Chapter 306. Enterovirus Infections

The Enteroviruses constitute a genus within the Picornaviridae family of viruses. As their family name implies, these viral agents are small (ie, “pico”), ribonucleic acid (RNA) genome (ie, “rna”), viruses (ie, “viridae”). Traditionally, the genus Enterovirus was speciated into 5 groups: polioviruses, Coxsackie A viruses, Coxsackie B viruses, echoviruses, and numbered enteroviruses (Table 306-1).

The current taxonomic classification of the enteroviruses is based on molecular and biologic characteristics of the viral isolates and divides the enteroviruses into 5 species: polioviruses and human enteroviruses A–D (Table 306-1).17 There are currently 68 recognized enteroviral serotypes. An additional 16 enterovirus serotypes await official recognition.

Morphologically, the enteroviruses are icosahedral-shaped virions that lack an envelope and measure 30 nm in diameter. The capsid is composed of 60 units each of 4 viral capsid proteins: VP1, VP2, VP3, and VP4. They are acid-, ether-, and chloroform-stable and insensitive to nonionic detergents. The enterovirusesare inactivated by heat (> 56°C), ultraviolet light, chlorination, and formaldehyde. These physical and chemical characteristics confer environmental stability to the enteroviruses, permitting them to survive for days to weeks in water and sewage.

Epidemiology

The enteroviruses are ubiquitous agents with a worldwide distribution. Enteroviral infections exhibit a strong seasonal epidemiology. In regions with temperate climates, the majority of enterovirus infections occur during the summer and early fall.30-32 In the United States, approximately 80% of reported nonpolio enterovirus infections occur from June to October, with the peak incidence of disease occurring in August.32 Enterovirus infections continue to occur during the winter but with significantly less frequency than during the warmer months of the year.33-36 In the world’s tropical regions, enterovirus infections occur year round or with increased incidence during the rainy season.37

In the United States and the Americas, as a result of effective vaccination programs against the polioviruses, these members of the genus no longer circulate endogenously and therefore no longer contribute to annual enteroviral disease burden. With the exception of Africa and the Indian subcontinent, the wild-type polioviruses have been eradicated from the endemic circulating pool of enteroviruses throughout the world.38 Although wild-type poliovirus infections no longer occur in North America and the Americas, occasional outbreaks or introductions of vaccine-derived polioviruses continue to occur.39,40

Vaccine-derived polioviruses are circulating strains derived from the vaccine (Sabin) strains of the polioviruses and, with rare exception, arise from recombination with naturally circulating enterovirus serotypes within the human enterovirus C species (Table 306-1). Vaccine-derived poliovirus-related paralytic disease or isolates have been reported in Cambodia, China, Dominican Republic, Egypt, Haiti, Indonesia, Iran, Israel, Kuwait, Madagascar, Myanmar, Niger, Nigeria, the Philippines, Tunisia, and the United States.40,42

The dominant circulating nonpolio enterovirus serotypes vary by geographic region and by year,32,43-45 and in any given year, multiple enteroviral serotypes may circulate within a community or geographic region.46-49 Information from the Centers for Disease Control and Prevention’s National Enterovirus Surveillance System from 1970 through 2005 indicate that the predominant nonpolio enterovirus isolates identified in the United States, listed in descending order, were echoviruses 9, 11, and 30; coxsackievirus B5; echovirus 6; coxsackievirus B2; coxsackievirus A9; echovirus 4; coxsackievirus B3; echovirus 7; coxsackievirus B4; echovirus18; coxsackievirus B1; and echoviruses 3 and 5.32 These 15 serotypes account for approximately 80% of all enteroviruses reported to the CDC during that period. The patterns of circulation vary depending on serotype. However, the majority of the commonly encountered enteroviruses exhibit an epidemic pattern of circulation.

The highest incidence of enteroviral infections is observed in infants under 1 year of age and in toddlers 1 to 4 years of age. Indeed, nearly 45% of cases reported to the CDC from 1970 to 2005 occurred in infants under 1 year.32 The lack of adequate personal hygiene exhibited by children may help to explain the high rates of infection among this population and their caregivers and families. Clinical or serologic evidence of secondary enteroviral infections are observed to occur in more than 50% of susceptible members of households with an infected child.46,50,51 In addition to well-recognized communitywide enteroviral outbreaks,33,46-48 outbreaks have been reported to occur in neonatal units and nurseries,52-55 schools,56,57 childcare centers,51,58,59 camps and pools,56,60-63 as well as among football teams.64-67

It is estimated that a billion or more individuals worldwide are infected with nonpolio enteroviruses annually.8 In the United States, the nonpolio enteroviruses are estimated to cause 30 to 50 million infections each year8,19 that result in 10 million to 15 million symptomatic nonpolio enterovirus infections annually.31 Enteroviral infections result in an estimated 30,000 to 50,000 hospitalizations annually for meningitis.29 Owing to underreporting, this figure may underestimate the actual number of cases.

