Nonpolio Enteroviruses

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Chapter 242 Nonpolio Enteroviruses

The genus Enterovirus contains a large number of agents that produce a broad range of illnesses. The genus name reflects the importance of the gastrointestinal tract as the primary site of invasion and replication and the source for transmission. Viremic spread to distant sites accounts for the majority of clinical manifestations.

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

Family	Picornaviridae
Genus	Enterovirus
Subgroups*	Poliovirus serotypes 1-3
	Coxsackie A virus serotypes 1-22, 24 (23 reclassified as echovirus 9)
	Coxsackie B virus serotypes 1-6
	Echovirus serotypes 1-9, 11-27, 29-33 (echoviruses 10 and 28 reclassified as non-enteroviruses; echovirus 34 reclassified as coxsackie A virus 24; echoviruses 22 and 23 reclassified within the genus Parechovirus)
	Numbered enterovirus serotypes (enterovirus 72 reclassified as hepatitis A virus)

* 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.

Nonspecific Febrile Illness

Nonspecific febrile illnesses are the most common symptomatic manifestations, especially in infants and young children. These are difficult to clinically differentiate from serious infections such as bacteremia and bacterial meningitis, necessitating diagnostic testing, presumptive therapy, and hospitalizations for suspected bacterial infection in young infants.

Illness usually begins abruptly with fever of 38.5-40°C (101-104°F), malaise, and irritability. Other symptoms are lethargy, anorexia, diarrhea, nausea, vomiting, abdominal discomfort, rash, sore throat, and respiratory symptoms, and, in older children, headache and myalgia. Findings are generally nonspecific and may include mild conjunctivitis pharyngeal injection and cervical lymphadenopathy. Meningitis may be present, but, in infants, specific clinical features distinguishing those with meningitis are often lacking. Fever lasts a mean of 3 days and, occasionally, is biphasic. Duration of illness is usually 4-7 days but can range from 1 day to >1 wk. White blood cell (WBC) count and results of routine laboratory tests are generally normal. Concomitant enterovirus and bacterial infection has been observed in a small number of infants.

Enterovirus illnesses may be associated with a wide variety of skin manifestations, including macular, maculopapular, urticarial, vesicular, and petechial eruptions. Rare cases of idiopathic thrombocytopenic purpura have been reported. Enteroviruses have also been implicated in pityriasis rosea. In general, the frequency of cutaneous manifestations is inversely related to age. Serotypes commonly associated with rashes are echoviruses 9, 11, 16, and 25; coxsackie A viruses 2, 4, 9, and 16; and coxsackie B viruses 3-5. Virus can occasionally be recovered from vesicular skin lesions.

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 71; coxsackie A viruses 5, 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. The oropharynx is inflamed and contains scattered vesicles on the tongue, buccal mucosa, posterior pharynx, palate, gingiva, and/or lips (Fig. 242-1). These may ulcerate, leaving 4- to 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; the hands are more commonly involved than the feet (see Fig. 242-1). Lesions on the hands and feet are usually tender, 3- to 7-mm vesicles that occur more commonly on dorsal surfaces but frequently also on palms and soles. Vesicles resolve in about 1 wk. Buttock lesions do not usually progress to vesiculation. Disseminated vesicular rashes may complicate preexisting eczema. Hand-foot-and-mouth disease caused by enterovirus 71 is frequently more severe than coxsackievirus A16 disease, with high rates of neurologic and cardiopulmonary involvement, including brainstem encephalomyelitis, neurogenic pulmonary edema, pulmonary hemorrhage, shock, and rapid death, especially in young children. Coxsackievirus A16 also can occasionally be associated with complications such as myocarditis, pericarditis, and shock.

Figure 242-1 A, Oval blisters of the palms in a child with hand-foot-and-mouth disease (coxsackievirus A16 infection). B, Oval blisters on the feet of a child with hand-foot-and-mouth disease. C, Erosion of the tongue in a child with hand-foot-and-mouth disease.

(From Weston WL, Lane AT, Morelli JG: Color textbook of pediatric dermatology, ed 3, St Louis, 2002, Mosby, p 109.)

