Enterovirus and parechovirus infections: Epidemiology and pathogenesis

INTRODUCTION — The human enteroviruses and parechoviruses are ubiquitous viruses that are transmitted from person to person via direct and indirect routes. Polioviruses, the prototypic enteroviruses, are the cause of paralytic poliomyelitis, a disease that has been highly controlled in the United States and other high-income countries and is targeted for global eradication.

The non-polio enteroviruses and parechoviruses are responsible for a wide spectrum of diseases in persons of all ages, although infection and illness occur most commonly in infants and young children. Epidemic hand-foot-mouth disease caused by enterovirus A71 has become an important global public health threat, particularly in the Asia-Pacific region, where vaccines are now available [1]. Acute flaccid myelitis (AFM), which has many epidemiologic and clinical characteristics that overlap with poliomyelitis, has caused periodic outbreaks in many countries since 2014 [2].

The epidemiology and pathogenesis of non-polio enterovirus and parechovirus infections are reviewed here. The clinical manifestations, diagnosis, management, and prevention of these infections are discussed in a separate topic. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention" and "Poliovirus vaccination".)

CLASSIFICATION — The enteroviruses and parechoviruses (and hepatitis A virus) are distinct genera within the Picornavirus family [3]. Enterovirus serotypes are distinguished from one another by neutralization with specific antisera. Originally, all enterovirus serotypes were assigned to one of four traditional sub-genera based on host range and pathogenic potential [4]. Of 69 serotypes once identified in these sub-genera, 64 remain after exclusion of redundant serotypes and reclassification of others [5].

●Polioviruses (serotypes 1 to 3)

●Group A coxsackieviruses (serotypes 1 to 22, 24)

●Group B coxsackieviruses (serotypes 1 to 6)

●Echoviruses (serotypes 1 to 9, 11 to 21, 24 to 27, 29 to 33)

Enteroviruses are now divided into four species, designated A through D, based on homology within the ribonucleic acid (RNA) region encoding the VP1 capsid protein [6]. Serotypes added since 1970 are simply named “enterovirus” with a species designation (eg, enterovirus D68). Multiple new enteroviruses have been identified and characterized by molecular methods, bringing the number of known serotypes to more than 100.

Isolates of the same serotype characteristically diverge in the VP1 region by less than 25 percent and less than 12 percent, respectively, within corresponding nucleotide and amino acid sequences [6].

The parechoviruses share many biological, clinical, and epidemiologic characteristics with the enteroviruses, but differ sufficiently in genomic sequence to be classified as a separate genus [7]. The prototypic parechovirus serotypes 1 and 2 were originally designated echovirus 22 and 23, respectively. Four species (parechovirus A to D) and 14 parechovirus serotypes are now recognized [3].

VIROLOGY — Enteroviruses and parechoviruses are small (approximately 27 nm), nonenveloped virions consisting of an icosahedral capsid composed of 60 subunits, each formed from four proteins (VP1 to VP4), that enclose a linear, single-strand, positive-sense RNA genome of about 7.5 kB. The translation product is a single polyprotein that is cleaved by viral coded proteases into the structural proteins (VP1 to VP4), an RNA polymerase, proteases, and other nonstructural proteins [8]. Enteroviruses are relatively acid resistant, maintaining infectivity over a wide pH range. They are resistant to ether and alcohol but inactivated at temperatures above 50°C, although molar magnesium chloride reduces lability at higher temperatures.

Intracellular replication — Infection is initiated by attachment to specific cell membrane receptors that determine host cell susceptibility (table 1). More than one receptor has been identified for some serotypes (eg, group B coxsackieviruses 1, 3, and 5 and enterovirus 71). Penetration and uncoating of the virion with release of RNA into the cell cytoplasm occurs within minutes, and synthesis of negative strand RNA begins within 30 minutes in vitro. The progeny positive-strand RNA serves as message for translation and is also encapsulated into newly formed virions. By 6 to 12 hours, complete virions are visible by electron microscopy. Each infected cell yields approximately 10⁴ to 10⁵ virions, although only 0.1 to 10 percent are infectious.