Pathophysiology

The RNA genome of the enteroviruses is approximately 7.4 kb in length and serves as a template for viral protein translation and RNA replication18 (eFig. 306.1). It is organized into a long (~ 740 nucleotides) 5-nontranslated or noncoding region (5NTR or NCR), which precedes the single open reading frame. The open reading frame is followed by a short 3NTR and a terminal polyadenylated tail. The enterovirus 5NTRs and 3NTRs play critical roles in the life cycle of the virus.18 A domain located at the extreme 5-terminus of the 5NTR is essential for replication of viral RNA.19 The 3NTR has been demonstrated to also play a role in viral RNA replication. The viral genome is translated in a cap-independent manner regulated by the internal ribosome entry site within the 5NTR.20 For the polioviruses, the 5NTR has been documented to be a major determinant of virulence phenotype (ie, the ability to cause paralysis).21

Neurovirulence-determining genomic regions have yet to be identified for the nonpolio enteroviruses. In animal models of nonpolio enteroviral disease, determinants of virulence for myocarditis and pancreatitis have been variably localized to the 5NTR and the viral capsid.22-24 The 5NTR possesses regions of high nucleotide identity in which nucleotide sequences with absolute (or near absolute) conservation exist among the enteroviruses.25,26 These regions have been exploited for the design of primers and probes used for the detection of the enterovirus through nucleic acid amplification techniques; eg, reverse transcriptionpolymerase chain reaction [RT-PCR] and nucleic acid sequence–based amplification [NASBA]).27 The enteroviral open reading frame is subdivided into 3 regions designated P1, P2, and P3.28

The P1 region codes for 4 structural proteins (VP1–4) that form the viral capsid. The capsid protein coding regions are contiguous to one another and are organized from 5 to 3 as VP4 (1A), VP2 (1B), VP3 (1C), and VP1 (1D) without intervening stop codons. The largest of the capsid proteins is VP1 and contains type-specific epitopes correlating with serotype.29 The VP1 coding sequences serve as the target for molecular serotyping of the enteroviruses.7 The P2 and P3 regions code for 7 nonstructural proteins (5-2A, 2B, 2C, 3A, 3B, 3C, and 3D-3) that are essential for the viral lifecycle. Viral cell entry and uncoating is receptor mediated. The enteroviruses replicate optimally at 36° to 37°C. Viral replication takes place in the cytoplasm of the cell and results in a lytic infection that kills the infected cell.

Humans are the only hosts for the enteroviruses. Most of what is known regarding the pathogenesis of human enteroviral infections has been derived from the study of the polioviruses in animal models68-70 and supplemented by observations in humans.71 While several modes for transmission of the enteroviruses exist (fecal-oral, respiratory, transplacental, perinatal, self-inoculation), the major route is that of the fecal-oral. For some serotypes (ie, coxsackievirus A21 and enteroviruses 68, 70, 71), respiratory transmission and self-inoculation are important routes of transmission. Once infected, individuals may shed virus from the respiratory tract for 1 to 2 weeks and from the gastrointestinal tract for 6 to 8 weeks.46,72-74

After oral or respiratory routes of infection, the enteroviruses infect cells in the upper respiratory and, predominantly, the lower gastrointestinal tracts.71 While the exact cells responsible for infection in the upper respiratory tract are unknown, it is believed that polioviruses infect M cells within Peyer patches or enterocytes in the lower gastrointestinal tract.68,71,75,76 Enteroviral replication in the gastrointestinal and upper respiratory tracts results in a primary or minor viremia that leads to seeding of organs (liver, lung, heart, and central nervous system) distant from the sites of primary infection. A second, major viremia ensues following replication at these sites. Replication in organs seeded during the minor viremia results in the clinical manifestations of enteroviral infection. Vertical transmission to the fetus is possible during the viremic stages of maternal infection. If the central nervous system (CNS) was spared during the minor viremia, it may become infected as a result of the major viremia. This may explain the biphasic nature of illness associated with polio and nonpolio enteroviral infections of the CNS. The mechanism(s) by which the enteroviruses gain entry to the CNS are not yet clearly determined. Viremia has been show to be essential to development of poliomyelitis in chimpanzees.68 Free and cell-associated enterovirus can be detected in blood of patients with enteroviral infections, supporting a role for hematogenous entry into the central nervous system.77 Pharmacokinetic analysis of intravenously injected poliovirus in a transgenic mouse model suggests that poliovirus can enter the central nervous system via the vascular system.78 Primate and transgenic mouse models, supplemented by anecdotal evidence in humans, indicates that poliovirus can also enter the central nervous system via a neural route using retrograde axonal transport.79-83 Thus, it is probable that the enteroviruses employ multiple means to gain access to the central nervous system.