Herpangina

Herpangina is characterized by sudden onset of fever, sore throat, dysphagia, and lesions in the posterior pharynx. Temperatures range from normal to 41°C (106°F); fever tends to be greater in younger patients. Headache and backache may occur in older children, and vomiting and abdominal pain occur in 25% of cases. Characteristic lesions, present on the anterior tonsillar pillars, soft palate, uvula, tonsils, posterior pharyngeal wall, and, occasionally, the posterior buccal surfaces, are discrete 1- to 2-mm vesicles and ulcers that enlarge over 2-3 days to 3-4 mm and are surrounded by erythematous rings that vary in size up to 10 mm. Typically about 5 lesions are present, with a range of 1 to >15. The remainder of the pharynx appears normal or minimally erythematous. Most cases are mild and have no complications; however, some are associated with meningitis or more severe illness. Fever generally lasts 1-4 days, and resolution of symptoms occurs in 3-7 days. A variety of enteroviruses cause herpangina, including enterovirus 71, although coxsackie A viruses are implicated most often.

Respiratory Manifestations

Symptoms such as sore throat and coryza frequently accompany and sometimes dominate enterovirus illnesses. Findings include upper respiratory symptoms, wheezing, exacerbation of asthma, apnea, respiratory distress, pneumonia, otitis media, bronchiolitis, croup, parotitis, and pharyngotonsillitis, which may occasionally be exudative. Lower respiratory tract infection may be significant in immunocompromised patients.

Pleurodynia (Bornholm disease), caused most frequently by coxsackie B viruses 3, 5, 1, and 2 and echoviruses 1 and 6, is an epidemic or sporadic illness characterized by paroxysmal thoracic pain, due to myositis involving chest and abdominal wall muscles. In epidemics, children and adults are affected, but most cases occur in persons younger than 30 yr. Malaise, myalgias, and headache are followed by sudden onset of fever and spasmodic, pleuritic pain in the chest or upper abdomen aggravated by coughing, sneezing, deep breathing, or other movement. During spasms, which last from a few minutes to several hours, pain may be severe and respirations are usually rapid, shallow, and grunting, suggesting pneumonia or pleural inflammation. A pleural friction rub may be noted during pain episodes, although chest radiographs are generally normal. Pain localized to the abdomen is frequently crampy, suggesting colic in the younger child. A pale, sweaty, shocklike appearance may suggest intestinal obstruction; tenderness and guarding may suggest appendicitis and peritonitis. Illness usually lasts 3-6 days, and, occasionally, up to 2 wk. It is frequently biphasic and is rarely associated with recurrent episodes over a few weeks, with less prominent fever during recurrences. Pleurodynia may be associated with meningitis, orchitis, myocarditis, or pericarditis.

Life-threatening pulmonary edema, hemorrhage, and/or interstitial pneumonitis may occur in patients with enterovirus 71 encephalitis.

Ocular Manifestations

Epidemics of acute hemorrhagic conjunctivitis, primarily caused by enterovirus 70 and coxsackievirus A24/A24 variant, are explosive, spreading mainly via eye-hand-fomite-eye transmission. School-aged children, teenagers, and adults 20-50 yr of age have the highest attack rates. Sudden onset of severe eye pain is associated with photophobia, blurred vision, lacrimation, conjunctival erythema and congestion, lid edema, preauricular lymphadenopathy, and, in some cases, subconjunctival hemorrhages and superficial punctate keratitis. Eye discharge is initially serous but becomes mucopurulent with secondary bacterial infection. Systemic symptoms including fever are rare, although manifestations suggestive of pharyngoconjunctival fever occasionally occur. Recovery is usually complete within 1-2 wk. Polyradiculoneuropathy or paralytic disease following enterovirus 70 disease occurs occasionally. Other enteroviruses have occasionally been implicated as causes of keratoconjunctivitis.

Epidemic and sporadic uveitis in infants caused by subtypes of enteroviruses 11 and 19 can be associated with severe complications, including destruction of the iris, cataracts, and glaucoma. Enteroviruses have been implicated in cases of chorioretinitis, uveoretinitis, optic neuritis, and unilateral acute idiopathic maculopathy.

