Pediatric Enteroviral Infections

Patients with enteroviral infections may present with symptoms as benign as an uncomplicated coryzal illness or as life-threatening as encephalitis, myocarditis, or neonatal sepsis. The Centers for Disease Control and Prevention (CDC) estimate that 10-15 million cases of enteroviral infection occur each year in the United States.

Enteroviral infections result in a large number of physician and emergency department visits, creating a social and economic burden. In 1998, Pichichero et al performed a prospective study and found that nonpolio enteroviral infections resulted in direct medical costs ranging from $69 to $771 per case.[1] More recently in China, it has been estimated that each episode of enteroviral infection costs $52 to $1104 per case.[2]  In addition, patients with nonpolio enteroviral infections missed a minimum of 1 day of school or camp; some missed as many as 3 days of school or camp. The significant economic and medical impacts of enteroviral infections occur mostly during the peak months of summer and fall. In temperate climates, enteroviral outbreaks occur year-round.

Enteroviruses belong to the Picornaviridae (small RNA viruses) family. The enteroviral species includes enteroviruses (EV), coxsackievirus (CV), echovirus (E), and poliovirus (PV). There are 12 species of enterovirus (A-L); however, only  A to D are known to cause disease in humans.[3]  The following viruses seen in humans belong to enterovirus species:

• Enterovirus A: CVA2-8, CVA10, CVA12, CVA14, CVA16, EV-A71, EV-A76, EV-A89-92, EV-A114, EV-A119-121 
• Enterovirus B: CVB1-6, CVA9, E1-7, E9, E11-21, E24-27, E29-33, EVB69, EV-B73-75, EV-B77-88, EV-B93, EV-B97-98, EV-B100-101, EV-B106-107, EV-B111
• Enterovirus C: PV1-3, CVA1, CVA11, CVA13, CVA17, CVA19-22, CVA24, EV-C95-96, EV-C99, EV-C102, EV-C104-105, EV-C109, EV-C113, EV-C116-118
• Enterovirus D: EV-D68, EV-D70, EV-D94, EV-D111

More recently, a related genus of viruses, Parechovirus, has been described; two enterovirus species (echovirus types 22 and 23) were reassigned as parechovirus.[4]  

Clinically, enteroviruses can be divided into polio and non-polio enteroviruses owing to the different clinical patterns and outcomes. Polioviruses can cause poliomyelitis, which causes muscle paralysis. Non-polio enteroviruses commonly cause illness such as HFM, herpangina, and conjuncitivitis but can also cause more burdensome conditions, such as aseptic meningitis and myocarditis. There is currently no established treatment for enteroviruses; however, drugs and vaccines are undergoing clinical research at present. 

Enterovirus A71 has gained notoriety in recent years for causing a rapidly fatal rhombencephalitis, in association with epidemics of HFM disease in East Asian countries. This appears to be a particularly aggressive neurotrophic serotype of enterovirus.

Coxsackievirus A6 was recently described as a somewhat distinct clinical entity of "atypical hand foot mouth disease," as the skin lesions described are vesiculobullous rather than the typical flat ulcers seen in HFM disease and may be more extensive, often involving areas of preexisting eczema.

Each virus obtains its antigenicity from the capsid proteins that surround the RNA core. According to the CDC, 65 human serotypes of enteroviruses have been identified; however, a small number cause most outbreaks. Since the implementation of polio vaccines, the incidence of wild-type polio has been almost eradicated.

The most common form of human transmission is the fecal-to-oral route. Although respiratory and oral-to-oral routes are possible, they are more likely to occur in crowded living conditions. Enteroviruses are quite resilient. They remain viable at room temperature for several days and can survive the acidic pH of the human gastrointestinal (GI) tract. The incubation period is usually 3-10 days.

The enterovirus enters the human host through the GI or respiratory tract. The cell surfaces of the GI tract serve as viral receptors, and initial replication begins in the local lymphatic GI tissue. The virus seeds into the bloodstream, causing a minor viremia on the third day of infection. The virus then invades organ systems, causing a second viremic episode on days 3-7. This second viremic episode is consistent with the biphasic prodromal illness. The infection can progress to central nervous system (CNS) involvement during the major viremic phase or at a later time. Antibody production in response to enteroviral infections occurs within the first 7-10 days.