Viremia and viral replication in the CNS ceases once the host produces a type-specific antibody response. Individuals with altered humoral immunity are at risk for severe and chronic enteroviral infections.

Clinical Manifestations

It is important to keep in mind that the vast majority of enteroviral infections result in a subclinical infection.46,84,85 However, given the large number of enteroviral infections that occur, it is easy to understand why these viral agents are the preeminent cause of summer and autumnal viral disease each year.

Nonfocal Febrile Illness

The enteroviruses are common causes of febrile illness without an apparent focus, particularly in infants and toddlers under 2 years of age.85-88 This syndrome may result in hospitalization of significant numbers of young infants and children for evaluation of possible bacterial infections.85,87 The onset of the illness is typically abrupt with fever (⩾ 38°C) in combination with 1 or multiple signs and symptoms: poor feeding, lethargy, irritability, emesis, diarrhea, and upper respiratory tract symptoms. In approximately one quarter of patients, an exanthem may be present. The fever may be biphasic in nature with an intervening period of euthermia.88 Older children may complain of abdominal pain. On physical examination, findings are absent or minimal and may consist of mild pharyngeal and conjunctival injection, lymphadenopathy, and exanthems. The duration of illness is generally less than 5 days.

Central Nervous System Syndromes

The nonpolio enteroviruses are the predominant cause of viral meningitis in children and adolescents, accounting for up to 90% of cases of viral meningitis where an etiology can be determined.89-92 The echoviruses and Coxsackie B viruses are the principle causes of enteroviral meningitis.32,91-93 The enterovirus serotypes most frequently associated with meningitis, in descending order of frequency, are echoviruses 9, 11, and 30; coxsackievirus B5; echovirus 6; coxsackievirus B2; coxsackievirus A9; echovirus 4; coxsackievirus B4; and echoviruses 7, 18, and 5.32 Although a great deal of attention has been focused on West Nile virus as a cause of summer-associated viral CNS infections, the enteroviruses continue to be the major cause of summer cases of aseptic meningitis, even during epizootic outbreaks.94

The clinical presentation of enteroviral meningitis varies with age. In neonates, the dominant symptoms consist of fever (⩾ 38.0°C) and irritability. The fontanelle may be full or bulging. A rash may be occasionally present. Meningoencephalitis in neonates may be manifested by fever, profound lethargy, seizures, full fontanelle, focal neurologic abnormalities, and, much less commonly, nuchal rigidity.95-99 Evidence of involvement of other organs (ie, hepatitis, myocarditis, pneumonitis) may be present in severe cases of neonatal meningitis or meningoencephalitis.100

In infants outside of the neonatal period and in children, the onset of enteroviral meningitis is generally abrupt with fever (38°–40°C) being the most common presenting sign.90,93,101,102 The fever lasts from 1 to 5 days. In some, the pattern of the fever may be biphasic: present for a day, then absent for 2 to 3 days, then reappearing.103-105 Young children and infants may be irritable or lethargic and exhibit other nonspecific signs such as poor feeding, emesis, diarrhea, and rash.93,98,106 In infants, the fontanelle may be full.90,98 The presence of signs of meningeal irritation (ie, nuchal rigidity, Brudzinski and Kernig signs) increases with advancing age after 3 months and are present in the majority of children older than a year.90,98 Less than 10% of infants under 3 months of age with enteroviral meningitis have signs of meningeal irritation.98 Headache, most likely as a result of increased intracranial pressure, is present in nearly all who can report it.106 The headache may be ameliorated by the performance of a lumbar puncture.107 Photophobia is a common clinical component of the disease. Seizures occur in less than 5% of cases.98,101 Nonspecific findings, singly or in combinations, such as rash, malaise, sore throat, abdominal pain, nausea, vomiting, and myalgia, are common. Other nonneurologic enterovirus-associated syndromes, such as herpangina, pleurodynia, and myocarditis, may occur concurrently with the meningitis. In some patients, the entire illness may exhibit a biphasic course consisting of an initial period of nonspecific signs and symptoms (eg, fever, headache, gastrointestinal symptoms, myalgia) that resolve and subsequently recrudesce, accompanied by evidence of frank neurologic involvement.104,108 The duration of enteroviral meningitis in infants and children is generally less than 1 week.

