Lymphocytic choriomeningitis

Lymphocytic choriomeningitis (LCM) is a rare viral disease caused by lymphocytic choriomeningitis virus (a member of the family Arenaviridae) that can be transmitted through the urine, droppings, saliva, or cage material of infected wild and domestic rodents, including hamsters, guinea pigs, rats, mice, and other small rodents ¹. The primary host of lymphocytic choriomeningitis virus is the common house mouse, Mus musculus. Infection in house mouse populations may vary by geographic location, though it is estimated that 5% of house mice throughout the United States carry lymphocytic choriomeningitis virus and are able to transmit virus for the duration of their lives without showing any sign of illness. Infected small rodents often appear normal or have small decreases in activity and appetite. Later, these infected animals may show more significant signs of weight loss, hunched posture, and ultimately die. Other types of rodents, such as hamsters, are not the natural reservoirs but can become infected with lymphocytic choriomeningitis virus from wild mice at the breeder, in the pet store, or home environment. Humans are more likely to contract lymphocytic choriomeningitis virus from house mice, but infections from pet rodents have also been reported.

Human infections with lymphocytic choriomeningitis virus are rare, especially from pet rodents. Lymphocytic choriomeningitis virus is most commonly transmitted via inhalation of infected excreta (urine, droppings, saliva, or nesting materials from infected rodents). Direct contact and animal bites are a potential route of lymphocytic choriomeningitis virus infection in pet handlers and laboratory technicians ². If people are infected, they generally have symptoms similar to those of the common flu. These symptoms include fever, stiff neck, loss of appetite, muscle aches, headache, nausea, and vomiting and often occur 1 to 2 weeks after exposure. People with weakened immune systems, especially young children and pregnant women, are the most at risk.

Lymphocytic choriomeningitis virus infections have been reported in Europe, the Americas, Australia, and Japan, and may occur wherever infected rodent hosts of the virus are found. Lymphocytic choriomeningitis disease has historically been underreported, often making it difficult to determine incidence rates or estimates of prevalence by geographic region. Several serologic studies conducted in urban areas have shown that the prevalence of lymphocytic choriomeningitis virus antibodies in human populations range from 2% to 5%.

Additionally, pregnancy-related lymphocytic choriomeningitis infection has been associated with congenital hydrocephalus, chorioretinitis, and mental retardation.

Lymphocytic choriomeningitis is usually not fatal. In general, mortality is less than 1%.

Lymphocytic choriomeningitis causes

Lymphocytic choriomeningitis infection is caused by the lymphocytic choriomeningitis virus, a member of the family Arenaviridae.

Lymphocytic choriomeningitis transmission

Lymphocytic choriomeningitis virus infections can occur after exposure to fresh urine, droppings, saliva, or nesting materials from infected rodents. Transmission may also occur when these materials are directly introduced into broken skin, the nose, the eyes, or the mouth, or presumably, via the bite of an infected rodent. Person-to-person transmission has not been reported, with the exception of vertical transmission from infected mother to fetus, and rarely, through organ transplantation. Smoking is a risk factor ³.

Risk of exposure to lymphocytic choriomeningitis virus

Individuals of all ages who come into contact with urine, feces, saliva, or blood of wild mice are potentially at risk for infection. Owners of pet mice or hamsters may be at risk for infection if these animals originate from colonies that were contaminated with lymphocytic choriomeningitis virus, or if their animals are infected from other wild mice. Human fetuses are at risk of acquiring infection vertically from an infected mother.

Laboratory workers who work with the lymphocytic choriomeningitis virus or handle infected animals are also at risk. However, this risk can be minimized by utilizing animals from sources that regularly test for the virus, wearing proper protective laboratory gear, and following appropriate safety precautions.

Lymphocytic choriomeningitis prevention

Lymphocytic choriomeningitis virus infection can be prevented by avoiding contact with wild mice and taking precautions when handling pet rodents (i.e. mice, hamsters, or guinea pigs).

Rarely, pet rodents may become infected with lymphocytic choriomeningitis virus from wild rodents. Breeders, pet stores, and pet owners should take measures to prevent infestations of wild rodents. Pet rodents should not come into contact with wild rodents. If you have a pet rodent, wash your hands with soap and water (or waterless alcohol-based hand rubs when soap is not available and hands are not visibly soiled) after handling rodents or their cages and bedding.

