Published on 22/03/2015 by admin
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Chapter 264 Lymphocytic Choriomeningitis Virus
Daniel J. Bonthius
Lymphocytic choriomeningitis virus (LCMV) is a prevalent human pathogen and an important cause of meningitis in children and adults. This virus is capable of crossing the placenta and infecting the fetus and is also an important cause of neurologic birth defects and encephalopathy in the newborn.
LCMV is a member of the family Arenaviridae, which are enveloped, negative-sense single-stranded RNA viruses. The name of the arenaviruses is derived from arenosus, the Latin word for “sandy,” because of the fine granularities observed within the virion on ultrathin electron microscopic sections.
Like all arenaviruses, LCMV utilizes rodents as its reservoir. The common house mouse, Mus musculus, is both the natural host and the primary reservoir for the virus, which is transferred vertically from one generation of mice to the next via intrauterine infection. Hamsters and guinea pigs are also potential reservoirs. Although heavily infected with LCMV, rodents that acquire the virus transplacentally often remain asymptomatic because congenital infection provides them with immunologic tolerance for the virus. Infected rodents shed the virus in large quantities in nasal secretions, urine, feces, saliva, and milk throughout their lives.
Humans typically acquire LCMV by contacting fomites contaminated with infectious virus or by inhaling aerosolized virus. Most human infections occur during the fall and early winter, when mice move into human habitations. Humans can also acquire the virus via organ transplantation. Congenital LCMV infection occurs when a woman acquires a primary LCMV infection during pregnancy. The virus passes through the placenta to the fetus during maternal viremia. The fetus may also acquire the virus during passage through the birth canal, due to exposure to infected vaginal secretions. Outside of organ transplantation and vertical transmission during pregnancy, there have been no cases of human-to-human transmission of LCMV.
LCMV is prevalent in the environment, has a great geographic range, and infects large numbers of humans. The virus is found throughout the world’s temperate regions and probably occurs wherever the genus Mus has been introduced (which is every continent but Antarctica). According to one epidemiologic study, 9% of house mice are infected. Serologic studies have demonstrated that approximately 5% of adult humans possess antibodies to LCMV, indicating prior exposure and infection.
LCMV is not a cytolytic virus. Thus, unlike the pathogenesis of many other nervous system pathogens that directly damage the brain by killing host brain cells, pathogenesis of LCMV involves other underlying mechanisms. Furthermore, the pathogenic mechanisms are different in postnatal (acquired) infection than in prenatal (congenital) infection. A critical difference in the pathogenesis of postnatal versus prenatal infection is that the virus infects brain parenchyma in the case of prenatal infection but is restricted to the meninges and choroid plexus in postnatal cases.
In postnatal infections, LCMV replicates to high titers in the choroid plexus and meninges. Viral antigen within these tissues becomes the target of an acute mononuclear cell infiltration driven by CD8+ T lymphocytes. The presence of lymphocytes in large numbers within the meninges and cerebrospinal fluid (CSF) leads to the symptoms of meningitis that mark acquired LCMV infection. As the lymphocytes clear the virus from the meninges and CSF, the density of lymphocytes declines, and the symptoms of meningitis resolve. Thus, symptoms of acquired (postnatal) LCMV infection are immune-mediated and are due to the presence of large numbers of lymphocytes.
Prenatal infection likewise inflames the tissues surrounding the brain parenchyma, and this inflammation leads to some of the signs of congenital LCMV. In particular, within the ventricular system, congenital LCMV infection often leads to ependymal inflammation, which may block the egress of CSF at the cerebral aqueduct and lead to hydrocephalus. However, unlike postnatal cases, prenatal infection with LCMV includes infection of the substance of the brain, rather than just the meninges or ependyma. This infection of brain parenchyma leads to the substantial neuropathologic changes typically accompanying congential LCMV infection. In particular, LCMV infects the mitotically active neuroblasts, located at periventricular sites. Through an unknown mechanism, presence of the virus kills these periventricular cells, leading to periventricular calcifications, a radiographic hallmark of this disorder. Within the fetal brain, LCMV infection of neurons and glial cells also disrupts neuronal migration, leading to abnormal gyral patterns, and interferes with neuronal mitosis, leading to microcephaly and cerebellar hypoplasia.
The clinical manifestations of LCMV infection depend on whether the infection occurs prenatally or postnatally. Congenital infection with LCMV is unique, as it involves both the postnatal infection of a pregnant woman and the prenatal infection of a fetus.
LCMV infection during postnatal life (during childhood or adulthood) typically consists of a brief, self-limited febrile illness. The illness classically consists of two clinical phases. In the first phase, the symptoms mimic a nonspecific viral syndrome and include fever, myalgia, malaise, nausea, anorexia, and vomiting. These symptoms usually resolve after several days but are followed by a second phase, consisting of central nervous system (CNS) disease. The symptoms of this second phase are those of aseptic meningitis, including headache, fever, nuchal rigidity, photophobia, and vomiting. The entire course of the biphasic disease is typically 1-3 wk.
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