92: Enteroviruses and Parechoviruses

Enteroviruses and parechoviruses are a large group of viral pathogens represented by 2 different genera of the family Picornaviridae. They are all of a single strand of RNA in a capsid of individually distinct polypeptides. The capsid proteins impart antigenicity and facilitate transfer of RNA into the cells of newly infected hosts.

1. Enteroviruses. The genus of enteroviruses traditionally consisted of 5 groups, each with well-known human infant pathogenicity: coxsackie A viruses, coxsackie B virus, echoviruses, numbered enteroviruses, and polio virus. The new classification (based on viral genomic structure) of the enterovirus genus has 4 species: human enteroviruses (HEV) A, B, C, and D. Although they were reclassified, virus serotypes continue to use their original name.

2. Parechoviruses. The genus of human parechoviruses (HPeVs) is made up of 16 described types but 8 sequenced human parechovirus types. Types 1 and 2 were formerly thought to be human enteroviruses 22 and 23, but after the discovery of capsid proteins distinctly different from those of the genus enterovirus, they have been relegated to a single genus. To date, only types 1–3 have been identified in neonatal sepsis-like viral syndromes. HPeV4–6 are associated with gastrointestinal and respiratory symptoms in young infants. Genotypes are continuing to be characterized and identified.

1. Enteroviruses. Enteroviruses are of worldwide distribution and produce human illness of varying severity, from mild coryza to life-threatening multisystem disease. The diseases have some seasonal variation such as summer-fall in temperate zones but of little variation in the more tropical regions of the world.

   Of special interest to neonatologists is the now well-established enteroviral transplacental passage, enteroviruses detected in breast milk, and vertical passage of enteroviruses within first-degree family members without clinical signs of illness. Enteroviral illnesses are transmitted by the fecal–oral route and, to a lesser extent, respiratory droplets. Incubation periods are typically 3–6 days. All subgroups of enteroviruses are linked to nursery and neonatal intensive care unit (NICU) outbreaks of enteroviral diseases.

   Numerous outbreaks of nonpolio neonatal enterovirus have been reported for newborn nurseries, NICUs, and maternity units over the past 3 decades. Overall incidence for newborn and neonatal infants is variable. The Centers for Disease Control and Prevention (CDC) have reported from the National Enterovirus Surveillance System, 2006–2008, that coxsackie B1 virus (CVB1) accounted for 17% of all reported enterovirus isolates. In contrast, from 1970–2005, they had only accounted for 2.3% of cases. During this time there was also an increase in reports of neonatal morbidity and 5 cases of neonatal death in the United States.

2. Parechoviruses. During 2006–2008 surveillance, HPeV type 1 was the most common isolate of that genus, but only accounted for <2% of identified enteroviral suspect specimens. More recently, a report from Edinburgh, Scotland, for enterovirus surveillance from 2006–2010 revealed an incidence of 2.8% for HPeV, but for infants <3 months of age, HPeV type 3 was the predominant isolate (22–25%).

1. Enteroviruses. Human enteroviruses manifest disease in nearly all body systems. Paradoxically, signs of disease can be mild to nearly nonexistent or life-threatening within the same serotype. Host susceptibility seems to be the distinguishing factor. For the great majority of children and adults, enteroviral illnesses are mild, but for the neonate, a more susceptible host, enteroviruses can cause serious multiorgan dysfunction and death. Some human enteroviruses are more pathogenic than others. Examples of the more serious infections by nonpolio enterovirus serotypes are echo 11, coxsackie B3, coxsackie A9, coxsackie B1, and enterovirus 71.

   1. Echo virus 11. This has been particularly associated with neonatal fatalities. Most pathologic findings have been extensive hepatic necrosis with adrenal hemorrhage and acute tubular necrosis as less frequent additional findings.

   2. Coxsackievirus B3 (CVB3). Neonatal infections have been marked by hepatitis, disseminated intravascular infection, fever, thrombocytopenia, and intracranial hemorrhage. CVB3 has also been closely associated with antenatal maternal infection and positive virus cultures from placenta, cord, and infant tissues at death. All circumstances suggested transplacental viral passage.

   3. Coxsackievirus A9 (CVA9). Although much less common than CVB3, it has a more protean spectrum of neonatal morbidity. It may present as aseptic meningitis, a nonspecific sepsis-like illness, myocarditis, pneumonia, or disseminated intravascular coagulation.

   4. Coxsackievirus B1 (CVB1). Until recently, this has been a fairly uncommon strain. In 2006, for the first time, CVB1 became the most commonly reported enterovirus and remained so through 2008. In 2007 there was a significant increase in neonatal disease, including febrile illness, hepatitis, coagulopathy, meningitis, respiratory distress, and myocarditis. In 2007, in 4 of 5 cases of neonatal death, mothers had chorioamnionitis or febrile illness near the time of delivery.

   5. Enterovirus 71. This has been less frequently reported but has been identified with aseptic meningitis, encephalitis, acute flaccid paralysis, and secondary pulmonary hemorrhage and cardiopulmonary collapse. Community-wide outbreaks in 2003 and 2005 in Denver, Colorado, revealed involvement of infants ≥4 weeks of age with most having central nervous system (CNS) disease.