If you have a rodent infestation in and around your home, take the following precautions to reduce the risk of lymphocytic choriomeningitis virus infection:

• Seal up rodent entry holes or gaps with steel wool, lath metal, or caulk.
• Trap rats and mice by using an appropriate snap trap.
• Clean up rodent food sources and nesting sites and take precautions when cleaning rodent-infected areas:
  • Use cross-ventilation when entering a previously unventilated enclosed room or dwelling prior to cleanup.
  • Put on rubber, latex, vinyl or nitrile gloves.
  • Do not stir up dust by vacuuming, sweeping, or any other means.
  • Thoroughly wet contaminated areas with a bleach solution or household disinfectant.
  • Hypochlorite (bleach) solution: Mix 1 and 1/2 cups of household bleach in 1 gallon of water.
  • Once everything is wet, take up contaminated materials with damp towel and then mop or sponge the area with bleach solution or household disinfectant.
  • Spray dead rodents with disinfectant and then double-bag along with all cleaning materials and throw bag out in an appropriate waste disposal system.
  • Remove the gloves and thoroughly wash your hands with soap and water (or waterless alcohol-based hand rubs when soap is not available and hands are not visibly soiled).

The geographic distributions of the rodent hosts are widespread both domestically and abroad. However, infrequent recognition and diagnosis, and historic underreporting of lymphocytic choriomeningitis, have limited scientists’ ability to estimate incidence rates and prevalence of disease among humans. Understanding the epidemiology of lymphocytic choriomeningitis and lymphocytic choriomeningitis virus infections will help to further delineate risk factors for infection and develop effective preventive strategies. Increasing physician awareness will improve disease recognition and reporting, which may lead to better characterization of the natural history and the underlying immunopathological mechanisms of disease, and stimulate future therapeutic research and development.

Lymphocytic choriomeningitis symptoms

Lymphocytic choriomeningitis virus is most commonly recognized as causing neurological disease, as its name implies, though infection without symptoms or mild febrile illnesses are more common clinical manifestations in immunocompetent individuals.

Patients with lymphocytic choriomeningitis virus infection may report a history of exposure to rodents, hamsters, or the excreta of these animals 1-3 weeks before the onset of symptoms. Infection is most common in the autumn. Approximately one third of lymphocytic choriomeningitis virus infections cause no symptoms, and up to one half of infected individuals have a nonspecific febrile illness without neurologic involvement. The remainder of patients experience classic biphasic symptoms associated with lymphocytic choriomeningitis virus infection and meningitis or encephalitis.

For infected persons who do become ill, onset of symptoms usually occurs 8-13 days after exposure to the virus as part of a biphasic febrile illness. This initial phase (phase 1), the initial viremia of lymphocytic choriomeningitis virus extensively seeds extra-central nervous system (CNS) tissue, typically begins with any or all of the following symptoms: fever, malaise, lack of appetite, muscle aches, headache, nausea, and vomiting, which may last as long as a week. Other symptoms appearing less frequently include sore throat, cough, joint pain, chest pain, testicular pain, and parotid (salivary gland) pain.

Following a few days of recovery, a second phase (phase 2) of illness may occur when the  lymphocytic choriomeningitis virus infects the meninges and, less commonly, the cortical tissue. The leptomeninges are infiltrated mainly by lymphocytes and histiocytes, with few neutrophils. In lymphocytic choriomeningitis virus encephalitis, the same type of inflammatory cells is observed in the perivascular Virchow-Robin spaces. Symptoms may consist of meningitis (fever, headache, stiff neck, etc.), encephalitis (drowsiness, confusion, sensory disturbances, and/or motor abnormalities, such as paralysis), or meningoencephalitis (inflammation of both the brain and meninges). Lymphocytic choriomeningitis virus has also been known to cause acute hydrocephalus (increased fluid on the brain), which often requires surgical shunting to relieve increased intracranial pressure. In rare instances, infection results in myelitis (inflammation of the spinal cord) and presents with symptoms such as muscle weakness, paralysis, or changes in body sensation. An association between lymphocytic choriomeningitis virus infection and myocarditis (inflammation of the heart muscles) has been suggested.

Initial nonspecific symptoms of lymphocytic choriomeningitis virus infection include the following:

• Fever
• Malaise
• Myalgias
• Nausea or vomiting
• Retro-orbital headache
• Photophobia
• Anorexia

Symptoms may subside for 2-4 days and then recur with the following:

• Increased headache
• Nuchal rigidity
• Decreased level of consciousness ranging from lethargy to coma
• Occasionally, patients develop the following:
• Orchitis
• Parotitis
• Myocarditis or pericarditis
• Paresis or paralysis (extremely rare)
• Alopecia
• Arthritis of the hand

Immunosuppressed individuals (eg, solid organ transplant recipients) may develop a syndrome of multisystem organ involvement including the following ⁴:

• Encephalitis/seizures
• Respiratory failure
• Leukopenia
• Thrombocytopenia
• Coagulopathy
• Renal/liver dysfunction
• Hemorrhagic foci in multiple tissues

Typical clinical features of lymphocytic choriomeningitis virus infection are as follows ⁵:

• Fever (generally 102.2 – 104 °F [39-40°C])
• Relative bradycardia
• Nonexudative pharyngitis
• Papilledema (rare)
• Nuchal rigidity (mild)
• Erythematous maculopapular rash (rare)
• Lymphadenopathy

Atypical clinical features of lymphocytic choriomeningitis virus infection include the following:

• Alterations in function of cranial, sensory, or autonomic nerves
• Encephalitis manifesting as paraplegia or psychosis

Neurologic complications are rare but may include chronic headache, hydrocephalus, deafness, transverse myelitis, and Guillain-Barré syndrome ⁶.

