Lassa fever pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [3]

Synonyms and keywords: Lassa hemorrhagic fever; LHF

Overview

Lassa fever is a zoonotic disease caused by Lassa virus and spread by multimammate rat vector. It is spread through person-to-person contact, direct contact with rodent excretion and after an incubation period of 1-24 days can manifest as fever, muscle aches, sore throat, nausea, vomiting, chest and abdominal pain, weakness, cough, headache, exudative pharyngitis, anemia, low blood pressure, and diarrhea.

Pathophysiology

The current case definition for suspecting Lassa fever is as follows.

Unexplained fever at least 38oC or 100.4oF for one week or more And 1 of the following: ▸ No response to standard treatment for most likely cause of fever (malaria, typhoid fever) the choice of regimen. ▸ Readmitted within 3 weeks of inpatient care for an illness with fever And 1 of the following ▸ Edema or bleeding ▸ Sore throat and retrosternal pain/vomiting ▸ Spontaneous abortion following fever ▸ Hearing loss following fever

Pathogenesis

• Lassa virus infects the endothelial cells and perturbation of vascular function is likely to be central to Lassa fever-associated pathobiology, since the signs of increased vascular permeability, such as facial edema and pleural and pericardial effusions, indicate a poor prognosis for the disease outcome.
• Failure to develop the cellular immune response that would control dissemination of LASV, which is indicated by high serum virus titers, combined with disseminated replication in tissues and absence of neutralizing antibodies, leads to the development of fatal Lassa fever.
• Some of the characteristic symptoms of the virus include: fever, muscle aches, sore throat, nausea, vomiting, chest and abdominal pain, weakness, cough, headache, exudative pharyngitis, anemia, low blood pressure, and diarrhea. Because its symptoms are similar to other febrile illness found in Africa, Lassa virus is hard to diagnose. It can eventually can cause pulmonary edema, pleural and pericardial effusion, facial edema, bleeding from mucosal surfaces, neurological complications, deafness, lymphocytopenia, thrombocytopenia, and ascites. Often sore throat, vomiting, and bleeding are associated with higher fatality. There are four clinical stages of Lassa fever. The first stages occurs within the first three days and its symptoms include a high fever, weakness, and a general depression in activity. The second stage transpires from day 4 to day 7 where the patient experiences some of the more common/characteristic symptoms as stated above. The third stage begins at the seventh day and includes more severe symptoms such as: facial edema, convulsions, mucosal bleeding, internal bleeding, and disorientation. The fourth stage usually occurs after the 14th day and ends in coma and death.
• Only 20% of people who contract Lassa fever have severe multisystem trauma, meaning that 80% of people have only the milder symptoms. It has also been found that most cases of Lassa fever occur as the seasons change from dry to wet.

Transmission

Lassa Fever wikipedia.png[1]

Rodent to Human

• Infection in humans typically occurs via exposure to animal excrement through the respiratory or gastrointestinal tracts.
• Inhalation of tiny particles of infective 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 infective material. In fatal cases, Lassa fever is characterized by impaired or delayed cellular immunity leading to fulminant viremia.
• Finally, because Mastomys rodents are sometimes consumed as a food source, infection may occur via direct contact when they are caught and prepared for food.

Human to Human

• There are a number of ways in which the virus may be transmitted, or spread, to humans.
• This type of transmission occurs when a person comes into contact with virus in the blood, tissue, secretions, or excretions of an individual infected with the Lassa virus.
• The virus cannot be spread through casual contact (including skin-to-skin contact without exchange of body fluids).
• Person-to-person transmission is common in both village and health care settings, where, along with the above-mentioned modes of transmission, the virus also may be spread in contaminated medical equipment, such as reused needles (this is called nosocomial transmission). Frequency of transmission via sexual contact has not been established. * Transmission through breast milk has also been observed.

Molecular Pathology

• Lassa virus infect the cells especially endothelial cells and release cytokines and other inflammatory cell mediators.
• The mediators cause platelet dysfunction and suppress cardiac function as well as produce clinical manifestation of shock and inflammation.
• Microscopically, the virus causes hepatocellular necrosis and capillary lesions that can cause certain organs to hemorrhage. Lassa virus travels through the body via the blood, lymph vessels, respiratory tract, and digestive tract. Because of the multitude of dissemination strategies in the body, it is able to infect almost every organ in the human body. It has even been found in the cerebrospinal fluid which suggests a malfunction or defect of the blood brain barrier. Even though the virus targets the entire body, the liver is usually the organ that is most affected. The virus escapes detection by suppressing the immune system.
• Patients infected with LASV produce IgM and IgG antibody isotypes..
• Microscopic findings include hepatocellular necrosis and apoptosis, splenic necrosis, adrenocortical necrosis, mild mononuclear interstitial myocarditis without myocardial fiber necrosis, alveolar edema with capillary congestion and mild interstitial pneumonitis, lymph nodal sinus histiocytosis with mitoses, gastrointestinal mucosal petechiae, renal tubular injury, and interstitial nephritis.
• The necrotic hepatocytes were randomly distributed often forming foci of contiguous cells. Mononuclear phagocytes were observed either contacting or phagocytosing necrotic hepatocytes.
• Splenic necrosis was found in the marginal zone of the periarteriolar lymphocytic sheath. Splenic venous subendothelium appeared to be infiltrated by lymphocytes and other mononuclear cells.

Microscopic Pathology

The images below display key features of the Lassa virus.

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  This photomicrograph shows hepatitis caused by the Lassa virus, using toluidine-blue azure II stain. Source: CDC microbiologist Dr. W. Winn.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  This transmission electron micrograph (TEM) demonstrates the ultrastructural morphologic changes in this tissue sample isolate.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Scanning electron micrograph (SEM) revealing ultrastructural morphologic features of the Ebola virus from the Ivory Coast of Africa.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Negatively-stained transmission electron micrograph (TEM) demonstrating the ultrastructural curvilinear morphologic features displayed by the Ebola virus from the Ivory Coast of Africa.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.