Coxsackievirus replicates in the pharynx (herpangina), the skin (HFM disease), the myocardium (myocarditis), and the meninges (aseptic meningitis). It can also involve the adrenal glands, pancreas, liver, pleura, and lung.

Echovirus can replicate in the liver (hepatic necrosis), the myocardium, the skin (viral exanthems), the meninges (aseptic meningitis), the lungs, and the adrenal glands.

After exposure, poliovirus replicates in the oropharynx and GI tissue. Following this replication, poliovirus advances, invading the motor neurons of the anterior horn cells of the spinal cord. It can progress to other CNS regions, including the motor cortex, cerebellum, thalamus, hypothalamus, midbrain, and medulla, causing the death of neurons and paralysis. Neuropathy occurs as a result of direct cellular destruction. Antibody production occurs in the lymphatic system of the GI tract, prior to invasion of the CNS tissue. Infants retain transplacental immunity for the first 4-6 months of life.

The enteroviruses are capable of directing almost all cellular protein translation to viral genes through the modification of host cell translation factors (messenger RNA [mRNA] cap-binding proteins) and using internal ribosome entry sites (IRES) to bypass the crippled host machinery. As such, they are highly damaging to the cells they infect.

Enteroviral risk factors include poor sanitation, crowded living conditions, and lower socioeconomic class status. In addition, children younger than 5 years are more susceptible because of poor hygiene habits and lack of prior immunity.

Although debatable, neonatal infections are most likely acquired after birth rather than transplacentally. Exposure from an infected mother or another infant in the nursery during the first 2 weeks of life is the probable mode of transmission. The enteroviral exposure may be perineally acquired during the delivery process.

A B-cell response is needed for the host to properly fight off the enteroviral infection and to prevent entry to the CNS. Children who lack a functioning B-cell system, such as those with X-linked agammaglobulinemia, are at risk of serious enteroviral infection, such as meningoencephalitis.

Poliovirus is a consideration in all unimmunized or partially immunized children.

United States data

Nonpolio

Nonpolio enteroviral infections cause an estimated 10-15 million symptomatic infections per year in the United States. Many are treated as potential episodes of sepsis, and antibiotics and acyclovir are administered to treat possible bacterial or herpetic infection. Children under 5 years of age are predominantly affected.[5]  Outbreaks tend to occur in warmer months.

The CDC reported a 2014 outbreak of enterovirus D68 that began in at least six US states from mid-August to mid-September, including Colorado, Illinois, Iowa, Kansas, Kentucky, and Missouri.[6] This outbreak caused 1153 cases of severe respiratory disease and 107 cases of acute flaccid myelitis (AFM) in the United States alone.[7]  Outbreaks spread across the United States, then Canada, Europe, and Asia. Enterovirus D68 was first identified in 1962 in California but had not been commonly reported in the United States before the 2014 outbreak. Children with underlying immunodeficiency and respiratory disease were noted to have a higher risk of severe respiratory illness from enterovirus D68.[7]

A 2014 outbreak in California of echovirus 30 caused 10 cases of viral meningitis; the outbreak was centered around the junior varsity American football team.[8]  In 2018, an outbreak of enterovirus A71 causing CNS disease was reported in Colorado. This outbreak caused meningitis, encephalitis, and AFM.[5]  There were no deaths, but 3 children with AFM had residual limb weakness at discharge. 

Polio

In 1952, an epidemic of polio occurred in the United States, causing 3,000 deaths and 57,879 cases. The vaccine has virtually eliminated wild-type polio in the United States. In 1994, the World Health Organization (WHO) declared the eradication of wild polio in the Western hemisphere; however, 8-10 cases of vaccine-associated paralytic polio (VAPP) continued to occur annually in the US from 1980 to 1999.[9]   Such cases occur when the attenuated vaccine virus in the oral polio vaccine (OPV) is excreted into an under-immunized population and undergoes genetic changes that cause it to become virulent again. VAPP is linked to the concomitant administration of live OPV with intramuscular injections (perhaps allowing the virus better access to myocytes and neuronal axons) and occurs in 1 per 2-4 million vaccinations, whereas paralytic polio occurs in 1 in 200 wild-type infections. In 2000, the risk of VAPP became greater than wild type disease, leading to the change from live OPV to the inactivated polio vaccine (IPV). 

