Etiology

Enteroviruses are non-enveloped, single-stranded, positive-sense viruses in the Picornaviridae (“small RNA virus”) family, which also includes the genera Rhinovirus, Hepatovirus (hepatitis A virus), and Parechovirus and genera containing related animal viruses. The original human enterovirus subgroups—polioviruses (Chapter 241), coxsackieviruses (named after Coxsackie, New York, where they were discovered), and echoviruses (named from the acronym enteric cytopathic human orphan viruses, applied before disease associations were identified)—were differentiated by their replication patterns in tissue culture and animals (Table 242-1). The human enteroviruses have been reclassified on the basis of nucleotide and amino acid sequences into 5 species, polioviruses and human enteroviruses A-D. Enterovirus types are distinguished by antigenic and genetic sequence differences; newer enteroviruses are classified by numbering. Although 100 or more types have been described, 10-15 account for the majority of disease. No disease is uniquely associated with any specific serotype, although certain manifestations are preferentially associated with specific serotypes.

Table 242-1 CLASSIFICATION OF HUMAN ENTEROVIRUSES

* The human enteroviruses have been alternatively classified on the basis of nucleotide and amino acid sequences into 5 species (polioviruses and human enteroviruses A-D).

Epidemiology

Enterovirus infections are common and have a worldwide distribution. In temperate climates there is an annual epidemic peak in summer/fall, although some transmission occurs year-round. Enteroviruses are responsible for 33-65% of acute febrile illnesses and 55-65% of hospitalizations for suspected sepsis in infants during the summer and fall in the USA, and 25% year-round. In tropical and semitropical areas, enteroviruses circulate year-round. In general, only a few serotypes circulate simultaneously. Infections by different serotypes can occur within the same season. Factors associated with increased incidence and/or severity include young age, male sex, poor hygiene, overcrowding, and low socioeconomic status; >25% of symptomatic infections occur in children <1 yr of age. Breast-feeding reduces the risk for infection, likely via enterovirus-specific antibodies.

Humans are the only known reservoir for human enteroviruses. Virus is primarily spread person to person, by the fecal-oral and respiratory routes, and vertically, from mother to neonate, prenatally or in the peripartum period, or, possibly, via breast-feeding. Enteroviruses can survive on environmental surfaces, permitting transmission via fomites. Enteroviruses also can frequently be isolated from water sources and sewage and can survive for months in wet soil. Although environmental contamination (of drinking water, swimming pools and ponds, and hospital water reservoirs) may occasionally be responsible for transmission, it is often considered the result, rather than the cause, of human infection. Transmission occurs within families (if a member of a household is infected, there is ≥50% risk of spread to nonimmune household contacts), daycare centers, playgrounds, summer camps, orphanages, and hospital nurseries; severe secondary infections may occur in nursery outbreaks. Diaper changing is a risk factor for spread, whereas handwashing decreases transmission. Tick-borne transmission has been suggested.

Large outbreaks of enterovirus infections have included epidemics of echovirus meningitis in numerous countries (echoviruses 4, 6, 9, 13, and 30 commonly); epidemics of hand-foot-and-mouth disease with severe central nervous system (CNS) and/or cardiopulmonary disease in young children due to enterovirus 71 in Asia and Australia; outbreaks of acute hemorrhagic conjunctivitis due to enterovirus 70, coxsackievirus A24, and coxsackievirus A24 variant in tropical and temperate regions; and community outbreaks of uveitis. Reverse transcription polymerase chain reaction (RT-PCR), restriction fragment length polymorphism (RFLP) analysis, single-strand conformation polymorphism analysis, heteroduplex mobility analysis, and genomic sequencing help identify outbreaks and allow phylogenetic analyses that demonstrate, depending on the outbreak, commonality of outbreak strains, differences among epidemic strains and older prototype strains, changes in circulating viral subgroups over time, co-circulation of multiple genetic lineages, and associations between specific genogroups and epidemiologic and clinical characteristics. Genetic analyses have demonstrated recombination and genetic drift that lead to evolutionary changes in genomic sequence and antigenicity and extensive genetic diversity. Recombination events associated with emergence of new subgenotypes of enterovirus 71 may contribute to sequential outbreaks.

The incubation period is typically 3-6 days, except for a 1- to 3-day incubation period for acute hemorrhagic conjunctivitis. Infected children, both symptomatic and asymptomatic, frequently shed cultivable enteroviruses from the respiratory tract for <1-3 wk, whereas fecal shedding continues up to 7-11 wk. Enterovirus RNA appears to be shed from mucosal sites for longer periods.

Pathogenesis

Following acquisition by the oral or respiratory route, initial replication occurs in the pharynx and intestine, possibly within mucosal M cells. The absence of an envelope favors survival in the gastrointestinal tract. Cell surface macromolecules, including poliovirus receptor, integrin very late activation antigen VLA-2, decay accelerating factor/complement regulatory protein (DAF/CD55), intercellular adhesion molecule-1 (ICAM-1), and coxsackievirus-adenovirus receptor, serve as receptors, as does sialic acid for enterovirus 70 and coxsackievirus A24 variants infecting the eye. Two or more enteroviruses may invade and replicate in the gastrointestinal tract simultaneously, but replication of 1 type often hinders growth of the heterologous type (interference).