Potential complications of meningitis include coma, increased intracranial pressure, as well as inappropriate secretion of antidiuretic hormone, but these occur uncommonly.98,109

The presentation of enteroviral meningitis in adolescents and adults is less well characterized than in children and infants.33,58,110-113 Headache is nearly universally present. In 1 report, 80% of adolescents and adults required narcotic analgesics to control the pain.110 Photophobia, fever (⩾ 37.5°C), signs of meningeal irritation, nausea, emesis, and neck stiffness are reported in greater than two thirds of patients. Myalgia has been reported in approximately 20% to 90% of patients. Less frequent findings include rash and abdominal pain. The time to full recovery in adults may take up to 2.5 weeks.110

Reports of enteroviral encephalitis predominate in children.106,108,111-122 Enterovirus infections may result in generalized or focal encephalitis. It is estimated that 500 to 1000 cases of enteroviral-related encephalitis occur each year in the United States.15 Prior to the incursion of West Nile virus into the Americas, enterovirus accounted for as much as approximately 10% to 20% of proven viral encephalidities in North America.123-126 In other parts of the world, the contribution of the enteroviruses to the overall burden of virally confirmed encephalitis may be significantly less.127,128

Fever, headache, malaise, myalgia and upper respiratory symptoms, nausea, emesis, or diarrhea may precede the onset of the neurologic findings of enteroviral encephalitis. Viral exanthems have occasionally been reported.118 CNS signs and symptoms may consist of confusion, irritability, weakness, lethargy, and somnolence. The patient may progress to a state of coma. Generalized or focal seizures may occur.116-118 Reported focal neurologic findings may include hemiplegia, hemichorea, and paraesthesia.108,114,117,122,129 The focal nature of the neurologic findings can mimic those seen with herpes simplex encephalitis.114,117,130 Fatal outcomes have been reported.106,118,122

Encephalitis due to enterovirus 71 deserves special mention. A severe brainstem encephalitis (ie, rhombencephalitis) has been reported primarily in children as a result of enterovirus 71 infection.131 The illness may have a biphasic presentation with either hand-foot-and-mouth disease or herpangina preceding the onset myoclonus, the principle neurologic manifestation. The severity of the rhombencephalitis varies. In Grade I rhombencephalitis, myoclonic jerks are associated with tremor and/or ataxia. Grade II myoclonus is associated with cranial nerve involvement. In its most severe presentation, Grade III, myoclonus is transient and followed by the rapid onset of respiratory distress secondary to neurogenic pulmonary edema, cyanosis, poor perfusion shock, coma, and apnea. Mortality with grade III disease may approach 70%. Reported neurologic sequelae include myoclonus, abducent-nerve palsy, facial diplegia, ataxia, dysarthria, internuclear ophthalmoplegia, and central apnea.

Although acute flaccid paralysis has been traditionally linked to the polioviruses, vaccine-derived polioviruses and several nonpolio enterovirus can also cause this syndrome. In regions of the world where the polioviruses have been eradicated, the nonpolio enteroviruses and circulating vaccine-derived polioviruses131,132 are now the principle causes of enteroviral-associated acute flaccid paralysis. Reported nonpolio enterovirus serotypes known to cause acute flaccid paralysis include coxsackieviruses A4, A7, A21, and A24; coxsackieviruses B2, B3, and B5; echoviruses 3, 7, 9, 18, 19, and 33; and enteroviruses 68 and 71.32,132-136 Acute flaccid paralysis due to the nonpolio enteroviruses tends to be milder than that observed with poliovirus infection. It lacks fever at the time of onset of paralysis, affects the upper extremities and face more frequently, is associated with a more rapid recovery, and is less likely to be associated with atrophy. Interestingly, acute flaccid paralysis due to the nonpolio enteroviruses tends to be more severe in infants.134,137