In 1979, an outbreak occurred in numerous Amish communities throughout the United States. A smaller outbreak occurred in 2005 in an Amish community in Minnesota. Genetic sequencing of the virus surprisingly revealed that it was only 2.3% different from the Sabin OPV strain and was likely acquired from overseas subclinical circulating infections.

International data

Nonpolio

Nonpolio enteroviral infections are prevalent worldwide, with clear outbreaks of HFM, herpangina, and aseptic meningitis occurring as well as non-specific viral illneses.[10, 11, 12]

Between 1999 and 2007, the Austrian reference laboratory for poliomyelitis received 1,388 stool specimens for enterovirus typing from patients with acute flaccid paralysis or aseptic meningitis; 201 samples from 181 cases were positive for nonpolio enterovirus.[13]  The mean patient age was 5-6 years, with 90% of cases in children younger than 14 years. Aseptic meningitis was identified in 65.6% of the cases. Echovirus 30 was the most frequent viral cause of aseptic meningitis, followed by coxsackievirus B types 1-6 and enterovirus 71. E-30 was also the leading viral pathogen in a Spanish study of aseptic meningitis.[14]

An outbreak of echovirus 30 infection occurred between April and September 2013 in Marseille, France. A study concluded that almost all E-30 infections emerged from local circulation of one parental virus. The findings also showed that human enterovirus outbreaks cause excess of emergency ward consultations and consultations to general practitioners for non-specific viral illness.[15]  Similar outbreaks have been reported in Germany, Finland, Italy, and China.[16, 17, 18, 19]

Polio

Poliomyelitis still occurs in low-income countries as a result of poor health care and an inability to access vaccines. However, the reduction in global cases of polio is a testament to the effectiveness of vaccination programs and the WHO strategy to eradicate polio globally.[20] The WHO reported over 35,000 cases globally in 1988, then only 33 in 2018.[21]  This significant drop is due to aggressive vaccination programs following a resolution at the World Health Assembly in 1988 to eradicate polio. The WHO estimates that the vaccination program has saved 16 million people from paralysis. 

In September 2019 the WHO announced that poliovirus 2 and 3 have now been eradicated globally.[22]  Poliovirus 1 remains endemic in Afghanistan and Pakistan, but no new cases have been detected in Africa since 2016.[21]  In 2018, 33 cases of poliovirus 1 were detected in Afghanistan and Pakistan, where there is incomplete vaccination, in part due to political and social instability.[21]

Some genetic evidence suggests that if the poliovirus is eradicated, genetic recombination between other enteroviruses may result in a phenotypically similar virus. However, this appears to be of academic interest only at this time.

Race-, sex-, and age-related demographics

Enteroviruses have a worldwide distribution and are not race-specific infections.

Males and females are equally affected. Males are more likely to be symptomatic.

People of all ages, including adults, elderly people, and young people, are at risk of manifesting symptoms of enteroviruses. Children have a higher rate of infection because of exposure, hygiene, and immunity status.[23]  Unlike most cases of nonpolio enteroviral infections, acute hemorrhagic conjunctivitis occurs most frequently in adults aged 20-50 years.

The prognosis for nonpolio enteroviral infections is excellent. Adverse outcomes are specifically related to cases of newborn infections and older children with myocarditis and encephalitis.

In most cases of polio, patients have some return of muscle function. Prognosis of final ability is determined 6 months or longer following the infection.

Morbidity/mortality

The overall mortality rate for nonpolio enteroviruses is extremely low. The patients at greatest risk are those with neonatal sepsis or myocarditis or those with underlying immunodeficiency and respiratory disease.[7]  One retrospective review of 30 hospitalized children with enterovirus infections in southern England described a mortality rate of 10%.[23]

Occasionally, enteroviruses cause global encephalitis, which has a good prognosis. However a few fatalities have been reported. Enterovirus 71 has been linked with a rhombencephalitis (inflammation of the brain stem) in outbreaks of hand-foot-and-mouth disease in the eastern hemisphere (Taiwan, Japan, Malaysia, and Australia). Fatality rates from these outbreaks have been as high as 14%. Myoclonus is a poor prognostic indicator, as are lethargy, persistent fever, and peak temperature higher than 101.3ºF (38.5ºC).[24]

The 2014 global outbreak of enterovirus D68 caused 14 deaths in the United States from a total of 1152 hospitalizations.[7]  Most cases of myocarditis and pericarditis are self-limited, but a potentially significant mortality rate is associated with myocarditis and some children have persistent myocardial dysfunction.[23]  Older patients can develop a dilated cardiomyopathy following myocarditis.