After the virus attaches to a cell surface receptor, a conformational change in surface capsid proteins facilitates penetration and uncoating with release of viral RNA in the cytoplasm. Translation of the positive-sense RNA results in synthesis of a polyprotein that undergoes cleavage by proteinases encoded in the polyprotein. Several proteins produced guide synthesis of negative-sense RNA that serves as a template for replication of new positive-sense RNA. The genome is approximately 7,500 nucleotides long and includes a highly conserved 5′ noncoding region important for replication efficiency and a highly conserved 3′ polyA region, which flank a continuous region encoding viral proteins. The 5 end is covalently linked to a small viral protein (VPg) necessary for initiation of RNA synthesis. There is significant variation within genomic regions encoding the structural proteins (with corresponding variability in antigenicity). Replication is followed by further cleavage of proteins and assembly into 30-nm icosahedral virions. Of the 4 structural proteins (VP1-VP4) in the capsid (additional regulatory proteins such as an RNA-dependent RNA polymerase and proteases are also present in the virion), VP1 is the most important determinant of serotype specificity. Approximately 10⁴-10⁵ virions are released from an infected cell by lysis within 5-10 hr of infection.

Initial replication in the pharynx and intestine is followed within days by multiplication in lymphoid tissue such as tonsils, Peyer patches, and regional lymph nodes. A primary, transient viremia (minor viremia) results in spread to distant parts of the reticuloendothelial system, including the liver, spleen, bone marrow, and distant lymph nodes. Host immune responses may limit replication and progression beyond the reticuloendothelial system, resulting in subclinical infection. Clinical infection occurs if replication proceeds in the reticuloendothelial system and virus spreads via a secondary, sustained viremia (major viremia) to target organs such as the CNS, heart, and skin. Tropism to target organs is determined in part by the infecting serotype.

Enteroviruses can damage a wide variety of organs and systems, including the CNS, heart, liver, lungs, pancreas, kidneys, muscle, and skin. Damage is mediated by necrosis and the inflammatory response. CNS infections are often associated with mononuclear pleocytosis of the cerebrospinal fluid (CSF), composed of macrophages and activated T lymphocytes, and a mixed meningeal inflammatory response. Parenchymal involvement may affect the cerebral white and gray matter, cerebellum, basal ganglia, brainstem, and spinal cord with perivascular and parenchymal mixed or lymphocytic inflammation, gliosis, cellular degeneration, and neuronophagocytosis. Encephalitis during epidemics of enterovirus 71 has been characterized by severe involvement of the brainstem, spinal cord gray matter, hypothalamus, and subthalamic and dentate nuclei, and frequently complicated by pulmonary edema and/or interstitial pneumonitis and cardiopulmonary failure, presumed to be secondary to brainstem damage, sympathetic hyperactivity, and CNS and systemic inflammatory responses (including cytokine and chemokine overexpression), and, only occasionally, myocarditis.

Enterovirus myocarditis is characterized by perivascular and interstitial mixed inflammatory infiltrates and myocyte damage, possibly mediated by viral cytolytic (e.g., cleavage of dystrophin) and innate and adaptive immune-mediated mechanisms. Chronic inflammation may persist after viral clearance. The potential for enteroviruses to cause persistent infection is controversial. Persistent infection has been implicated in dilated cardiomyopathy and in myocardial infarction, with enteroviral RNA sequences and/or antigens demonstrated in cardiac tissues in some, but not other, series. Infections with enteroviruses such as coxsackievirus B4 have been implicated as a trigger for type 1 diabetes in genetically susceptible hosts, and persistent infection in the pancreas or intestine has been suggested. Similarly, persistent infection has been implicated in amyotrophic lateral sclerosis and Sjögren syndrome, and evidence of chronic infection has been described in some studies of chronic fatigue syndrome but not in others.

Severe neonatal infections can manifest as hepatic necrosis, hemorrhage, inflammation, endotheliitis, and veno-occlusive disease; myocardial mixed inflammatory infiltrates, edema, and necrosis; meningeal and brain inflammation, hemorrhage, gliosis, necrosis, and white matter damage; inflammation, hemorrhage, thrombosis, and necrosis in the lungs, pancreas, and adrenal glands; and disseminated intravascular coagulation. In utero infections are characterized by placentitis and infection of multiple fetal organs such as heart, lung, and brain.

Development of circulating type-specific neutralizing antibodies appears to be the most important immune defense, mediating prevention against and recovery from infection. Immunoglobulin M (IgM) antibodies, followed by long-lasting IgA and IgG antibodies, and secretory IgA, mediating mucosal immunity, are produced. Although local re-infection of the gastrointestinal tract can occur, replication is usually limited and not associated with disease. In vitro and animal experiments suggest that heterotypic antibody may enhance disease caused by a different serotype. Innate and cellular defenses (macrophages and cytotoxic T lymphocytes) may also play important roles in recovery from infection. Altered cellular responses to enterovirus 71, including T lymphocyte depletion, were associated with severe meningoencephalitis ± pulmonary edema during recent epidemics.

Hypogammaglobulinemia and agammaglobulinemia predispose to severe, often chronic enterovirus infections. Similarly, perinatally infected neonates lacking maternal type-specific antibody to the infecting virus are at risk for severe disease. Other risk factors for significant illness include young age, immune suppression (post-transplantation and lymphoid malignancy), and, according to animal models and/or epidemiologic observations, exercise, cold exposure, malnutrition, and pregnancy. Specific HLA genes have been linked to enterovirus 71 susceptibility and severe disease.

Clinical Manifestations

Manifestations are protean, ranging from asymptomatic infection or undifferentiated febrile or respiratory illnesses in the majority, to, less frequently, severe diseases such as meningoencephalitis, myocarditis, and neonatal sepsis. A majority of individuals are asymptomatic or have very mild illness, yet may serve as significant sources for spread of infection. Symptomatic disease is generally more common in young children.