2. Parechovirus. Parechovirus infections are now recognized as an agent for nursery outbreaks of diarrhea coupled with respiratory illnesses. Several cases of more severe illness have been reported, including meningoencephalitis, neonatal sepsis-like disease, hepatitis, and coagulopathy. Other conditions have included myocarditis and conjunctivitis. Parechoviruses occur in association with other conditions (hemorrhage hepatitis syndrome, necrotizing enterocolitis, myocarditis, herpangina, and febrile illness), but further studies are needed to link them.

   1. HPeV1 (previously echovirus 21). Most common HPeV identified. Usually asymptomatic or mild gastrointestinal (GI) or respiratory symptoms. Very rarely it can cause myocarditis, paralysis, and CNS involvement (encephalitis and paralysis).

   2. HPeV2 (previously echovirus 22). Rare GI symptoms but can have respiratory tract and GI infections with otitis media.

   3. HPeV3. Aseptic meningitis, sepsis-like disease with more severe disease (neonatal sepsis, meningitis, encephalitis with white matter injury, and hepatitis). Also associated with gastroenteritis, respiratory illness, and transient paralysis. Fatal cases have been reported.

   4. HPeV4, 5, and 6. HPeV4 was first isolated from an infant with a fever and feeding problems. These are associated with GI and respiratory symptoms in younger infants. HPeV6 has been associated with flaccid paralysis.

1. Infants born to mothers who have symptoms of enterovirus/parechovirus around the time of the delivery have a higher chance of being infected. In 2010, a study of 242 pregnant Taiwanese women affected by herpangina during their pregnancy had a significantly higher risk for infants being low birthweight, small for gestational age, or preterm.

2. Risk of severe infection is higher if the infant is infected during the first 2 weeks of life.

HPeV infections may mimic HEV infections. When evaluating an infant and looking at clinical signs, it is not possible to distinguish neonatal parechovirus from an enterovirus infection.

1. Enteroviruses. The clinical presentations of nonpolio enterovirus diseases are varied and overlap with the many subspecies and serotypes. In neonates, the signs that suggest an enteroviral outbreak in a nursery might include a cluster of infants with similar findings of coryza, morbilliform rash, low-grade fever, or cough. The latter is a most unusual occurrence in neonates, prompting close observation and investigation. A sepsis-like illness is frequently ascribed to enteroviral illnesses. Sepsis evaluation is often negative, but findings of lethargy, poor feeding, and fever are hallmarks suggesting sepsis. It can also cause hepatitis, coagulopathy, pneumonia, meningoencephalitis, and myocarditis. Hemophagocytic lymphohistiocytosis and severe enteroviral infection can be difficult to distinguish based on clinical presentation and cerebrospinal fluid findings.

2. Parechoviruses. May mimic the presentation of enteroviruses. The majority of infants with HPeV1 and 2 have mild GI and respiratory syndromes. HPeV serotype 3 has been associated with severe neonatal infection, including CNS infection. The most common clinical presentation of HPeV3 is a sepsis-like syndrome. In one study, parechovirus CNS infection was found to be more common in male infants during the late summer or autumn season. Symptoms included irritability, fever, and a nonspecific rash. Infants with parechoviruses may present with an acute distended abdomen accompanied by an erythematous rash, low C-reactive protein, and low lymphocyte count and have been associated with small clusters of patients with necrotizing enterocolitis.

1. Enteroviruses. Polymerase chain reaction (PCR) is readily available in commercial laboratories but lacks specificity for serotyping. Advanced PCR techniques are required to further identify most enterovirus subspecies. PCR is both more rapid and more sensitive than cell culture. Some serotypes are difficult to isolate from cerebrospinal fluid, but can be readily isolated from either throat or rectal swab. Cell culture had been the standard method for isolation and diagnosis, but specific serotype identification requires expensive neutralization assays or genomic sequencing. Several serotypes cannot be grown effectively in culture. Specimens for cell culture or PCR assays should include cerebrospinal fluid, blood, urine, nasal swabs, throat swabs, and stool specimens. Real-time PCR assay for enterovirus RNA allows shorter turnover time for the detection.

2. Parechoviruses. Current enterovirus specific testing does not detect parechovirus infection because of the genetic differences between the two. The best diagnostic tests are PCR primers that have been developed by the CDC that detect all known parechoviruses. White matter injury has been visualized with a cranial ultrasound and magnetic resonance imaging with diffusion weighted imaging in infants with HPeV3 with encephalitis. Many of the parechoviruses do not grow well in cell culture. A direct PCR of stool samples can be obtained.

No specific therapy for human enteroviruses or parechoviruses exists. Overall care involves supportive measures, close observation for organ-specific disease (eg, meningitis, myocarditis), and diagnostic testing to confirm infection. In cases of severe neonatal disease, high-dose human immune globulin has been suggested, but depending on antibody per lot of immune globulin, efficacy varies. Prophylactic immune globulin has been reported to be helpful in controlling hospital nursery outbreaks of enterovirus disease. Observation for bacterial colonization and secondary infection is appropriate, especially for staphylococcal disease. If fulminate hepatic disease is present, oral neomycin therapy to minimize gut flora may be beneficial. Currently the safety and efficacy of the antiviral drug pleconaril is being studied in neonatal viremia.

The illness is usually mild and recoverable. Mortality is increased with the more severe forms of the infection.