EPIDEMIOLOGY

Seasonal and demographic distribution — Enterovirus and parechovirus infection occurs throughout the year, with persons living in temperate climates experiencing higher rates of infection in summer and fall [9]. While enterovirus infections occur in all age groups, infants less than one year of age become infected at rates that exceed those of older children and adults by several-fold [10-12]. For unknown reasons, males have a risk of disease that exceeds the risk in females by as much as 50 percent.

Transmission — Transmission of enteroviruses and parechoviruses occurs predominantly via direct or indirect oral contact with virus shed in the upper respiratory tract and feces. Transmission is enhanced by poor sanitary conditions and may occur via numerous routes, including contaminated water, food, and fomites. Epidemiologic and experimental observations suggest that the respiratory route is the principal mode of transmission for some serotypes, including coxsackievirus A21 and enterovirus D68 [13,14]. Enterovirus D70 is shed in tears and is readily spread via fingers and fomites [15].

Longitudinal studies demonstrate that secondary infections occur at high rates in susceptible household contacts [16,17]. Infants, particularly those in diapers, are efficient transmitters. The relative role of virus shedding by symptomatic and asymptomatic persons is not known, but it is likely that both are important.

Periodicity and variability of disease by serotype — The contribution of individual enterovirus and parechovirus serotypes to human infection and disease varies substantially for reasons that are not fully known. Multi-year cycles with different periodicities are observed for many serotypes that follow rhythmic variation in population immunity whereby an accumulation of a "critical mass" of susceptible children may be necessary to exceed a population immunity threshold to sustain transmission [18,19].

A small number of serotypes cause endemic disease in patterns that vary regionally over short cycles. Other serotypes are responsible for widespread outbreaks in which the epidemic strain accounts for more than 30 percent of all isolated enteroviruses, followed by several years of relative quiescence [20]. During outbreaks, the number of reported enterovirus disease cases may increase many-fold over background rates of infection during intervening periods [21]. Occasional epidemics are nearly global, such as those caused by echovirus 9 in the late 1950s, the worldwide pandemic of acute hemorrhagic conjunctivitis due to enterovirus D70 that began in 1969, and the 1979 to 1980 echovirus 11 epidemic.

According to the most recent report of the National Enterovirus Surveillance System maintained at the Centers for Disease Control and Prevention (CDC), the most common serotypes reported in the United States in 2022 were enterovirus D68 and human parechovirus 3 [22].

Some enterovirus serotypes (eg, echovirus 1, coxsackievirus B6, and enterovirus B69) are rarely recognized clinically and to date have exhibited little epidemic potential.

Other previously obscure serotypes have recently emerged to cause widespread disease including:

●Coxsackievirus A6 is the cause of outbreaks of an atypical form of hand, foot, and mouth disease in infants and young children in multiple sites in Europe, the Far East, and North America [23,24]. (See "Atypical exanthems in children", section on 'Atypical hand, foot, and mouth disease'.)

●Enterovirus D68 has been responsible for clusters of respiratory disease in the United States and other countries since 2008, and more recently in many states throughout the United States in the late summer/early autumn [25,26]. Rare cases of acute motor neuron disease similar to poliomyelitis (acute flaccid myelitis), attributed to enterovirus D68 and initially reported in California in 2012, occurred throughout the United States and other countries in the context of biennial surges of respiratory infections between 2014 and 2018 [27-29]. Clinical issues related to enterovirus D68 are discussed elsewhere. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Respiratory disease' and "Acute flaccid myelitis".)

Enterovirus A71 has evolved as a unique cause of epidemic paralysis in localized outbreaks involving small numbers of patients [30-33] and in far larger regional epidemics in the Asia-Pacific region, affecting hundreds to thousands of persons in a single season [34-38]. Infants and young children are at risk of brain stem encephalitis associated with high mortality related to rapid cardiovascular collapse and pulmonary edema [39-41]. Effective vaccines have been developed and licensed in China but have not yet been applied broadly in public immunization programs [42]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Vaccines'.)