Myocarditis and Pericarditis

Enteroviruses account for approximately 25-35% of cases of myocarditis and pericarditis with proven cause (Chapters 433 and 434). Coxsackie B viruses are most commonly implicated, although coxsackie A viruses and echoviruses also may be causative. Adolescents and young adults, especially males, are disproportionately affected. Myopericarditis may be the dominant feature or it may be part of disseminated disease, as in neonates. Disease ranges from relatively mild to severe. Upper respiratory symptoms frequently precede fatigue, dyspnea, chest pain, congestive heart failure, and dysrhythmias. Presentations may mimic myocardial infarction; sudden death may also occur (including apparent sudden infant death syndrome). A pericardial friction rub indicates pericardial involvement. Chest radiography often demonstrates cardiac enlargement. Electrocardiography frequently reveals ST segment, T wave, and/or rhythm abnormalities, and echocardiography may confirm cardiac dilatation, reduced contractility, and/or pericardial effusion. Myocardial enzyme serum concentrations may be elevated. The acute mortality of enterovirus myocarditis is 0-4%. Recovery is complete without residual disability in the majority. Occasionally, chronic cardiomyopathy, inflammatory ventricular microaneurysms, or constrictive pericarditis may result. The role of persistent infection in chronic dilated cardiomyopathy is controversial. Enteroviruses have also been implicated in late adverse cardiac events following heart transplantation and acute coronary events, and in peripartum cardiomyopathy. Myocardial dysfunction observed in enterovirus 71 epidemics most commonly has occurred without evidence of myocarditis and may be of neurogenic origin; however, true myocarditis has also been described.

Gastrointestinal and Genitourinary Manifestations

Symptoms such as emesis (especially with meningitis), diarrhea (rarely severe), and abdominal pain are frequent but generally not dominant. Diarrhea, hematochezia, pneumatosis intestinalis, and necrotizing enterocolitis have occurred in premature infants during nursery outbreaks. Enterovirus infection has been implicated in chronic intestinal inflammation in hypogammaglobulinemic patients, sporadic hepatitis in normal children, severe hepatitis in neonates, and pancreatitis, which may result in transient exocrine pancreatic insufficiency.

Coxsackie B viruses are 2nd only to mumps as causes of orchitis. The illness is frequently biphasic; fever and pleurodynia or meningitis are followed, in about 2 wk, by orchitis, often with epididymitis. Enteroviruses have also been implicated in cases of nephritis and IgA nephropathy.

Neurologic Manifestations

Enteroviruses are the most common cause of viral meningitis in mumps-immunized populations, accounting for up to 90% or more of cases in which a cause is identified. Meningitis is particularly common in infants, especially those <3 mo of age, often in community epidemics. Frequently implicated serotypes include coxsackie B viruses 2-5; echoviruses 4, 6, 7, 9, 11, 13, 16, and 30; parechoviruses 1-6; and enteroviruses 70 and 71. Most cases in infants and young children are mild and lack specific signs and symptoms. Fever is present in 50-100%, accompanied by irritability, malaise, headache, photophobia, nausea, emesis, anorexia, lethargy, hypotonia, rash, cough, rhinorrhea, pharyngitis, diarrhea, and/or myalgia. Nuchal rigidity is apparent in more than half of children >1-2 yr of age. Some cases are biphasic, with fever and nonspecific symptoms for a few days followed by return of fever with meningeal signs several days later. Fever usually resolves in 3-5 days, and other symptoms in infants and young children usually resolve within 1 wk. Symptoms tend to be more severe and longer lasting in adults. CSF findings include pleocytosis (generally <500 but occasionally as high as 1,000-8,000 WBCs/mm³; often predominantly polymorphonuclear cells in the 1st 48 hr before becoming mostly mononuclear); normal or slightly low glucose content (10% <40 mg/dL); and normal or mildly increased protein content (generally <100 mg/dL). CSF occasionally has normal parameters despite positive viral culture or PCR results, particularly in the 1st few months of life. Complications occur in approximately 10% of young children, including simple and complex seizures, obtundation, increased intracranial pressure, syndrome of inappropriate antidiuretic hormone secretion, ventriculitis, transient cerebral arteriopathy, and coma. The prognosis for most children is good.

Enteroviruses are also responsible for ≥10-20% of cases of encephalitis with an identified cause. Frequently implicated serotypes include echoviruses 3, 4, 6, 9, and 11; coxsackie B viruses 2, 4, and 5; coxsackie A virus 9; and enterovirus 71. After initial nonspecific symptoms, there is progression to confusion, weakness, lethargy, and/or irritability. Depression is usually generalized, although focal findings, including focal motor seizures, hemichorea, acute cerebellar ataxia, aphasia, extrapyramidal symptoms, and/or focal imaging abnormalities, may occur. Manifestations range from altered mental status to coma to decerebrate status. Long-term sequelae, including epilepsy, weakness, cranial nerve palsy, spasticity, psychomotor retardation, and hearing loss, or death may follow severe disease. Persistent or recurrent cases have been observed rarely.