Exanthems

Enterovirus infections can result in a plethora of exanthematous syndromes,138 with any particular serotype capable of causing several different types of rash. The exanthems of enteroviral infection are more commonly associated with infections of individuals 15 years or younger.139 With the exception of coxsackievirus A16, no single enterovirus serotype is associated with a unique exanthem. The characteristics of the rashes include maculopapular, macular, papular, morbilliform, rubelliform, vesicular, urticarial, papulopustular, and scarlatiniform.138,140 In some cases, a petechial rash reminiscent of that seen with meningococcemia may occur.138,141

One syndrome, hand-foot-and-mouth disease, has been typically associated with coxsackievirus A16.138,142 However, other group A coxsackieviruses and enterovirus 71 may also cause this syndrome.138,143 The illness is heralded by low-grade fever, malaise, anorexia, and oral soreness. One to 2 days later, an oral enanthem appears, characterized by macules that rapidly vesiculate and rapidly vesiculate and ultimately ulcerate. The evolution of the enanthem may be so rapid that only the ulcerative lesions are seen.The lesions resemble those of aphthous stomatitis and are typically distributed on the buccal mucosa and tongue. They may also occur on the palate, uvula, anterior pillars, and gums. The exanthem occurs in approximately two thirds of cases and consists of 3-mm to 7-mm vesicles on slightly erythematous bases. The hands are most commonly involved, followed by the feet and buttocks. Lesions at the latter site tend not to be vesicular. The vesicles predominantly involve the dorsal surfaces of the hands and feet, but the palms and soles are also involved (Fig. 306-1). The illness usually lasts less than a week.

Respiratory Tract Syndromes

Upper respiratory tract signs and symptoms may accompany enteroviral-associated fevers as well as many of the system- or organ-specific enteroviral syndromes. They may result in both upper and lower respiratory tract syndromes: herpangina, summer cold, pharyngitis, tonsillitis, laryngotracheobronchitis, and pneumonia.144 The enteroviruses are responsible for up to 15% of etiologically linked upper respiratory tract syndromes.144 Recently, the use of nucleic acid detection methodologies has demonstrated that 18% of children hospitalized with lower respiratory tract infections and 25% hospitalized with acute wheezing had evidence of enteroviral infection.145,146

Herpangina is most commonly caused by the group A coxsackieviruses but has also been associated with group B coxsackieviruses, echoviruses, and numbered enteroviruses.144 The onset of syndrome is marked by fever to as high as 41°C with the higher temperatures more commonly seen in younger patients.147-149 The enanthem is principally located to the anterior pillars of the tonsillar fauces. It may also be present on the soft palate, uvula, and tonsils. Rarely, involvement of the posterior buccal surfaces and dorsal tip of the tongue may occur. The enanthem consists of papulovesicular, grayish-white lesions, 1 to 2 mm in diameter, with an areola of erythema. Over 2 to 3 days, tThe lesions progress from papular to vesicular, increase in size (3–4 mm), and ultimately ulcerate. On average, 5 lesions are present. Associated findings and symptoms include sore throat, mild cervical lymphadenopathy, sialorrhea, anorexia, dysphagia, abdominal pain, and emesis. The illness generally lasts 10 days.

The typical enteroviral summer cold consists of nasal congestion, rhinorrhea, and sneezing. Malaise and cough may sometimes be present. Fever and sore throat are minimal or typically absent. The illness lasts less than a week.

Pharyngitis and tonsillitis, alone or in combination (pharyngotonsillitis), has an abrupt onset with fever (38° to 40°C) in association with sore throat and typically lasts 6 days or less.144 Examination of the throat reveals erythema and inflammation of the nasopharynx, tonsils, uvula, and soft palate. Petechiae may be present. Cervical lymphadenitis is common.

Pneumonias due to the enteroviruses are clinically indistinguishable from those due to other viral agents.144 The onset of the illness is gradual, helping to differentiate it from that of bacterial causes, consisting of coryza, anorexia, and low-grade fever. This is followed by a nonproductive cough, tachypnea, retractions, nasal flaring, and, in severe cases, cyanosis. Wheezing may be present if there is concomitant bronchiolitis or bronchospasm. Radiographic findings consist of perihilar infiltrates, patchy consolidation, air trapping, and atelectasis.