Laboratory evidence of parechovirus infection is found in about 5 to 10 percent of specimens submitted for enterovirus testing [43]. The most common parechovirus serotypes are 1 and 3, with type 3 (PeV-A3) predominating as a cause of central nervous system infection [43,44]. In July 2022, the United States Centers for Disease Control and Prevention alerted clinicians to the circulation of PeV-A3 in multiple states. Since parechovirus laboratory testing has become more widely available, it is unclear if the identified cases are reflective of increased testing rather than an increased number of infections [45,46].

PATHOGENESIS

Viral replication and dissemination — Knowledge of in vivo enterovirus replication and dissemination is largely based upon the studies of poliovirus infection in primates [47,48]. The initial sites of virus replication include both the pharynx and terminal ileum. Replication gives rise to a transient, "minor" viremia, which spreads virus hematogenously to lymphoid tissue throughout the body. Subsequent replication at these sites produces a "major" viremia, which coincides with the onset of symptoms, and results in spread of virus to target organs such as the skin, heart, and central nervous system.

Immune response — Convention holds that immunity to enterovirus and parechovirus infection is serotype specific, in part because when reinfection with the same enterovirus serotype occurs, it is invariably asymptomatic. However, studies with monovalent poliovirus vaccines have clearly shown that primary infection may induce heterotypic immune responses [49].

Early studies in mice identified the importance of resident host macrophages in protection from disease [50-52]; experimental poliovirus and group B coxsackievirus infections have demonstrated the role of macrophage TLR-3 signaling and induction of innate interferon responses [50-53]. The humoral immune response plays a central role in response to infection and in prevention of reinfection through generation of antibody-producing plasma cells and memory B cells.

Circulating poliovirus type-specific IgA alpha4beta7-positive cells home to mucosal surfaces and precede the development of secretory IgA in mucosal secretions and colostrum approximately two weeks after infection [54,55].

Th1 helper T cells generated from transgenic mice bearing human poliovirus receptor (PVR), in particular, induce MHC Class II activity against poliovirus-infected cells in vitro and provide helper activity for humoral immune responses in vivo [56]. However, T lymphocytes do not necessarily contribute to viral clearance. To the contrary, in the murine model of coxsackievirus B3 myocarditis, the cytotoxic T cell response enhances myocardial inflammation and increases mortality [57,58].

Certain hosts are more susceptible to serious, life-threatening disease. Neonates may develop serious and sometimes fatal systemic enterovirus infections, which may be transmitted from infected mothers or acquired from other close contacts in the perinatal period. In addition, enteroviruses can cause persistent infections in patients with hereditary or acquired defects in B lymphocyte function, such as X-linked agammaglobulinemia or adults with common variable immunodeficiency. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Immunocompromised patients'.)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hand, foot, and mouth disease and herpangina (The Basics)" and "Patient education: Enterovirus D68 (The Basics)")

SUMMARY

●Classification – The human enteroviruses include polioviruses, group A and B coxsackieviruses, echoviruses, and enteroviruses. Human parechoviruses are genetically related to enteroviruses (but are classified in a separate picornavirus genus) and together share many epidemiological and clinical characteristics. (See 'Classification' above.)

●Epidemiology

•Enteroviruses and parechoviruses are transmitted predominately via fecal-oral contact and cause infection throughout the year, although persons in temperate climates experience higher rates of infection in summer and fall. Infants less than one year of age become infected at rates that exceed those of older children and adults by several-fold. (See 'Epidemiology' above.)

•The more common enterovirus serotypes include group B coxsackieviruses 1 to 5 and some echoviruses. A small number of serotypes cause endemic disease in patterns that vary regionally on an annual basis. Other serotypes (eg, echoviruses 9, 11, and 30, enterovirus D68) are responsible for widespread outbreaks followed by several years of relative quiescence. (See 'Periodicity and variability of disease by serotype' above.)

•Enterovirus A71 has caused widespread outbreaks in China, Taiwan, and Southeast Asia associated with serious central nervous system complications that are similar to poliomyelitis. Outbreaks of respiratory infections caused by enterovirus D68 in the United States and elsewhere have also included paralysis as a rare complication. (See 'Periodicity and variability of disease by serotype' above and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Acute paralysis and brainstem encephalitis'.)

•Most parechovirus infections are caused by types 1 to 3. (See 'Periodicity and variability of disease by serotype' above.)