virus usually is associated with a particular rodent host species in which it is maintained.

• Lassa virus is an enveloped, single-stranded, bisegmented, ambisense RNA virus.

• Lassa virus genome is contained in two RNA segments, each of which encodes 2 viral proteins (total 4 viral proteins)^[3][4]
  • The large segment encodes RNA polymerase (L) and a small zinc-binding protein (Z) that regulates transcription and replication^[5][6]
  • The small segment encodes the nucleoprotein (NP) and the surface glycoprotein precursor (GP or viral spike). The GP protein is cleaved into the envelope glycoproteins, GP1 and GP2, that bind to the alpha-dystroglycan receptor and mediate host cell entry^[7]
• Nucleotide studies of the genome have shown that Lassa has four lineages: Three in Nigeria and a fourth in Guinea, Liberia, and Sierra Leone. The Nigerian strains are thought to be ancestral to the others.^[8].

• The most common natural reservoir of Lassa virus is the rodent, Mastomys natalensis. Mastomys natalensis is commonly known as the “multimammate rat/mouse” due to the female’s multiple and prominent mammary glands.
• The mastomys rodents are abundant in the Savannas and forests of West, Central, and East Africa.
• Once infected, the rodent is able to excrete the virus in the urine and feces for an extended time period. Mastomys rodents breed frequently, produce large numbers of offspring, and commonly inhabit human homes with food storage. All of these factors contribute to the relatively efficient spread of Lassa virus from infected rodents to humans.

The images below display key features of the Lassa virus.

• 
  This transmission electron micrograph (TEM) demonstrates Lassa virus virions adjacent to host cell debris.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[10]
• 
  This highly magnified transmission electron micrograph (TEM) demonstrates ultrastructural details of 3 Lassa virus virions.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[10]
• 
  This transmission electron micrograph depicted eight virions (viral particles) of an Arenavirus.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Lassa fever must be differentiated from other diseases that cause hemorrhagic fever, diarrhea, muscle fatigue, such as Ebola infection, Typhoid fever, Malaria, Diphtheria, Legionellosis, Congo-hemorrhagic fever, yellow fever, and Shigellosis.

The table below summarizes the findings that differentiate Lassa fever from other conditions that cause fever, diarrhea and mucosal bleeding:^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Lassa fever is endemic in West Africa and is rare in developed countries. Lassa virus infects 100,000-300,000 individuals annually with a case fatality rate typically reaching 1-5% but may be as high as 65% during outbreaks.^[1] There is no predilection to specific age groups, gender, or race. However, young age and pregnancy are associated with increased risk of Lassa fever-associated complications.

• Lassa virus infects 100,000-300,000 individuals annually. However, these figures are inaccurate given that disease surveillance for cases is not routinely performed.
• In areas of high endemicity, up to 10%-15% of hospitalized patients are diagnosed with Lassa fever.

• Generally, the overall case-fatality rate is 5-15%.
• The case fatality rate increases among patients hospitalized for severe infection, and during outbreaks, Lassa fever may be associated with case-fatality rates that reach up to 35-65%.^[2]

• There is no age preponderance for Lassa virus infection.
• However, fetuses are at high-risk of death following infection with Lassa fever.

• There is no gender preponderance for Lassa virus infection.
• Women in the third trimester of pregnancy are considered high-risk for development of Lassa fever-associated complications and death.

• The highest incidence of Lassa fever occurs during the dry months from November to April.^[3]

• There is no races preponderance for Lassa virus infection.

• The following table lists the individuals infected with Lassa fever and were imported and hospitalized in the United States:^[4]

Data from the Center of Disease Control and Prevention, as of May 2015

• The following table lists the individuals infected with Lassa fever who were imported and hospitalized in other non-endemic countries except the United States:^[4]

Data from the Center of Disease Control and Prevention, as of May 2015

Lassa virus is most prevalent in countries of West and Central Africa:^[5][6][7],^{[8][9][10][11]}

• Sierra Leone
• Guinea
• Nigeria
• Ivory Coast
• Mali
• Benin
• Central African Republic
• Liberia
• Burkina Faso
• Senegal
• Ghana
• Gambia
  

The maps below demonstrate the outbreak distribution of Lassa fever:^[12][13][14]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Individuals at risk are those who live or visit areas with a high population of Mastomys rodents infected with Lassa virus or are exposed to infected humans. Hospital staff are not at great risk for infection as long as protective measures are taken.