Muscular Syndromes

Pleurodynia was fully characterized during an outbreak of the syndrome in Bornholm, Demark, thereby providing its common geographically linked name: Bornholm disease.150 It is known by other descriptive designations, such as epidemic myalgia and devil’s grip. The group B coxsackieviruses are the usual causes of sporadic and epidemic pleurodynia (Bornholm disease), but pleurodynia may also be caused by other enterovirus serotypes.15,151

Pleurodynia is a misnomer for this clinical condition, which is primarily a muscular disease with clinical manifestations suggestive of a pleuritic origin. The onset of fever and pain is abrupt in the majority of patients. However, a prodrome of up to 10 days consisting of headache, malaise, anorexia, and vague myalgia may occur. The fever may be biphasic. The pain is severe and paroxysmal, referred to the lower ribs or the sternum.150-152 It may radiate to the shoulders, neck, or scapula. During the paroxysms of pain, patients tend to be tachypneic, breath shallowly, and exhibit grunting respirations. The pain may be so severe as to be associated with diaphoresis and pallor. Deep breathing, coughing, sneezing, or other movement accentuate the pain. Abdominal pain may also be present or occur alone and is more commonly seen in children. If the pain is localized to the abdomen, it may be confused with conditions associated with an acute abdomen. Other symptoms include headache, cough, anorexia, nausea, vomiting, and diarrhea. There may be splinting of the chest. Tenderness of the involved muscles and, on abdominal examination, especially in the upper quadrants and periumbilical area, may be present but is not pronounced. A pleural friction rub may be heard in a quarter of the patients. The mean duration of the illness is generally less than a week. Enteroviral-related myositis has been observed in patients with agammaglobulinemia and chronic CNS infection.153 In these patients, cultivable virus is recovered from muscle tissue.

Neonatal Infections

The vast majority of enteroviral infections in neonates result in a benign febrile illness.53,95,97,99,100 However, infants under 2 weeks of age may be at greater risk for development of severe neonatal enteroviral infections.154 The greatest risk for increased mortality and severe morbidity is seen when signs and symptoms of infection develop in the first days after delivery.52,97,99,100 Multiple lines of evidence support in utero acquisition of enterovirus infections.100 Maternal illness manifested as fever, abdominal pain, respiratory symptoms, pleurodynia, or meningitis has been reported in up to two thirds of mothers of infected neonates.97,99,100 Over a 20-year period, echovirus 11 (14.0%), coxsackievirus B2 (8.9%), coxsackievirus B5 (7.5%), echovirus 9, echovirus 6, coxsackievirus B4 (6.8% each), echovirus 30 (6.0%), coxsackievirus B3 (5.9%), coxsackievirus B1 (5.7%), coxsackievirus A9 (4.9%), and echovirus 7 (4.6%) accounted for approximately 75% of all isolates from neonates reported to the Centers for Disease Control and Prevention.155

As stated previously, the majority of enterovirus-infected neonates exhibit a benign and self-limited febrile illness in which the fever resolves in an average of 3 days and other signs and symptoms in about a week.95,97,100 A biphasic presentation has been reported in which a mild nonspecific febrile illness precedes the onset of severe disease.97Severe neonatal enterovirus disease is a multisystem organ syndrome consisting of combinations of hepatitis, meningoencephalitis, myocarditis, coagulopathy, sepsis, and pneumonia.100 Two major clinical presentations are encountered: encephalomyocarditis syndrome (severe myocarditis in association with heart failure and meningoencephalitis) and hepatitis-hemorrhage syndrome (severe hepatitis with hepatic failure and disseminated intravascular coagulopathy).155 The former is predominantly associated with group B coxsackievirus infections; the latter is often associated with echovirus 11 infection.53,97 Nonspecific symptoms include fever, temperature instability, irritability, lethargy, hypotonia, poor feeding, emesis, abdominal distension, apnea, retractions, grunting, and rashes. Neurologic involvement may or may not be associated with nuchal rigidity and a bulging anterior fontanelle. CNS involvement may progress to an encephalitic picture: lethargy, seizures, and focal neurologic findings. The latter may be suggestive of herpes simplex virus infections. Myocarditis may be manifested by cardiomegaly, hepatomegaly, poor perfusion, cyanosis, congestive heart failure, metabolic acidosis, and arrhythmias. Clinical findings of severe hepatitis include hepatomegaly, jaundice, increased transaminases, and hyperbilirubinemia. The combination of disseminated intravascular coagulation with other findings of “sepsis” are indistinguishable from those that result from overwhelming bacterial infection. Patients with pneumonia may require mechanical ventilation. Renal failure, intracranial hemorrhage, adrenal hemorrhage, necrotizing enterocolitis, and inappropriate secretion of antidiuretic hormone have been reported.100

The risk of death associated with enterovirus infections in neonates is greater than that in older infants and children, reported to be 3.3% in a Centers for Disease Control and Prevention review of cases reported over 20 years.155

