Lymphocytic Choriomeningitis Virus (LCMV) Infection

Lymphocytic choriomeningitis virus (LCMV) is an enveloped single-stranded RNA virus first isolated in the cerebrospinal fluid of a woman during the 1933 Saint Louis encephalitis epidemic.[1]

LCMV belongs to the viral family Arenaviridae and was the first one discovered. Members of the Arenaviridae family are divided based on geographic distribution and genetic similarities as either Old World (Eastern hemisphere) or New World (Western hemisphere) arenavirdiae. Old world viruses include the Lassa virus (LASV) and Lujo fever in Africa, while New World viruses include several viral hemorrhagic fevers (Junin, Machupo, Guanarito, Sabia, Chapare) found in South America.[2, 3]  LCMV has potential for worldwide distribution; however, human cases have been documented only in the Americans and Europe, thus it is the only Old World arenavirus found in both the Eastern and Western Hemisphere.[3, 4]  

Arenaviruses are transmitted by rodents. Often 1 or a few rodent species serves as the natural reservoir for a given virus.[3]  There are 3 possible outcomes for an infected rodent: rapid clearance of virus, development of an acute lethal disease, and persistent chronic infection which is clinically benign but results in the release of virus into excreta, specifically urine.[2, 5, 6]  These infected but asymptomatic (carrier state) rodents, most commonly mice (Mus domesticus, Mus musculus), hamsters, and Guinea pigs, may serve as reservoirs for LCMV to be spread to humans.[5, 6]  Both vertical transmission to rodent offspring and horizontal spread contribute to the maintenance of virus in the rodent population.

LCMV is most commonly transmitted from mice to humans via inhalation of infected excreta (urine, droppings, saliva, or other nesting materials) which can be aerosolized during sweeping or cleaning. Direct contact with excreta and animal bites are another potential route of LCMV infection in pet handlers, rural workers, or laboratory technicians.[6, 7]  Other methods of human transmission include solid organ transplant and perinatal infection from mother to fetus.[2, 3, 4, 8, 9, 10, 11, 12]

The initial viremia of LCMV infection (phase 1) extensively seeds extra-CNS tissue. The secondary viremia (phase 2) infects the meninges and, less commonly, the cortical tissue. The leptomeninges are infiltrated mainly by lymphocytes and histiocytes, with few neutrophils. In LCMV encephalitis, the same type of inflammatory cells is observed in the perivascular Virchow-Robin spaces. LCMV 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. LCMV antibodies become detectable during the second febrile episode. In addition, LCMV can suppress the production of acetylcholine neuronal cells in cell culture.[2, 13, 14, 3, 15]

LCMV may affect the autonomic nervous system, various sensory modalities, and cranial nerves. Rarely, the virus can cause long-term neurologic sequelae, including chronic headache, hydrocephalus, deafness, transverse myelitis, and Guillain-Barré syndrome.[16] Other organs, especially the testes, heart, and joints, may be involved. Orchitis usually is unilateral and develops 1-3 weeks after illness onset. Cardiac involvement can occur in the form of viral myocarditis or pericarditis. The metacarpophalangeal joint and the proximal interphalangeal joint are the most common sites of arthritis caused by LCMV. The objective swelling, redness, and pain resolve within a few weeks.[14, 3, 17]

Pathopysiology in Special Populations:

Vertical transmission of LCMV during pregnancy has been associated with increased risk for spontaneous abortion and severe birth defects which can result in fetal death.[2, 18, 19] It also can cause a syndrome of hydrocephalus, chorioretinitis, and perivascular calcifications similar to that seen in congenital cytomegalovirus (CMV) infection and toxoplasmosis, potentially leading to mental retardation, microcephaly, seizures, and blindness.[18]

In solid organ transplant recipients with donor-derived infection (DDI), LCMV has been shown to cause severe illness characterized by multisystem organ failure.[8]  Four clusters of donor-derived LCMV infection have been described in the United States involving between 2003 and 2011, and an additional cluster was reported in Australia in 2008.[9, 10, 20, 11, 12]  The first US clusters occured in 2003 (4 recipients) and 2005 (4 recipients), and 7 of 8 died. Recent acquistion of a pet hamster with LCMV proven in the 2005 cluster.[20, 9]  A third US cluster occured in 2008 in 2 renal transplant recipients, 1 of whom died.[11]  A fourth US cluster occured in 4 patients in 2011, with death occuring in 2 patients.[10]  Meningitis is a less-prominent feature in these individuals and pathology at autotopsy has shown hepatocellular necrosis even in patients who did not receive a liver transplant.[10, 20]  In total, only 14 US organ recipients have acquired LCMV from an organ donor, 11 of whom died. The high degree of morbidity and mortality can be attributed to profoundly decreased cell-medicated immunity due to immunosuppression.

