Nonpolio Enteroviruses

Etiology

Enteroviruses are nonenveloped, single-stranded, positive-sense viruses in the Picornaviridae (“small RNA virus”) family, which also includes the rhinoviruses, hepatitis A virus, and parechoviruses. The original human enterovirus subgroups—polioviruses (see Chapter 276 ), coxsackieviruses, and echoviruses—were differentiated by their replication patterns in tissue culture and animals ( Table 277.1 ). Enteroviruses have been reclassified on the basis of genetic similarity into 4 species, human enteroviruses A-D. Specific enterovirus types are distinguished by antigenic and genetic sequence differences, with enteroviruses discovered after 1970 classified by species and number (e.g., enterovirus D68 and A71). Although more than 100 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. The closely related human parechoviruses can cause clinical presentations similar to those associated with enteroviruses.

Pathogenesis

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), ICAM-5, and coxsackievirus-adenovirus receptor, serve as viral receptors. In addition, respiratory epithelial cell sialic acids serve as receptors for enterovirus D68, enterovirus D70, and coxsackievirus A24 variants, and human scavenger receptor class B2 (SCARB2), human P-selectin glycoprotein ligand-1, and DC-SIGN are receptors for enterovirus A71. After virus attaches to a cell surface receptor, a conformational change in surface capsid proteins expels a hydrophobic pocket factor, facilitating penetration and uncoating with release of viral RNA in the cytoplasm. Translation of the positive-sense RNA produces a polyprotein that undergoes cleavage by proteases 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; these 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, leading to 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, VP1 is the most important determinant of serotype specificity. Additional regulatory proteins such as an RNA-dependent RNA polymerase and proteases are also present in the virion. Approximately 10 ⁴ -10 ⁵ virions are released from an infected cell by lysis within 5-10 hr of infection.

Following oral or respiratory acquisition, initial replication for most enteroviruses occurs in the pharynx and intestine, possibly within mucosal M cells. The acid stability of most enteroviruses favors survival in the gastrointestinal tract. Two or more enteroviruses may invade and replicate in the gastrointestinal tract simultaneously, but interference due to replication of 1 type often hinders growth of the heterologous type. Initial replication of most enteroviruses 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. Some enteroviruses, such as enterovirus D68, can be acid-labile and bind sialic acid receptors on respiratory epithelial cells in the upper and lower respiratory tract and primarily produce respiratory illness. Cytokine responses may contribute to development of respiratory disease by these viruses. Transient early viremia following respiratory enterovirus D68 infection has also been demonstrated.

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 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 enterovirus A71 epidemics has been characterized by severe involvement of the brainstem, spinal cord gray matter, hypothalamus, and subthalamic and dentate nuclei, and can be complicated by pulmonary edema, pulmonary hemorrhage, and/or interstitial pneumonitis, presumed secondary to brainstem damage, sympathetic hyperactivity, myoclonus, ataxia, autonomic dysfunction, and CNS and systemic inflammatory responses (including cytokine and chemokine overexpression). Immunologic cross-reactivity with brain tissue has been postulated as 1 mechanism responsible for neurologic damage and sequelae following enterovirus A71 infection.

Enterovirus myocarditis is characterized by perivascular and interstitial mixed inflammatory infiltrates and myocyte damage, possibly mediated by viral cytolytic (e.g., cleavage of dystrophin or serum response factor) 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 in dilated cardiomyopathy and in myocardial infarction has been suggested, but enterovirus RNA sequences and/or antigens have been demonstrated in cardiac tissues in some, but not other, series. Infections with enteroviruses such as coxsackievirus B4, during gestation or subsequently, have been implicated as a trigger for development of β-cell autoantibodies and/or type 1 diabetes in genetically susceptible hosts. Persistent infection in the pancreas, intestine, or peripheral blood mononuclear cells, with downstream immunomodulatory effects, has been suggested, but data are inconsistent. Similarly, persistent infection has been implicated in a variety of conditions, including amyotrophic lateral sclerosis, Sjögren syndrome, chronic fatigue syndrome, and gastrointestinal tumors. Early enterovirus infection was associated with reduced risk of developing lymphocytic and myeloid leukemia in 1 large retrospective Taiwanese cohort study.

Severe neonatal infections can produce hepatic necrosis, hemorrhage, inflammation, endotheliitis, and venoocclusive 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 type-specific neutralizing antibodies appears to be the most important immune defense, mediating prevention against and recovery from infection. Immunoglobulin (Ig) M antibodies, followed by long-lasting IgA and IgG antibodies, and secretory IgA, mediating mucosal immunity, are produced. Although local reinfection 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. Evidence also suggests that subneutralizing concentrations of serotype-specific antibody may lead to antibody-dependent enhancement of enterovirus A71 infection. Innate and cellular defenses (macrophages and cytotoxic T lymphocytes) may play important roles in recovery from infection. Altered cellular responses to enterovirus A71, including T lymphocyte and natural killer cell depletion, were associated with severe meningoencephalitis and pulmonary edema.

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. Enterovirus A71 disease increases after 6 mo of age, when maternal serotype-specific antibody levels have declined. Other risk factors for significant illness include young age, immune suppression (posttransplantation and lymphoid malignancy), and, according to animal models and/or epidemiologic observations, exercise, cold exposure, malnutrition, and pregnancy. Specific human leukocyte antigen genes, immune response gene (e.g., interleukin-10 and interferon-γ) polymorphisms, and low vitamin A levels have been linked to enterovirus A71 susceptibility and severe disease.

Clinical Manifestations

Manifestations are protean, ranging from asymptomatic infection to 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 important sources for spread of infection. Symptomatic disease is generally more common in young children.

Hand-Foot-and-Mouth Disease

Hand-foot-and-mouth disease, one of the more distinctive rash syndromes, is most frequently caused by coxsackievirus A16, sometimes in large outbreaks, and can also be caused by enterovirus A71; coxsackie A viruses 5, 6, 7, 9, and 10; coxsackie B viruses 2 and 5; and some echoviruses. It is usually a mild illness, with or without low-grade fever. When the mouth is involved, the oropharynx is inflamed and often contains scattered, painful vesicles on the tongue, buccal mucosa, posterior pharynx, palate, gingiva, and/or lips ( Fig. 277.1 ). These may ulcerate, leaving 4-8 mm shallow lesions with surrounding erythema. Maculopapular, vesicular, and/or pustular lesions may occur on the hands and fingers, feet, and buttocks and groin (see Figs. 277.1 and 277.2 ). Skin lesions occur more commonly on the hands than feet and are more common on dorsal surfaces, but frequently also affect palms and soles. Hand and feet lesions are usually tender, 3-7 mm vesicles that resolve in about 1 wk. Buttock lesions do not usually progress to vesiculation. Disseminated vesicular rashes described as eczema coxsackium may complicate preexisting eczema. Coxsackievirus A6, in particular, is responsible for relatively severe, atypical hand-foot-and-mouth disease (and herpangina) affecting adults and children that is characterized by fever, generalized rash (face, proximal extremities, and trunk, in addition to hands, feet, and buttocks), pain, dehydration, and desquamation of palms and soles ( Fig. 277.2 ). Onychomadesis (nail shedding) has been observed following coxsackievirus A6 and other coxsackievirus infections. Hand-foot-and-mouth disease caused by enterovirus A71 can be associated with neurologic and cardiopulmonary involvement, especially in young children (see Neurologic Manifestations below). Hand-foot-and-mouth disease caused by coxsackievirus A16 also can occasionally be associated with complications such as encephalitis, acute flaccid paralysis, myocarditis, pericarditis, and shock.