The following are considered risk factors for developing Lassa fever:

• Travel to endemic region (West Africa)
• Exposure to infected individuals
• Exposure to rodents (Mastomys natalensis rat/mouse) or contaminated household items (including food)
• Occupational exposure in healthcare settings

• Young age
• Pregnancy (especially 3rd trimester)
• Immunosuppression

• Individuals at greatest risk of Lassa virus infection are those who live in or visit endemic regions, including Sierra Leone, Liberia, Guinea, and Nigeria and have exposure to the multimammate rat. Risk of exposure may also exist in other west African countries where Mastomys rodents exist. Hospital staff are not at great risk for infection as long as protective measures and proper sterilization methods are used. ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Following exposure, infected patients remain asymptomatic for approximately 3 to 21 days. The majority of patients experience no or mild clinical manifestations. Typically, patients first develop persistent high-grade fever and other non-specific signs and symptoms. If left untreated, the majority of cases self-resolve without intervention. However, in the minority of cases, clinical manifestations may progress to hemorrhage, deafness, abdominal/chest pain, pleural/pericardial effusions and ascites, and facial edema. Eventually, manifestations progress to include convulsions, hypovolemic shock, coma, and eventually death. The most common complications of Lassa fever are neurosensory deafness and hepatic injury, which may be a mild hepatitis or fulminant hepatic necrosis. Although prognosis of Lassa fever is generally good, development of complications, pregnancy, infancy, are associated with poorer prognosis and increased risk of death.

• Infected patients remain asymptomatic for 3 to 21 days following exposure.^[1]

• The majority of patients experience no or mild symptoms. Only a minority (approximately 15-20%) of patients experience multiorgan dysfunction, and typically 5-15% of infected patients die of Lassa fever.
• Patients typically first develop persistent high-grade fever (39 °C to 41 °C) and other non-specific symptoms, such as muscle aches, conjunctival injection, headache, sore throat, nausea, and vomiting.
• If left untreated, the majority of patients self-resolve without any intervention.
• In a minority of cases, patients may develop worsening abdominal/chest pain, temporary/permanent deafness, facial edema, mucosal bleeding and hemorrhage, pulmonary edema, pleural/pericardial effusions or ascites, multi-organ failure, and shock.
• Prolonged and worsening symptoms are usually associated with worsening prognosis, typically resulting in convulsions, encephalitis, seizures, coma and finally death.

• The following table demonstrates the 4 clinical stages of Lassa fever (adapted from McCarthy et al. 2002^[2] and Richmond et al. 2003^[3])

Complications of Lassa fever include the following:

• Sensorineural Deafness
  • The most common complication of Lassa fever is deafness (1/3 of patients)
  • Deafness may be either temporary or permanent and may either by unilateral or bilateral.
  • Deafness does not seem to be associated with the severity of disease and may develop equally among patients with mild or severe infections.
• Spontaneous abortion among pregnant women
• Hepatitis and hepatic necrosis
• Splenic necrosis
• Adrenocortical necrosis
• Pulmonary alveolar edema
• Interstitial pneumonitis
• Lymph node histiocytosis
• Mucosal (e.g. GI) bleeding
• Renal tubular injury and interstitial nephritis
• Swollen baby syndrome (edema and bleeding among fetuses)

• Approximately 5-15% of patients hospitalized for Lassa fever die from the illness. The following factors are associated with poorer prognosis of Lassa fever:^[4]
  • Infection during the third trimester of pregnancy or during infancy
  • Increased viremia concentration
  • Serum AST level > 150 IU/L
  • Bleeding, hypotension, and shock
  • Development of encephalitis, confusion, or coma
  • Edema (facial edema, pleural/pericardial effusion, ascites)

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