Frequency

United States

Underreporting and a lack of routine testing for LCMV infection in most patients presenting with an acute viral illness limit ability to estimate incidence rates and prevalence of disease among humans. A human seroprevalence study from the 1990s detected antibodies to LCMV in 4.7% of 1180 patients living in urban Baltimore, while LMCV antibody was detected in 9% of the house mice living in the same area.[21, 6]  Other seroprevelance studies of patients in Texas and Alabama showed seropositivity for LCMV in the range of 2-5%[22]  

The incidence of LCMV is unknown. In a 2011 study of 1,185 patients from across the United States with acute central nervous system disease or undifferentiated febrile illnesses, antibody to LCMV was positive in 29 (2.4%) patients, though it is unclear in which it may have explained the illness in question.[23]  The true incidence of LCMV infection is suspected to be higher because of underreporting and missed diagnoses, with some sources citing 10% or more cases of aseptic meningitis may be due to LCMV.[24] LCMV infection in humans is most common in autumn due to migration of mice into warm structures prior to winter.[3]

International

Seropositvity of LCMV exposure has been studies in other countries outside of the United States, and LCMV infections have been reported in North America, South America, Europe, Australia, and Japan.[3, 25, 26]

Race

LCMV infection has no racial predilection.

Sex

LCMV infection has no sexual predilection.

Age

LCMV infection is more common in young adults, although illness may occur in any age group.[3]

Mortality/Morbidity

Mortality and morbidity can result from the following:

• Post Natal infection : The true mortality and morbidity for LCMV in adults and children is difficult to discern since the exact incidence is unknown. Estimates put the overall mortality rate of less than 1%, however, immunosuppressed patients are more prone to the complications of encephalitis or multisystem organ failure including hemorrhage, which may result in death. ^[24]
• Congenital infection : The prognosis for infants with congenital LCMV infection generally is poor. A 1997 case series of congenital LCMV infection found a mortality rate of 35% by 21 months of age and severe neurodevelopmental disorders in those that survived. ^[19]  A more recent 2022 series of 70 reported cases of congenital LCMV infection found major cerebral abnormalities in 70% (49/70), a high mortality rate (30%), and severe neurologic sequelae reported in survivors. ^[18]
• Infection acquired via Solid-Organ Transplant : Four clusters of LCMV acquired from donor to recipients via solid-organ transplant have been described in the United States. ^{[9, 10, 20, 11]}  Prognosis in donor-derived diseases is poor, with death reported in 11 of 14 transplant recipients (79%).

Clinical manifestations of lymphocytic choriomeningitis virus (LCMV) infection in immunocompetent individuals range from asymptomatic to severe meningoencephalitis and death. More commonly, patients are asymptomatic or have mild febrile illness.[3, 4]  Approximately one third of LCMV 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 LCMV infection and meningitis or encephalitis. The incubation period varies, with symptoms occuring 8-13 days after exposure to the virus as part of a biphasic febrile illness in those who become symptomatic. 

Phase 1 of LCM typically manifests as fever and headache, often with lymphadenopathy and a maculopapular rash, resolving after 3-5 days. In some patients, a more severe headache returns within 2-4 days, associated with typical signs of frank aseptic meningitis during this second febrile period.[3, 13, 14, 24]  Cerebrospinal fluid pressure usually is elevated, occasionally even with papilledema.[3]

Patients with LCMV 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. 

Initial nonspecific symptoms and signs of LCMV infection include the following:

• Fever
• Malaise
• Myalgias
• Nausea or vomiting
• Retro-orbital headache
• Photophobia
• Anorexia
• Rash
• Swollen lymph nodes

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
• Papilledema
• 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[9, 24] :

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

Neurologic sequelae are rare but may include chronic headache, hydrocephalus, deafness, transverse myelitis, and Guillain-Barré syndrome.[16]

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

Typical clinical features of LCMV infection are as follows[3, 13, 14] :

• Fever (generally 39-40°C)
• Relative bradycardia
• Nonexudative pharyngitis
• Papilledema (rare)
• Nuchal rigidity (mild)
• Erythematous maculopapular rash (rare)
• Lymphadenopathy

Atypical clinical features of LCMV infection include the following:

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

Infection is caused by the lymphocytic choriomeningitis virus (LCMV), a member of the family Arenaviridae.

Transmission is generally via inhalation of LCMV virions in the aerosolized excreta (urine or feces) from chronically infected rodents.[3]

Transmission is also possible through close contact with infected animals, via direct inoculation through the skin or mucous membranes.

