Rudolph's Pediatrics, 22nd Ed.

CHAPTER 306. Enterovirus Infections

José R. Romero

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

Morphologically, the enteroviruses are icosahedral-shaped virions that lack an envelope. 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 are inactivated by heat (> 56°C), ultraviolet light, chlorination, and formaldehyde. These characteristics confer environmental stability, permitting them to survive for days to weeks in water and sewage.

 EPIDEMIOLOGY

The enteroviruses are ubiquitous agents with a worldwide distribution. In 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.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. 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 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. 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

Table 306-1. The Human Enteroviruses

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 infections annually.31 Enteroviral infections result in an estimated 30,000 to 50,000 hospitalizations annually for meningitis.29 This figure may underestimate the actual number of cases.

 PATHOPHYSIOLOGY

Humans are the only hosts for the enteroviruses. 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.  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 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 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

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 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 exan-them may be present. The fever may be biphasic.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

In infants outside of the neonatal period and in children, the onset of enteroviral meningitis is generally abrupt with fever (38°– 40°C).90,93,101,102 The pattern of the fever may be biphasic.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 The fontanelle may be full.90,98 Signs of meningeal irritation increases with advancing age.90,98 Headache is present in nearly all who can report it.106 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. The entire illness may exhibit a biphasic course.104,108

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.33,58,110-113 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

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

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.118CNS 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

Encephalitis due to enterovirus 71 deserves special mention. A severe brainstem encephalitis (ie, rhombencephalitis) has been reported primarily in children.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, 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.

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 A petechial rash reminiscent of that seen with meningococcemia may occur.138,141

Hand-foot-and-mouth disease, has been typically associated with coxsackievirus A16.138,142 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 ultimately ulcerate. The lesions resemble those of aphthous stomatitis and are typically distributed on the buccal mucosa and tongue. 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. 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.144 The onset 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. The enanthem consists of papulovesicular, grayish-white lesions, 1 to 2 mm in diameter, with an areola of erythema. The lesions progress from papular to vesicular, increase in size (3–4 mm), and ulcerate (Fig. 306-2). Associated findings and include sore throat, mild cervical lymphadenopathy, sialorrhea, anorexia, dysphagia, abdominal pain, and emesis. The illness generally lasts 10 days.

FIGURE 306-1. Hand-foot-and-mouth disease. A: Multiple, discrete, small, vesicular lesions on the fingers and palms. B: Multiple, superficial erosions and small, vesicular lesions surrounded by an erythematous halo on the lower labial mucosa. (Source: Wolff K, Johnson RA. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill; 2009.)

FIGURE 306-2. Infectious enanthem: herpangina. Multiple, small vesicles and erosions with erythematous halos on the soft palate. (Source: Wolff K, Johnson RA. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill; 2009.)

Muscular Syndromes

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 muscular disease. The onset of fever and pain is abrupt. A prodrome of up to 10 days consisting of headache, malaise, anorexia, and vague myalgia may occur. The pain is severe and paroxysmal.150-152 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. Abdominal pain is more commonly seen in children. It may be confused with conditions associated with an acute abdomen. Other symptoms include headache, cough, anorexia, nausea, vomiting, and diarrhea. A pleural friction rub may be heard. The chest x-ray is typically normal. 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

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

Severe 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.53,97Nonspecific 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. 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. Patients present with fever and upper respiratory symptoms followed by the onset of chest pain and shortness of breath. 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 include low-voltage QRS complexes, ST segment depressions, and T-wave inversions.

Nonpolio Enteroviral Infections in Immunocompromised Hosts

Individuals with congenital or acquired B-cell immunodeficiencies are at risk for chronic nonpolio enteroviral. 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 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.

 DIAGNOSTIC EVALUATION

In enteroviral CNS infections, the definitive diagnostic procedure is the lumbar puncture. Analysis of the cerebrospinal fluid in meningitis or meningoencephalitis typically reveals a mild to moderate lymphocytic pleocytosis.93,95,98,99,101,106,111 If the lumbar puncture is performed early in 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 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

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 disease. In 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. 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

Serologic confirmation of enteroviral infection is generally impractical27 and not useful in acute management of the patient.

 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 immuno-compromised 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. 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

Handwashing prevents the spread of the enteroviruses. During nursery outbreaks, cohorting infected neonates is effective in limiting outbreaks. 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.