Neurologic disorders have been prominent in recent epidemics of enterovirus 71 disease. The majority of affected children had hand-foot-and-mouth disease, some had herpangina, and others had no mucocutaneous manifestations. Neurologic syndromes in a fraction of children included meningitis, meningoencephalomyelitis, poliomyelitis-like acute flaccid paralysis, Guillain-Barré syndrome, transverse myelitis, cerebellar ataxia, opsoclonus-myoclonus syndrome, benign intracranial hypertension, and brainstem encephalitis (rhombencephalitis involving the midbrain, pons, and medulla). The last is characterized by myoclonus, vomiting, ataxia, nystagmus, tremor, cranial nerve abnormalities, autonomic dysfunction, and MRI demonstration of brainstem lesions. Although the disease was mild and reversible in some children, others had rapid progression to neurogenic pulmonary edema and hemorrhage, cardiopulmonary failure, shock, and coma. High mortality rates have been reported, especially in children <5 yr of age. Deficits such as central hypoventilation, bulbar dysfunction, neurodevelopmental delay, cerebellar defects, attention deficit/hyperactivity–related symptoms, and limb weakness and atrophy have been observed among survivors, especially those who experienced cardiopulmonary failure during their acute illness. Similar clinical pictures have been produced by other enterovirus serotypes (e.g., echovirus 7).

Patients with antibody deficiencies and combined immunodeficiencies (including human immunodeficiency virus infection and acute lymphocytic leukemia) are at risk for acute or, more commonly, chronic meningoencephalitis. The latter is characterized by persistent CSF abnormalities, viral detection by culture or PCR for years, and recurrent encephalitis and/or progressive neurologic deterioration, including insidious intellectual or personality deterioration, altered mental status, seizures, motor weakness, and increased intracranial pressure. Although disease may wax and wane, deficits generally become progressive and ultimately are frequently fatal or lead to long-term sequelae. A dermatomyositis-like syndrome, hepatitis, arthritis, myocarditis, or disseminated infection may also occur. Chronic enterovirus meningoencephalitis has become less common now that treatment with antibody replacement with high-dose intravenous immunoglobulin is available.

A variety of nonpoliovirus enteroviruses, including enteroviruses 70 and 71, coxsackie A viruses 7 and 24, coxsackie B viruses, and several echoviruses, can cause poliomyelitis-like acute flaccid paralysis with motor weakness due to anterior horn cell involvement. Disease tends to be milder than that caused by poliovirus, with less bulbar involvement and less persistent weakness. Other neurologic syndromes include cerebellar ataxia, transverse myelitis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, peripheral neuritis, optic neuritis, other cranial neuropathies, sudden hearing loss, tinnitus, and inner ear disorders such as vestibular neuritis.

Myositis and Arthritis

Although myalgia is common, direct evidence of muscle involvement, including rhabdomyolysis, muscle swelling, focal myositis, and polymyositis, has uncommonly been reported. A dermatomyositis-like syndrome and arthritis can be seen in enterovirus-infected hypogammaglobulinemic patients. Enteroviruses are a rare cause of arthritis in normal hosts.

Neonatal Infections

Neonatal infections are relatively common, with a disease incidence comparable to or greater than that of neonatal herpes simplex virus, cytomegalovirus, and group B streptococcus disease. Infection frequently is caused by coxsackie B viruses 2-5 and echoviruses 6, 9, 11, and 19, although many serotypes have been implicated, including, in later years, coxsackie B virus 1 and echovirus 30. Enteroviruses may be acquired vertically before, during, or after delivery, including possible transmission via breast milk; horizontally from family members; or by sporadic or epidemic transmission in nurseries. In utero infection can lead to fetal demise, nonimmune hydrops fetalis, or neonatal illness; additionally, intrauterine infection has been speculatively linked to congenital anomalies, intrauterine growth retardation, neurodevelopmental sequelae, unexplained neonatal illness and death, and increased risk of type 1 diabetes.