Populations at high risk for LCMV infection include the following:

• Individuals in locations with large mouse populations, particularly those who directly maintain homes and other properties.
• Laboratory workers involved in the handling of mice or hamsters
• Workers at facilities that breed mice for research or feeding purposes ^[27]
• Five clusters (4 in the United States) of donor-derived infection in solid organ transplant recipients. ^{[9, 10, 11, 12, 20]}

Rarely, LCMV can cause long-term neurologic sequelae in healthy adults and children. These complications include chronic headache, hydrocephalus, deafness, transverse myelitis, and Guillain-Barré syndrome.[16]  Other organs, especially the testes (orchitis), heart (mycarditis or pericarditis), and joints (arthritis) can be affected, although this is rare.[3, 14, 17]

Long-term neurologic complications are common in infants who survive congential LCMV infection including hydrocephalus, microcephaly, chorioretinitis, and intellectual disability.[18, 19]

Lymphocytic choriomeningitis virus (LCMV) infection is initially diagnosed based on a suggestive history that is confirmed by various laboratory investigations. Reverse-transcriptase polymerase chain reaction (PCR) to detect virus in the serum or cerebrospinal fluid is the most sensitive and fastest diagnostic method.[3]

Assessment of acute and convalescent immunoglobulin M (IgM) and immunoglobulin G (IgG) titers from both the serum and cerebrospinal fluid (CSF) can be useful. The sensitivity of enzyme-linked immunosorbent assay (ELISA) is greater than that of immunofluorescence (IFA)–based assays. Complement fixation is insensitive and should not be used.[28]

Complete blood cell (CBC) count may reveal leukopenia and thrombocytopenia early in the course of illness.

Immunohistochemical staining, virus culture, and reverse transcription-polymerase chain reaction (RT-PCR) of tissues may be useful.

Typical findings of lumbar puncture are as follows[3] :

• Elevated opening pressure, occasionally with papilledema
• Protein concentration from 50-300 mg/dL (can exceed 600 mg/dL) ^[16]
• Lymphocytic pleocytosis with several hundred cells/µL (range, 10 to >3000 cells/µL)
• Hypoglycorrhachia (in fewer than one third of patients)

No antiviral agents have undergone clinical trials for the treatment of lymphocytic choriomeningitis virus (LCMV) infection.

Early diagnosis and supportive care (eg, fluid replacement, NSAID therapy) are essential, particularly in immunocompromised patients. Reduce immunosuppression, when feasible.

No specific drug treatment is indicated in most cases of LCMV infection. Most patients improve spontaneously within 1-3 weeks with no sequelae.

Ribavirin has in vitro activity against LCMV and has been used with success in transplant recipients with severe disease. 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, 9]

Favipiravir (T-705), a selective inhibitor of RNA-dependent RNA polymerase (RdRp), has been shown to inhibit LCMV 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 LCMV in humans.[29, 30]

There are no specific vaccines available to protect against LCMV infection. Multi-epitope vaccine targets have been proposed; however, no potential vaccine candidates are commercially available.[31]

LCMV infection is best prevented by avoiding contact with wild mice and taking precautions when handling pet rodents such as mice, hamsters, or guinea pigs. If a rodent infestation occurs, one should avoid stirring up dust by vaccuuming, sweeping, or disrupting the area. Any infested areas to be cleaned should be done so by a professional, including thoroughly wetting the contaminated area with a bleach solution to prevent aerosolization.[4]

Laboratory personnel who handle mice or hamsters are at increased risk for LCMV infection. No established method of preventing infection in these situations exists. Prudence dictates the use of gloves when handling these animals, especially if the person's hands are abraded. If the risk for infection is high, consider the use of a personal respirator.

No method is effective to prevent transmission by organ transplantation since determination of pet rodent ownership by the donor is neither sensitive nor specific. Testing tissue with RT-PCR and immunohistochemical analysis is extremely expensive and may not necessarily be effective, therefore, is not routinely screened during organ procurement.

Patients with severe meningoencephalitis are usually hospitalized.

Lymphocytic choriomeningitis (LCM) 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.

Prognosis for infants with congenital LCMV infection is poor, including mortality rates of 30-35% and a high burden of neurodevelopemental sequelae in survivors.[18, 19]

Prognosis for organ-recipients who acquire LCMV from an organ donor is poor. Four clusters of LCMV infection in organ receipents have been described in the United States. Eleven of 14 patients died (79%).[8, 9, 10, 11, 20]

Avoid exposure to rodent secreta and excreta.