Cardiac Syndromes

Isolated myocarditis or pericarditis in older children and adults may result from group B coxsackievirus or echovirus infections. The spectrum of illness ranges from benign, self-limited pericarditis to severe, chronic, or fatal myocardial disease. Virus has been isolated from pericardial fluid and heart tissue, particularly in samples obtained within the first 7 to 10 days of disease. Patients present with fever and upper respiratory symptoms followed by the onset of chest pain and shortness of breath. On physical examination, a gallop rhythm might be present as well as a friction rub when auscultating the heart. Echocardiographic findings may demonstrate a decreased ejection fraction or ventricular dilatation. Electrocardiographic findings vary and include low-voltage QRS complexes, ST segment depressions, and T-wave inversions. Cardiac enzymes are commonly elevated.

Nonpolio Enteroviral Infections in Immunocompromised Hosts

Individuals with congenital or acquired B-cell immunodeficiencies are at risk for chronic nonpolio enteroviral and poliovirus infections. Due to a lack or impairment of antibody production, enterovirus cannot be cleared by the host, resulting in chronic infection. Chronic enteroviral has been reported in children with X-linked agammaglobulinemia, hyper-IgM syndrome, severe combined immunodeficiency syndrome, common variable immunodeficiency, and individuals receiving chemotherapy or immunomodulatory therapy.153,156-158 Disseminated or chronic enteroviral infection has been described in patients undergoing bone marrow and solid organ transplantation.159,160 Meningoencephalitis, pulmonary infections, and severe gastroenteritis have been reported. These infections can be severe and may result in poor outcomes.

Chronic nonpoliovirus meningoencephalitis in patients with X-linked agammaglobulinemia has a subtle presentation.153 Patients initially complain of persistent headaches and lethargy. As the syndrome progresses, a constellation of neurologic symptoms develops and includes ataxia, loss of cognitive skills and memory, dementia, emotional lability, paresthesias, weakness, dysarthria, and seizures. Nonneurologic manifestations include a dermatomyositis-like syndrome, edema, exanthems, and hepatitis. The cerebrospinal fluid demonstrates a persistently elevated protein concentration and pleocytosis. Viral culture and polymerase chain reaction from the cerebrospinal fluid are repeatedly positive for enterovirus. Children with humoral immunodeficiency should receive lifelong intravenous immunoglobulin (IVIG) replacement therapy in an attempt to prevent chronic infection. Reports exist of immunodeficient patients developing chronic enterovirus meningoencephalitis despite immunoglobulin therapy.

Diagnostic Evaluation

In the case of enteroviral CNS infections, the definitive diagnostic procedure is the lumbar puncture. Cytochemical analysis of the cerebrospinal fluid in cases of meningitis or meningoencephalitis typically reveals a mild to moderate lymphocytic pleocytosis.93,95,98,99,101,106,111 Much less commonly, white cell counts up to or greater than 2000 cells/mm3 can be encountered. If the lumbar puncture is performed early in the course of the illness, a predominantly polymorphonuclear pleocytosis may be present.98,99,101,106,108,111,161,162 Reexamination of the cerebrospinal fluid several hours later will document a typical lymphocytic pleocytosis.108,161 Reports of eosinophilic pleocytosis in association with enteroviral meningitis exist.163 The cerebrospinal fluid protein concentration is mildly to moderately increased. In cases of encephalitis, the sole abnormality may be an elevated protein concentration. Glucose concentration in the cerebrospinal fluid is generally normal. However, hypoglycorrhachia may occur and befuddles the assessment, suggesting a bacterial etiology.101,102,162,164,165 Glucose concentration in the cerebrospinal fluid is generally normal. However, hypoglycorrhachia may occur and befuddles the assessment, suggesting a bacterial etiology.101,102,162,164,165

In infants, children, and adolescents suspected of having an enteroviral CNS infection, cerebrospinal fluid should be submitted for detection of enterovirus genome by a nucleic acid amplification test. Because of the lack of sensitivity of viral culture for detection of the enteroviruses in cerebrospinal fluid, it should be reserved for instances when nucleic acid amplification test is not available.27 For neonates with possible enterovirus infections, attempts to detect enterovirus in cerebrospinal fluid as well as blood should be made using nucleic acid amplification test, particularly for those with severe enterovirus disease. Additionally, In infantsof infants, throat swabs, stool, or rectal swabs should also be submitted for viral culture. The use of samples for viral culture from these sites in older patients to establish the diagnosis of enterovirus infections should be tempered by the understanding that the enteroviruses may be shed from these sites for weeks to months after infection. Thus, the isolation of an enterovirus from one of these sites may represent residual shedding and not be linked causally to the illness under investigation.