The overall mortality rate for paralytic polio is 5-10%; death usually results from paralysis of the respiratory muscles.[25]  For those who survive, a 6-month period is allowed to predict how much muscle function will return.

Complications

Both coxsackievirus and enterovirus have been associated with the development of Guillain-Barré syndrome.

Enteroviruses, specifically coxsackie B, have been hypothesized to play a role in the development of type 1 diabetes. This is based on epidemiological studies and that in post-mortem and in vitro studies have suggested that coxsackie B has a predilection for the pancreatic islet cells. Rodent models have demonstrated enteroviral destruction of pancreatic beta-islet cells, but no definitive link has been established.[26]

Several studies have investigated a possible link between enteroviral infections and increased risk of myocardial infarction, but no definite conclusions have been proven.

Nonpolio enteroviruses cause a large number number of infections per year. More than 90% of enteroviral infections are either asymptomatic or cause a nonspecific febrile illness. A wide range of symptoms is observed, but most cases include fever, a viral prodrome, and gastrointestinal (GI) symptoms.

Patients with nonspecific febrile illness, the most common form of enteroviral infection, present with a sudden onset of fever, temperature ranging from 38.5-40°C. Accompanying symptoms include general upper respiratory and GI complaints. Clinical indicators include a flulike syndrome consisting of malaise, myalgias, sore throat, headache, conjunctivitis, nausea, emesis, and diarrhea. Genitourinary manifestations such as orchitis and epididymitis are possible. Symptoms generally last 3-7 days and are caused by all enteroviral subtypes.

Herpangina occurs in children aged 3-10 years. These patients report painful vesicles on the posterior pharynx and tonsils. These lesions are associated with fever, sore throat, odynophagia, and other viral symptoms. Mothers may notice a decreased oral intake by the child due to the painful ulcers. The causative agent is most commonly coxsackievirus group A and, sometimes, coxsackievirus group B. Herpangina is self-limited, and symptoms last 3-7 days.

Hand-foot-and-mouth (HFM) disease is a vesicular eruption in the oropharynx, palms, soles, and interdigits of toddlers and school-aged children. The oral vesicles are not usually painful. Patients often present after 1-2 days of fever and have a characteristic viral exanthem. Lesions are more common on the dorsal surfaces of the hands and feet than in other locations. The most common causative agent is coxsackievirus group A16, but strains of enterovirus 71 circulating in East Asia are currently causing outbreaks of HFM disease that are associated with a serious rhombencephalitis, with significant mortality.

Atypical HFM disease was recently reported around the globe and is caused by coxsackievirus A6.[27] It is characterized by a relatively paucity of oral lesions, but a striking bullous eruption on the extremities. Children with eczema may be more affected and "eczema coxsackium" was coined as far back as 1968 for this condition.[28] Postinfectious loss of the nails is reported frequently.

Viral exanthems, a frequent cause of emergency department visits, manifest as rubelliform or roseolalike rashes that occur in the summer months. These exanthems occur in children younger than 5 years and have a benign 3-day to 5-day course. The responsible agents are usually echoviruses.

Patients with aseptic meningitis have symptoms that mimic the initial symptoms of nonspecific febrile illnesses, but, as aseptic meningitis progresses, patients report a headache, stiff neck, and photophobia. A nonspecific rash can accompany these symptoms, raising the question of meningococcemia. The clinical course of aseptic meningitis is self-limited and resolves in 1-2 weeks.

The coxsackievirus group B and echoviruses are responsible for 80-90% cases in which a causative organism of aseptic meningitis is identified.

Neurotropic strains, such as enterovirus 71, can be responsible for more aggressive cases of CNS infections. Ninety percent of some cohorts with enterovirus 71 infection also had rhombencephalitis. This can lead to neurogenic pulmonary edema and has an overall fatality rate of 14%. Early signs of severe infection include myoclonus and sleep disturbance. Fever that lasts longer than 3 days duration, high fevers (>38.5C), and lethargy are predictors of CNS involvement.

Patients with myocarditis or pericarditis report chest pain, fatigue, and dyspnea on exertion. These symptoms can progress to dysrhythmia and heart failure. The most common cause of cardiac involvement is coxsackievirus group B5 infection, but echoviruses are also etiologies of infection.