Neonatal infection may range from asymptomatic (the majority) to benign febrile illness to severe multisystem disease. Most affected newborns are full term and previously well; maternal history often reveals a recent viral illness, including fever and, frequently, abdominal pain. Neonatal symptoms may occur as early as day 1 of life, with onset of severe disease generally within the 1st 2 wk of life. Frequent findings include fever or hypothermia, irritability, lethargy, anorexia, rash (usually maculopapular, occasionally petechial or papulovesicular), jaundice, respiratory symptoms, apnea, hepatomegaly, abdominal distention, emesis, diarrhea, and decreased perfusion. Most patients have benign courses, with resolution of fever in an average of 3 days and of other symptoms in about 1 wk. A biphasic course may occur occasionally. A minority have severe disease dominated by any combination of sepsis, meningoencephalitis, myocarditis, hepatitis, coagulopathy, and pneumonitis. Meningoencephalitis may be manifested by focal or complex seizures, bulging fontanelle, nuchal rigidity, or reduced level of consciousness. Myocarditis, most often associated with coxsackie B virus infection, may be suggested by tachycardia, dyspnea, cyanosis, and cardiomegaly. Hepatitis and pneumonitis are associated with echovirus infection, although they may occur with coxsackie B viruses. Gastrointestinal manifestations may predominate in premature neonates. Laboratory and radiographic evaluation may reveal leukocytosis, thrombocytopenia, CSF pleocytosis, CNS white matter damage, elevations of serum transaminases and bilirubin, coagulopathy, pulmonary infiltrates, and electrocardiographic changes.

Complications of severe neonatal disease include CNS necrosis and generalized or focal neurologic compromise; arrhythmias, congestive heart failure, myocardial infarction, and pericarditis; hepatic necrosis and failure; intracranial or other bleeding; adrenal necrosis and hemorrhage; and rapidly progressive pneumonitis and pulmonary hypertension. Myositis, arthritis, necrotizing enterocolitis, inappropriate antidiuretic hormone secretion, hemophagocytic syndrome, bone marrow failure, and sudden death are rare events. Mortality with severe disease is significant and most often associated with hepatitis and bleeding complications, myocarditis, or pneumonitis.

The majority of survivors of severe neonatal disease have gradual resolution of hepatic and cardiac dysfunction, although chronic calcific myocarditis and ventricular aneurysm can occur. Meningoencephalitis may be associated with speech and language impairment; cognitive deficits; spasticity, hypotonicity, or weakness; seizure disorders; microcephaly or hydrocephaly; and ocular abnormalities. However, most survivors appear not to have long-term sequelae. Risk factors for severe disease include illness onset in the first few days of life, maternal illness just prior to or at delivery, prematurity, male sex, infection by echovirus 11 or a coxsackie B virus, positive serum viral culture result, absence of neutralizing antibody to the infecting virus, and evidence of severe hepatitis and/or multisystem disease.

Stem Cell Transplant Recipients and Patients with Malignancies

Severe and/or prolonged enterovirus infections in stem cell transplant recipients include progressive pneumonia, severe diarrhea, pericarditis, heart failure, meningoencephalitis, and disseminated disease. Enterovirus-associated hemophagocytic syndrome, meningitis, encephalitis, and myocarditis have been reported in children with malignancies. Infections in both groups are associated with high fatality rates.

Diagnosis

Clues to enterovirus infection include characteristic findings such as hand-foot-and-mouth disease or herpangina lesions, consistent seasonality, known community outbreak, and exposure to enterovirus-compatible disease. In the neonate, history of maternal fever, malaise, and/or abdominal pain near delivery during enterovirus season is suggestive.

Viral culture using a combination of cell lines is the gold standard for confirmation. Sensitivity ranges from 50% to 75% and can be increased by sampling of multiple sites. In children with meningitis, yield of culture is enhanced by sampling CSF plus the throat and rectum. In neonates, yields of 30-70% are achieved when blood, urine, CSF, and mucosal swabs are cultured. A major limitation is the inability of most coxsackie A viruses to grow in culture. Yield may also be limited by neutralizing antibody in patient specimens, improper specimen handling, or insensitivity of the cell lines. Culture is relatively slow, with 3-8 days usually required to detect growth. Centrifugation-enhanced antigen detection coupled with culture (shell vial techniques) can shorten the time to detection, but the sensitivity of this method has been limiting. Although cultivation of an enterovirus from any site can generally be considered evidence of recent infection, isolation from the rectum or stool can reflect more remote shedding. Similarly, recovery from a mucosal site may suggest an association with an illness, whereas recovery from a normally sterile site (e.g., CSF, blood, or tissue) is more conclusive evidence of causation. Serotype identification is generally required only for investigation of an outbreak or an unusual disease manifestation or to distinguish nonpoliovirus enteroviruses from vaccine or wild-type polioviruses.