Complete recovery within 1-3 weeks is the rule, although convalescence may be prolonged.

Women who become infected with lymphocytic choriomeningitis virus during pregnancy may pass the infection on to the fetus. Infections occurring during the first trimester may result in fetal death and pregnancy termination, while in the second and third trimesters, birth defects can develop. Infants infected In utero can have many serious and permanent birth defects, including vision problems, blindess, mental retardation, hydrocephalus (water on the brain), microcephaly (a condition in which a baby’s head is significantly smaller than expected) and seizures ⁷. Pregnant women may recall a flu-like illness during pregnancy, or may not recall any illness.

In solid organ transplant recipients with donor-derived infection, lymphocytic choriomeningitis virus has been shown to cause severe illness characterized by multisystem organ failure ⁸. Meningitis is a less-prominent feature in these individuals. Their high degree of morbidity and mortality can be attributed to profoundly decreased cell-mediated immunity due to immunosuppression.

Lymphocytic choriomeningitis virus is not cytotoxic. It appears that the host’s immune response to the infected cells produces the various manifestations of this disease. Natural killer (NK) cells are first to respond, followed by the production of interferon by cytotoxic T cells. lymphocytic choriomeningitis virus antibodies become detectable during the second febrile episode. In addition, lymphocytic choriomeningitis virus can suppress the production of acetylcholine neuronal cells in cell culture ⁵.

Previous observations show that most patients who develop aseptic meningitis or encephalitis due to lymphocytic choriomeningitis virus survive. No chronic infection has been described in humans, and after the acute phase of illness, the virus is cleared from the body. However, as in all infections of the central nervous system, particularly encephalitis, temporary or permanent neurological damage is possible. Nerve deafness and arthritis have been reported.

Lymphocytic choriomeningitis diagnosis

During the first phase of the disease, the most common laboratory abnormalities are a low white blood cell count (leukopenia) and a low platelet count (thrombocytopenia). Liver enzymes in the serum may also be mildly elevated. After the onset of neurological disease during the second phase, an increase in protein levels, an increase in the number of white blood cells or a decrease in the glucose levels in the cerebrospinal fluid (CSF) is usually found.

Laboratory diagnosis is usually made by detecting immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies in the CSF and serum. Virus can be detected by polymerase chain reaction (PCR) or virus isolation in the CSF at during the acute stage of illness.

Typical findings of lumbar puncture are as follows ⁵:

• Elevated opening pressure, occasionally with papilledema
• Protein concentration from 50-300 mg/dL (can exceed 600 mg/dL) ⁶
• Lymphocytic pleocytosis with several hundred cells/µL (range, 10 to >3000 cells/µL)
• Hypoglycorrhachia (in fewer than one third of patients)

Lymphocytic choriomeningitis treatment

Aseptic meningitis, encephalitis, or meningoencephalitis requires hospitalization and supportive treatment based on severity. Anti-inflammatory drugs, such as corticosteroids, may be considered under specific circumstances. Although studies have shown that ribavirin, a drug used to treat several other viral diseases, is effective against lymphocytic choriomeningitis virus in laboratory test tube, there is no established evidence to support its routine use for treatment of lymphocytic choriomeningitis in humans. Intravenous ribavirin is not commercially available. Oral ribavirin is dosed based on ideal body weight and renal function. Patients should be monitored carefully for potential toxicity, including hemolytic anemia, while receiving ribavirin ⁸.

Favipiravir (T-705), a selective inhibitor of RNA-dependent RNA polymerase (RdRp), has been shown to inhibit lymphocytic choriomeningitisV in vitro. It has also demonstrated promising efficacy at reducing mortality of other arenavirus infections in animal models. Further study is needed to ascertain if favipiravir could be safely used to treat infections with arenaviruses, including lymphocytic choriomeningitisV in humans ⁹.

Most patients improve spontaneously within 1-3 weeks with no complications.

Lymphocytic choriomeningitis prognosis

Lymphocytic choriomeningitis is rarely fatal; the overall prognosis is excellent.

Patients with encephalitis are at higher risk for neurologic sequelae.

Convalescence may be prolonged, with continuing dizziness, somnolence, and fatigue.

Severe disease leading to death has been reported in immunocompromised patients and organ transplant recipients (7 of 8 infected patients died) ¹⁰.

References

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