Pleurodynia (Bornholm disease, devil's grippe) is an uncommon epidemic that causes severe muscular pains in the chest and abdomen. These sharp pains worsen with breathing or coughing and are associated with profuse sweating. Spasmodic muscular pains last 15-30 minutes in older children and adolescents. The condition can mimic serious surgical conditions and can cause periodic episodes of respiratory difficulty. These symptoms are accompanied by fever, headache, anorexia, nausea, and emesis. Symptoms last for 2 days. Coxsackieviruses B3 and B5 infect the intercostals muscles, causing these frightening but rare outbreaks.

Neonates with nonpolio enterovirus infections are at a high risk of developing a sepsis-like condition, including meningoencephalitis, myocarditis, and hepatitis. Presenting symptoms include poor feeding, lethargy, fever, irritability, hypoperfusion, and jaundice. Differentiating these infections on clinical grounds from bacterial sepsis is almost impossible A history of a mother who had a febrile illness with GI symptoms around the time of birth is often reported; this acute presentation results in exposure to viral shedding without significant transplacental transfer of maternal antibodies.

Poliovirus infections are divided into the following 4 groups of clinical syndromes (asymptomatic, abortive, nonparalytic, and paralytic):

• Most infections (90-95%) are asymptomatic.
• Abortive poliomyelitis involves a nonspecific febrile illness that spares the CNS and spontaneously resolves after a few days. Temperature is not higher than 103°F. Patients report a minor febrile upper respiratory infection, such as cough and sore throat, and gastrointestinal infection with nausea and diarrhea.
• Patients with nonparalytic poliomyelitis (aseptic meningitis) present in the same manner as patients with abortive poliovirus, but nonparalytic poliomyelitis progresses to aseptic meningitis. During the initial flulike illness, patients report stiffness in the posterior neck muscles, limbs, and trunk. This minor viremia is followed by nuchal and spinal rigidity, the hallmark of nonparalytic polio.
• Paralytic poliomyelitis starts with a nonspecific febrile illness and muscle weakness that resolves after 2-3 days but is followed by a sudden onset of asymmetric flaccid paralysis. Pain, nuchal rigidity, and hypertonia are indicators of brainstem, spinal ganglia, and posterior column involvement. Bulbar poliomyelitis involves the speech and central cardiorespiratory centers of the brain stem and can cause death because of cessation of cardiac and respiratory activity.

Nonspecific febrile illness can include normal findings on physical examination or can include an erythematous pharynx, mild conjunctivitis, and cervical lymphadenopathy.

Herpangina presents with punctate macules that progress to vesicles that eventually ulcerate. Usually, 3-6 erythematous vesicles about 1-2 mm in size are found on the posterior pharynx, anterior tonsils, and soft palate. The oropharynx may be erythematous, but no exudates are present.

HFM disease presents with less painful or painless vesicles that may ulcerate on the buccal mucosa and tongue; the less significant pain differentiates the vesicles of HFM disease from the posterior pharyngeal vesicles of herpangina. See the image below.

Erosions on the base of the tongue.

In addition to the oral findings, an exanthem of vesicles appears on the palms, soles, and intertriginous digits of the hands and feet. These vesicles heal by resorption of fluid and do not crust over. See the images below.

A red halo surrounds several vesicles on the finger flexures and palms.

Small linear vesicle on the thumb.

Vesicle on the dorsal hand of a young adult.

Occasionally, nonvesicular eruptions are present on the buttocks, proximal extremities, and genitalia. The truncal area is not usually involved, differentiating HFM disease from varicella infections.

The absence of gingival erythema, high fevers, and lack of significant cervical lymphadenopathy aid in distinguishing HFM disease from herpetic gingivostomatitis.

Viral exanthems appear as a pink, maculopapular, blanching rash that can mimic rubella and roseola. This rash is less commonly vesicular, urticarial, and petechial. Unlike rubella, no significant adenopathy is present. Similar to roseola, it may appear following the cessation of fever.

Atypical HFM disease tends to present with bullous lesions on the extremities and may be more severe over areas of preexisting eczema.[27]  The lesions are not limited to the hands and feet and may be seen on the arms and legs. See the image below.