The traditional approach of cell culture for the diagnosis of enteroviral infections suffers from multiple limitations that lead to a significant lack of sensitivity. No single cell line will support the growth of all members of the genus. In order to optimize the isolation of the enteroviruses using cell culture, multiple cell lines must be used either individually166 or as “mixtures.”167,168 Even using such an approach, some members of the genus (ie, the Coxsackie A viruses) can only be detected using suckling mouse inoculation, a technique rarely available today in the clinical diagnostic laboratory. Cell culture detection also suffers from a lack of sensitivity for the detection of enteroviruses.169 As many as 25% to 40% of cerebrospinal fluid specimens from patients with clinical syndromes consistent with enteroviral CNS disease fail to yield cytopathic effect in cell culture. The time required for isolation and identification of the enteroviruses from cerebrospinal fluid is too long to be of clinical utility. Reported mean isolation times for enteroviruses from cerebrospinal fluid using traditional cell culture techniques ranges from 3.7 to 8.2 days170 and from 2 to 3 days using shell vial culture in combination with monoclonal antibodies.171,172

Nucleic acid amplification techniques27 are rapidly becoming the standard for the detection of enteroviruses from clinical specimens such as cerebrospinal fluid. Regions of conserved nucleotide sequence within the enterovirus 5NTR have been used to design primers and probes used in commercial173,174 and inhouse-developed27 assays that permit near universal detection of the enteroviruses. When compared to cell culture as the criterion standard, reverse transcription-polymerase chain reaction assays have a sensitivity and specificity that ranges from 86% to 100% and 92% to 100%, respectively. Nucleic acid amplification techniques for detection of the enteroviruses from cerebrospinal fluid are significantly more sensitive than cell culture.27 Another significant advantage of nucleic acid amplification techniques is that the assays can be completed in a matter of hours rather than days, making then clinically useful tools. Indeed, multiple reports have documented that reverse transcription-polymerase chain reaction–based detection of enteroviral infections of the central nervous system can shorten hospitalization and reduce cost.

Serologic confirmation of enteroviral infection is generally impractical27 and not useful in acute management of the patient. While homotypic assays for the detection enterovirus serotype-specific IgM (ie, Coxsackie B virus–specific IgM and enterovirus 71–specific IgM) and heterotypic assays for the detection of the enteroviruses have been reported, they have important limitations. Homotypic assays are useful only if there is suspicion for a specific enterovirus serotype. The IgM response to enteroviruses may be nonspecific, resulting in false-positive results. The development of heterotypic assays for the detection of enterovirus is limited by the lack of a common antigen among all serotypes.

Treatment

There is currently no specific treatment for any of the enterovirus infections. Supportive measures include bed rest, antipyretics, and analgesics, as indicated. Immune globulin has been used both in newborn infants and in immunocompromised individuals, such as children with agammaglobulinemia, but its efficacy is not established.100,153,178-181 Intravenous, as well as intrathecal, administration may be necessary to ameliorate or prevent CNS infection in immunocompromised patients.

Prognosis and Prevention

The overall prognosis for enteroviral infections not involving the CNS outside of the early neonatal period is excellent with respect to mortality and morbidity. The short-term and long-term neurocognitive prognosis following enterovirus meningitis in children appears to be favorable. A controlled study failed to identify differences between patients and controls.178 In contrast, enteroviral encephalitis can result in more profound long-term sequelae, particularly in the case of enterovirus 71. In these children, CNS and brainstem involvement were associated with neurologic sequelae, delayed neurodevelopment, and reduced cognitive functioning.131,179,180

Enteroviruses are spread primarily by the lack of good hygiene.Handwashing , in particular, prevents the spread of the enteroviruses, since they are transmitted via the fecal-oral route and, in rare cases, respiratory droplets. During nursery outbreaks of enterovirus infections, cohorting infected neonates is effective in limiting outbreaks. For patients hospitalized with enterovirus-related syndromes, infection-control measures using standard precautions are sufficient.

Women at the end of their pregnancy should avoid interactions with individuals who potentially have an enteroviral infection. If a pregnant woman has an illness consistent with an enterovirus-related disease and the fetus is doing well, attempts should be made to not deliver the baby. Waiting allows the baby time to acquire protective maternal antibodies.