Pathogenesis of enterovirus infections

After ingestion of fecally contaminated material, virus implants in susceptible tissues of the pharynx and distal small intestine. Whereas some replication occurs in the pharynx, the primary site of infection is the distal small intestine; virus traverses the intestinal lining cells without causing detectable cytopathology and reaches Peyer’s patches in the lamina propria, where significant replication occurs. Within 1 or 2 days, virus spreads to regional lymph nodes and, on about the third day, small quantities escape into the bloodstream (the “minor viremia”) and are disseminated throughout the reticuloendothelial system and to other receptor-bearing target tissues. In most cases, infection is contained at this stage by host defense mechanisms with no further progression, resulting in asymptomatic infection. In a minority of infected persons, replication continues in reticuloendothelial tissues producing, by about the fifth day, heavy sustained viremia (the “major viremia”) that coincides with the “minor illness” of poliovirus infection and with the “nonspecific febrile illness” caused by other human EVs.

The major viremia disseminates large amounts of virus to target organs, such as the spinal cord, brain, meninges, heart, skeletal muscles, and skin, where further virus replication results in inflammatory lesions and cell necrosis. In most such patients, host defense mechanisms quickly terminate the major viremia and halt virus replication in target organs; only rarely is virus replication in target organs extensive enough to be clinically manifest. Serotype-specific neutralizing antibodies may be detected in the serum within 4 or 5 days of infection, and they generally persist for life. Evidence for the critical role of antibodies in terminating infection is provided by the occurrence of chronic persistent EV infections in agammaglobulinemic children. Host defenses do not, however, terminate virus replication in the intestine, and fecal shedding continues for weeks after both symptomatic and asymptomatic EV infections. Immunity to EV is serotype specific; neutralizing antibodies in the blood prevent EV dissemination and disease. Reinfection is relatively uncommon and is confined to the alimentary tract; it is asymptomatic, and the duration of virus shedding is markedly reduced.

Epidemiology

Human EVs are worldwide in distribution, and humans are their only known reservoir. The prevalence of EV infection varies markedly with season and climate, and with the age and socioeconomic status of the population. In tropical and semitropical regions, EV infections are frequent throughout the year. In temperate climates, the incidence of infection is markedly increased in the summer and early fall; within the United States, climatic and socioeconomic factors affect the prevalence of EV infections. EV isolation rates from young children are 2- to 3-fold higher in southern than in northern cities and 3- to 6-fold higher in lower than in middle and upper socioeconomic districts. In the United States, one to three EV serotypes usually predominate in a given location each year. Some serotypes are present each year, whereas others disappear and may re-emerge after years of inactivity.

Transmission of human EV is chiefly by the fecal–oral route directly from person to person or through fomites; spread by respiratory secretions plays a lesser role. After infection by most serotypes, virus can be recovered from the oropharynx and intestine of both symptomatic and asymptomatic individuals, but virus is shed in greater amounts and for a longer period (a month or more) in the feces.

Infants and young children have the highest rates of EV infection and illness, and EVs are most efficiently disseminated by infected children younger than 2 years of age. Spread is facilitated by crowding and poor hygiene. Secondary attack rates in families are 90% for polioviruses, 75% for Coxsackieviruses, and 50% to 70% for echoviruses. Maternal antibodies passively acquired transplacentally or in breast milk prevent or modify EV infections in early infancy, and may interfere with oral polio vaccine in breastfed infants.

Although the epidemiology of most EVs is similar, patterns of infection with some serotypes are distinctive. EV-70 and Coxsackievirus A24, etiologic agents of acute hemorrhagic conjunctivitis, are transmitted by direct inoculation of the conjunctivae by fingers, fomites, and ophthalmologic instruments contaminated with infected tears. Replication of these viruses in the alimentary tract, if it occurs at all, is limited. Coxsackievirus A21 is shed primarily from the upper respiratory tract, where it produces a rhinovirus-like illness. It is transmitted by respiratory secretions.

The incubation period for EVs varies from less than 1 day to more than 3 weeks, but it is generally 2 to 7 days. It is shortest when symptoms are the result of virus replication at the portal of entry and longest when they reflect tissue injury following viremia (e.g., Coxsackievirus myocarditis).

Clinical manifestations of enterovirus infections

The majority of nonpolio EV infections (50% to 80%) are asymptomatic. Most symptomatic infections consist of undifferentiated febrile illnesses (“summer grippe”), often accompanied by upper respiratory symptoms. These are generally mild and last only a few days. This syndrome is totally nonspecific; it can be caused by any EV serotype. The characteristic EV syndromes, such as aseptic meningitis, hand-foot-and-mouth disease (HFMD), and pleurodynia, are, in fact, unusual manifestations of EV infection.

Some syndromes are associated with certain EV serotypes or subgroups (Table 184.2), but even these associations are not specific. The same syndrome may also be caused by a number of other EV serotypes. Conversely, a single EV serotype may cause several different syndromes, even within the same outbreak.

Central nervous system syndromes

Aseptic meningitis

EVs are responsible for more than 80% of cases of aseptic meningitis in developed countries. Almost every serotype has been implicated. Although attack rates are generally highest in children, cases also occur in adults, especially during larger outbreaks. Initial symptoms, which are typical of the undifferentiated febrile illness (e.g., fever, headache, malaise, myalgia, and sore throat), are followed, usually within a day, by signs and symptoms of meningitis, including a more severe headache that is often retrobulbar, photophobia, meningismus, stiffness of the neck and back, and nausea and vomiting, especially in children. The illness is sometimes biphasic like poliomyelitis. The cerebrospinal fluid (CSF) is clear and under slightly increased pressure. The total cell count, which can vary from less than 10/mm³ to more than 3000/mm³, averages 50 to 500/mm³. Initially, neutrophils may predominate (although they rarely exceed 90%), but they are quickly replaced by mononuclear cells. Pleocytosis may be absent in up to 30% of infants and children with EV meningitis diagnosed by CSF PCR assay. The glucose concentration is usually normal, although levels less than 40 mg/dL are occasionally observed. The protein concentration is normal or slightly elevated but rarely exceeds 100 mg/dL. Fever and signs of meningeal inflammation subside in 3 to 7 days, although pleocytosis may persist for an additional week or more. The great majority of children and adults recover fully without sequelae. However, enteroviral meningitis during the first year of life may result in permanent neurologic damage in up to 10% of affected infants, manifested by paresis, reduced head circumference, spasticity, and impaired intellect.

Related posts:

Peritonitis Infectious complications in the injection and non-injection drug user Intracranial suppuration Mucormycosis (and entomophthoramycosis) Hantavirus cardiopulmonary syndrome in the Americas Esophageal infections

Stay updated, free articles. Join our Telegram channel

Join