Calf blisters from coxsackievirus A6 as seen in atypical hand-foot-mouth disease. Courtesy of Elsevier (Feder HM Jr, Bennett N, Modlin JF. Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by Coxsackie virus A6. Lancet Infect Dis. Jan 2014;14(1):83-6).

Aseptic meningitis reveals physical findings consistent with meningeal irritation, including nuchal rigidity, a bulging fontanel, and, possibly, positive Kernig and Brudzinski signs in children older than 1 year. The accompanying rash is often nonspecific but can occasionally be petechial.

Myocarditis and pericarditis symptoms depend on the severity of the disease. The physician should look for signs of congestive heart failure. Patients with pericarditis may have an auscultatory friction rub, Hamman crunch, and poor perfusion.

Patients with pleurodynia (Bornholm disease) may present with respiratory distress or in a shock like state. Patients may localize pain in the abdomen and may have tender abdominal muscular walls. A pleural friction rub may be auscultated during the muscular spasm.

Patients with acute hemorrhagic conjunctivitis present with subconjunctival hemorrhage, erythema, lacrimation, chemosis, preauricular lymphadenopathy, and serous eye discharge. Some of these cases may progress to a bacterial conjunctivitis with purulent ocular discharge.

Neonatal infections cause the infant to be irritable, lethargic, and inconsolable by the mother. The infection can progress to signs and symptoms that reflect hypoperfusion, such as cool mottled skin, delayed capillary refill, and ashen gray color.

Poliovirus infections should be differentiated into the following subtypes:

• Abortive (nonspecific febrile) illness appears as a general viral upper respiratory and GI infection. Cough, coryza, and pharyngeal exudates are common.
• Patients with nonparalytic (aseptic meningitis) illness have a nonspecific viral picture, but the physician should recognize symptoms of meningeal irritation. Increase or decrease of the superficial and deep tendon reflex usually occurs prior to onset of weakness. If these reflexes are decreased, the physician should be wary of impending weakness and paralysis. As with all types of polio, sensory examination findings remain intact.
• The paralytic form is similar to the nonparalytic with the additional classic finding of asymmetric flaccid paralysis. Proximal muscle groups are usually more affected than the distal musculature. Deep tendon reflexes are decreased or absent, and sensory findings are unchanged. Associated symptoms include hypertonia, respiratory and cardiac arrhythmias, and blood pressure and vasomotor changes. Observe for symptoms of respiratory distress, including difficulty speaking, nasal flaring, tachypnea, and immobility of accessory muscles of respiration. Impending respiratory failure may rapidly occur.

The diagnosis of enteroviral infection is most often based on the clinician's assessment of the patient in conjunction with seasonal outbreaks, known exposure risks, geographic locations, and age groups. Ancillary laboratory test results aid the physician in supportive care of the patient and eliminate other potentially harmful and treatable bacterial illnesses. Diagnostic testing plays a role in enteroviral infections. As newer methods have demonstrated increased sensitivities, determining viral etiologies of aseptic meningitis and neonatal sepsis has resulted in improved patient care.

Cell culture, serology, and polymerase chain reaction (PCR) laboratory testing can diagnostically isolate enteroviral infections. Enteroviruses are found in stool, the pharynx, blood, and cerebral spinal fluid (CSF). Blood cultures and serology are of questionable use because the viral levels may be undetectable by the time symptoms have appeared. Pharyngeal viral levels remain present from 2 days to 2 weeks after the infection. Stool isolation of enteroviruses is not specific to acute infections because viral stool shedding persists for as long as 3 months after the infection.

Historically, the criterion standard of isolation has been cell cultures; however, clinical evidence is proving PCR tests to be both more sensitive and more efficient. Tissue cultures take approximately 3-8 days to grow the enterovirus, and the identification of the subtype requires even more time. Overall, low cell culture sensitivity rates of 65-75% have been repeatedly demonstrated in enteroviral meningitis.

Another method, serologic testing, uses multiple titers to identify a pattern of rising antibody levels over a 2-week to 4-week period. A single level of enteroviral antibodies can be present in a healthy patient; therefore, monitoring the serology to identify a 4-fold increase in levels is needed. Identifying the specific subtype and monitoring the antibody levels are labor intensive. Furthermore, waiting for periods of 2-4 weeks for tissue results is not useful in improving patient care.