Direct testing for nucleic acid overcomes the imperfect sensitivity and delayed results of culture. RT-PCR detection of highly conserved areas of the enterovirus genome can detect the majority of enteroviruses, including coxsackie A viruses (but frequently not the parechoviruses) in CSF; serum; urine; conjunctival, nasopharyngeal, throat, tracheal, rectal, stool, and dried blood spot specimens; and tissues such as myocardium, liver, and brain. Sensitivity and specificity of RT-PCR are high, with results in as short as 2-3 hr. Real-time, quantitative PCR assays and nested PCR assays with enhanced sensitivity have been developed, as have enterovirus-containing multiplex PCR assays, nucleic acid sequence–based amplification (NASBA) assays, culture-enhanced PCR assays, and PCR-based microarray assays. Results of PCR testing of CSF from children with meningitis and from hypogammaglobulinemic patients with chronic meningoencephalitis are frequently positive despite negative culture results. PCR testing of tracheal aspirates of children with myocarditis has good concordance with testing of myocardial specimens. In ill neonates and young infants, PCR testing of serum and urine has higher yields than culture, and viral load in blood is correlated with severity. Routine application of CSF PCR for infants and young children with suspected meningitis decreases the number of diagnostic tests, duration of hospital stay, antibiotic use, and overall costs. Sequence analysis of amplified nucleic acid can be used for serotype identification and phylogenetic analysis. Serotype-specific (e.g., enterovirus 71 and coxsackie A virus 16) PCR assays have also been developed. For enterovirus 71, the yield of specimens other than CSF (throat, nasopharyngeal, rectal, and vesicle swabs and CNS tissue) is greater (by PCR or culture) than the yield of CSF specimens, which are infrequently virus-positive.

Enterovirus infections can be detected serologically by a rise, in serum or CSF, of neutralizing, complement fixation, enzyme-linked immunosorbent assay (ELISA), or other type-specific antibody or by serotype-specific IgM antibody. However, serologic testing requires presumptive knowledge of the infecting serotype or an assay with sufficiently broad cross reactivity. Sensitivity may be limited. Except for epidemiologic studies or severe cases characteristic of specific serotypes (e.g., enterovirus 71), serology is generally less useful than culture or nucleic acid detection.

Differential Diagnosis

The differential diagnosis of enterovirus infections varies with the clinical presentation (Table 242-2).

Table 242-2 DIFFERENTIAL DIAGNOSIS OF ENTEROVIRUS INFECTIONS

CLINICAL MANIFESTATION	BACTERIAL PATHOGENS	VIRAL PATHOGENS
Nonspecific febrile illness	Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis	Influenza viruses, human herpesviruses 6 and 7
Exanthems/enanthems	Group A streptococcus, Staphylococcus aureus, N. meningitidis	Herpes simplex virus, adenoviruses, varicella-zoster virus, Epstein-Barr virus, measles virus, rubella virus, human herpesviruses 6 and 7
Respiratory illness/conjunctivitis	S. pneumoniae, H. influenzae (nontypable and type b), N. meningitidis, Mycoplasma pneumoniae, Chlamydia pneumoniae	Adenoviruses, influenza viruses, respiratory syncytial virus, parainfluenza viruses, rhinovirus, human metapneumovirus
Myocarditis/pericarditis	S. aureus, H. influenzae type b, M. pneumoniae	Adenoviruses, influenza virus, parvovirus, cytomegalovirus
Meningitis/encephalitis	S. pneumoniae, H. influenzae type b, N. meningitidis, Mycobacterium tuberculosis, Borrelia burgdorferi, M. pneumoniae, Bartonella henselae, Listeria monocytogenes	Herpes simplex virus, West Nile virus, influenza viruses, adenovirus, Epstein-Barr virus, mumps virus, lymphocytic choriomeningitis virus, arboviruses
Neonatal infections	Group B streptococcus, gram-negative enteric bacilli, L. monocytogenes, Enterococcus	Herpes simplex virus, adenoviruses, cytomegalovirus, rubella virus