In contrast, the reverse transcriptase PCR testing is designed to detect a common genetic area in the enteroviral subtypes. The results are available in 24 hours, making detection more sensitive (95%), more specific (97%), and more time efficient. Both Chonmaitree et al in 1982 and Singer et al in 1980 demonstrated the positive outcomes of viral detection in aseptic meningitis, yielding shortened hospital stay and antibiotic course.[29, 30]

Recent studies have demonstrated the efficacy and increased sensitivity of using the PCR technique to isolate CSF enterovirus. PCR testing may also play a pivotal role in identifying epidemiological outbreaks of infections.

In 1997, Ahmed et al demonstrated 100% sensitivity and 90% specificity using PCR CSF assays in conjunction with viral cultures to detect enteroviral meningitis in infants younger than 3 months.[31]

Poliomyelitis can be isolated from stool, nasopharyngeal mucosa, and CSF. Stool specimens have the greatest yield for polio. Antibody serology titers demonstrate a 4-fold rise and must be acquired at early onset of illness. If positive, samples must be sent to the CDC.

Ancillary laboratory tests may also be helpful in treating patients. CBC count results vary, demonstrating a WBC count within the reference range or demonstrating a mild elevation of WBCs with neutrophilia or leukocytosis.

A basic chemistry panel is only useful in patients with extreme lethargy or dehydration and is used to eliminate possible diagnosis of electrolyte imbalances. Erythrocyte sedimentation rate is a nonspecific test, and the results should be elevated in any inflammatory process, including enteroviral infections.

Urinalysis is a part of the sepsis workup in neonates and young children to eliminate bacterial infections. Also, blood and urine cultures should be obtained. In addition, measure cardiac enzymes.

Imaging studies

Chest radiographs should be obtained as part of the neonatal sepsis workup and in cases of pleurodynia. Radiographic findings are normal in patients with pleurodynia.

Obtain echocardiograms in patients with suspected cardiac involvement.

Electrocardiography

Obtain an electrocardiogram (ECG) in suspected cases of pericarditis. The ECG results can be normal, can be nonspecific, or can have changes common to all causes of pericarditis.

Lumbar puncture

Lumbar puncture is the most important test in meningitis. Send CSF for cell count with differential, protein, glucose, Gram stain, and bacterial cultures. Send extra fluid for PCR testing and viral cell cultures.

CSF fluid demonstrates aseptic meningitis in patients with polio and nonpolio virus. Importantly, some patients may not demonstrate pleocytosis, so the PCR results should be sought. One study showed 18% of enteroviral meningitis cases did not demonstrate CSF pleocytosis.[32]  Another series has shown pleocytosis in patients with sepsis-like features but no clinical features of meningitis.[23]  The protein level can be within the reference range or mildly elevated (80-100 mg/100 mL). The glucose level is within the reference range. 

No specific antiviral medication or treatment is yet available for an enteroviral infection. The best care is provided through supportive measures and through ruling out bacterial infection and rationalizing antimicrobial use. Fluid hydration and analgesia are the mainstays of care for a viral syndrome.

In patients with severe illness, if a bacterial infection is suspected, antibiotics are administered at the physician’s discretion or according to local guidelines. Test results, such as polymerase chain reaction (PCR) test results from cerebrospinal fluid (CSF) samples, require 24 hours to return, and a positive result does not necessarily eliminate a bacterial infection. Thus, the use of cultures is important.

Corticosteroids have been proposed to have a beneficial effect on myocarditis, but no significant improvement has been demonstrated. Furthermore, because of deleterious side effects, steroids are not recommended for treatment.

Pleconaril is a capsid-binding antiviral agent with activity against most strains of enterovirus. One small randomized, controlled trial of pleconaril in newborns with suspected enterovirus has shown some efficacy, although further data are needed.[33]  At present, it is not being manufactured. Many potential targets for anti-enteroviral treatments have been identified; however, a very small number have been pursued in clinical trials.[33]  EV-71 specific immunoglobulin has been investigated in mice; however, clinical trials in humans are awaited.[34]

Vaccines are also in development against EV-71 and have been subject to clinical trials in China with promising results.[35, 36]  The vaccines appeared safe and reduced the burden of associated hand-foot-and-mouth disease and herpangina. Further data are needed to assess the vaccines’ impact on neurologic disease caused by EV-71.

The best medical care involves continued efforts for worldwide poliovirus vaccination.

If poliomyelitis is suspected, consultation with a neurologist and a physical medicine specialist is helpful. Furthermore, CDC notification is required because they are responsible for virus surveillance. The CDC investigates cases of suspected polio and helps to identify the etiology of the case.

For nonpoliovirus enteroviruses, no consultations are specifically required, but the physician should address individual clinical situations.

Diet

Patients can continue with a normal diet. Soft foods and liquids are appeasing to children with herpangina.

Activity

As with any illness, children should avoid vigorous activity that may contribute to fluid losses and exhaustion.

Antiviral therapy is not currently a component in the standard of care for enteroviral infection. Studies with investigational antiviral agents are currently ongoing. Current treatment remains purely supportive.

Class Summary

These agents are used to treat fever, myalgia, and headache associated with enterovirus.

Acetaminophen (Tylenol, FeverAll)

Analgesic effect and also reduces fever by directly acting on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating. 

Ibuprofen (Motrin, Advil)

For use as an analgesic.

Class Summary

This agent is a purified preparation of gamma globulin derived from large pools of human plasma and is composed of 4 subclasses of antibodies, approximating the distribution of human serum.

Immune globulin, intravenous (Carimune NF, Gammagard, Polygam S/D)

Neutralizes circulating myelin antibodies through anti-idiotypic antibodies. Down-regulates proinflammatory cytokines, including INF-gamma. Blocks Fc receptors on macrophages. Suppresses inducer T and B cells and augments suppressor T cells. Blocks complement cascade and promotes remyelination. May increase CSF IgG (10%).

Class Summary

One antiviral medication (pleconaril) has shown promise in treating enteroviral infections, but its use has so far been largely restricted to experimental protocols. Its release has been repeatedly delayed, and it is still not yet licensed in the United States.

Pleconaril (Picovir)

Low-molecular weight capsid-inhibitor fits into the hydrophobic pocket of the VP1 capsid protein and interferes with viral attachment and uncoating. Has shown some efficacy in a neonatal sepsis in one small RCT.

Inpatient care

The course of enterovirus infection widely varies; therefore, each case must be individually handled. Neonatal meningitis and sepsis cases require careful observation for CNS changes. Cultures must be carefully obtained and monitored.

Patients with paralytic poliovirus should be admitted to the intensive care unit (ICU). Ventilatory support should be arranged as needed.

Bulbar poliomyelitis involves cranial nerve weakness, respiratory problems, and circulatory problems. These patients should be carefully handled and provided with ventilatory support. 

Patients with poliomyelitis who have bladder paresis may require urinary catheterization. Constipation, another effect of poliomyelitis, can be treated with stool softeners and cathartics as needed.

Outpatient care

Pediatric patients with nonpolio infections can be discharged if they are not septic and if they do not have symptoms of meningitis. Arrange for follow-up with a pediatrician in 1-2 days.

Outpatient medications consist of antipyretics and analgesics to be used as needed.

No specific indications for transfer are recognized in patients with enteroviral infections.

Transfer may be needed for lack of an intensive care setting, in such cases as a neonatal setting or poliomyelitis.

As is the general rule of transfer, the main concern is to ensure airway patency prior to travel. If any question of airway stability is present, the physician should intubate the patient before transfer.

Vaccination

All children should receive vaccination for poliovirus. Two forms of the vaccine are available, and both are equally effective in creating immunity.

The inactivated poliovirus vaccine, developed by Salk, offers immunity without the risk of vaccine-associated paralytic polio (VAPP). The inactivated poliovirus vaccine is more invasive, which means the child receives more injections.

The oral polio vaccine (OPV), developed by Sabin, consists of live-attenuated poliovirus. OPV creates local community and herd immunity through viral shedding by the intestinal tract and is less invasive. This continues to be used in areas where poliovirus infection persists.

As of June 1999, recommendations by the Advisory Committee on Immunization Practices (ACIP) suggest inactivated polio vaccine administration. Because of decreased worldwide incidence of polio and likelihood of imported cases, a regimen consisting solely of inactivated polio vaccine has replaced the former combined inactivated polio vaccine and OPV regimen. This change reflects an effort to decrease the cases of vaccine-associated polio. All children should receive the inactivated polio vaccine at age 2 months, age 4 months, age 6-18 months, and age 4-6 years.

Guidelines for increasing immunization coverage have been established.[37]

Other preventive measures

Frequent handwashing and good hygiene can reduce the risk of acquiring an enteroviral infection.