eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Enteroviral Infections

Nicholas John Bennett, MB, BCh, PhD, Fellow in Pediatric Infectious Disease, Department of Pediatrics, State University of New York Upstate Medical University
Joseph Domachowske, MD, Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York-Upstate Medical University; Mobeen H Rathore, MD, CPE, FAAP, FIDSA, Chief of Division of Pediatric Infectious Diseases/Immunology, Associate Chairman of Department of Pediatrics, University of Florida College of Medicine at Jacksonville; Hospital Epidemiologist and Section Chief of Infectious Disease and Immunology, Wolfson Children's Hospital; Director of University of Florida Center for HIV/AIDS Research, Education and Service (UF CARES)

Updated: Jun 5, 2009

Introduction

Background

Enteroviruses, a group of single-stranded sense RNA viruses, are commonly encountered infections, especially in infants and children. They are responsible for a myriad of clinical syndromes, including hand-foot-and-mouth (HFM) disease, herpangina, myocarditis, aseptic meningitis, and pleurodynia.

Patients with enterovirus infections may present with symptoms as benign as an uncomplicated summer cold or as threatening as encephalitis, myocarditis, or neonatal sepsis. Enteroviral infections annually result in a large number of physician and emergency department visits. In 1998, Pichichero et al performed a prospective study and found that nonpolio enteroviral infections resulted in direct medical costs ranging from $69-771 per case.¹ 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 group includes coxsackievirus, echovirus, and poliovirus. Enteroviruses are believed to have 2 distinct classes: polioviruses (types 1, 2, and 3) and nonpolioviruses (coxsackievirus, enterovirus, echoviruses, and unclassified enteroviruses). Enteroviral infections consist of 23 coxsackievirus A, 6 coxsackievirus B, 28 echovirus, and 5 unclassified enteroviruses.

More recently, a related genus of viruses, Parechovirus, has been described; two enterovirus species (echovirus types 22 and 23) were reassigned as parechovirus.²  To date, more than a dozen parechovirus strains have been described; however, not all sequences have been published. The clinical appearance of Parechovirus infection can be similar to enteroviral infections, but tests for Parechovirus are mostly confined to research laboratories.

Enterovirus 71 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 neutrophic serotype of enterovirus.

Each virus obtains its antigenicity from the capsid proteins that surround the RNA core. According to the Centers for Disease Control and Prevention (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 eradicated in the western hemisphere.

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 GI tract. The incubation period is usually 3-10 days.

Pathophysiology

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 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 notoriously 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, polio 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 death of neurons and paralysis. Neuropathy occurs due to 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.

Frequency

United States

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.

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. Approximately 6 cases of vaccine-associated paralytic polio (VAPP) occur yearly, leading to the recommendation of inactivated vaccine because the risk of natural disease is so rare in the United States. VAPP is linked to the concomitant administration of live (oral) polio vaccine with intramuscular injections (perhaps allowing the virus better access to myocytes and neuronal axons) and occurs in 1 per 2-4 million vaccinations (paralytic polio occurs in 1 in 200 wild-type infections).

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 vaccine strain and was likely acquired from subclinical circulating infections from overseas.

International

Nonpolio enteroviral infections are quite prevalent worldwide. The exact numbers are unavailable.

Poliomyelitis still occurs in many developing countries as a result of poor health care and an inability to access vaccines. The CDC reported 6227 cases in 1998.³ This significant drop from the previous decade, in which 35,251 cases were reported, is due to aggressive vaccination programs. Worldwide eradication is hoped to occur in the near future.

Recently, setbacks have been noted in Nigeria, where suspicion about the motivations of the vaccination program led to a refusal to vaccinate children. One outbreak in 2003 crossed 15 other African countries and even spread as far as Indonesia, resulting in the paralysis of over 200 children. A more recent outbreak in 2006 affected mostly adults who were missed by vaccination campaigns. As of June 2006, 7 people had died and 27 people had been paralyzed. Nigeria had about half of the reported polio infections in the first 3 months of 2009. The data below suggests that the outbreak continues.

Worldwide polio cases from January-March 2009 are reported as follows:⁴

• Nigeria (endemic) – 51 (801 cases in 2008)
• India (endemic) – 17 (559 cases in 2008)
• Democratic Republic of Congo (importation) – 0 (5 cases in 2008)
• Pakistan (endemic) – 8 (118 cases in 2008)
• Niger (importation) - 3 (12 cases in 2008)
• Afghanistan (endemic) - 4 (31 cases in 2008)
• Angola (importation) - 1 (29 cases in 2008)
• Ethiopia (importation) - 0 (3 cases in 2008)
• Chad (importation) – 0 (37 case in 2008)
• Kenya (importation) - 2 (0 cases in 2008)
• Nepal (importation) - 0 (6 cases in 2008)
• Uganda (importation) - 3 (0 cases in 2008)
• Sudan (importation) - 11 (26 cases in 2008)
• Togo (importation) - 3 (3 cases in 2008)
• Benin (importation ) - 2 (6 cases in 2008)
• Burkina Faso (importation) - 4 (6 cases in 2008)
• Mali (importation) - 1 (1 case in 2008)
• Côte d'Ivoire (importation) - 0 (1 case in 2008)
• Ghana (importation) - 0 (8 cases in 2008)

Mortality/Morbidity

The overall mortality rate for nonpolio viruses is extremely low. The patients at greatest risk are those with neonatal sepsis.

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 38.5 º C.⁵

Most cases of myocarditis and pericarditis are self-limited, but a potentially significant mortality rate is associated with myocarditis. Older patients can develop a dilated cardiomyopathy following myocarditis.

The overall mortality rate for paralytic polio is 2-10%. For those who survive, a 6-month period is allowed to predict how much muscle function will return.

Race

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

Sex

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

Age

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. The infection course tends to be benign in older children and more serious in neonates. Unlike most cases of nonpolio enteroviral infections, acute hemorrhagic conjunctivitis occurs most frequently in adults aged 20-50 years.

Clinical

History

Nonpolio enteroviruses cause an astronomical 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 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 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 A, serotype 16, but strains of enterovirus 71 circulating in East Asia are currently causing outbreaks of hand-foot-and-mouth (HFM) disease that are associated with a serious rhombencephalitis, with significant mortality.
• 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 sepsislike 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 impossible. Infants younger than 10 days are unable to mount a significant immune response and are at a higher risk of a serious infection from echoviruses and coxsackie group B viruses. 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 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.

Physical

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

• Patients with herpangina present 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. 
• Patients with HFM disease present 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.
  
  

  

  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.
  
  

  

  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.
• 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 shocklike 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.
• Polioviruses should be differentiated into their 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.

Causes

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.

Differential Diagnoses

Other Problems to Be Considered

Guillain-Barré syndrome
Viral encephalitis
Tick-borne paralysis

Workup

Laboratory Studies

• 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 is 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.^6,7
  • 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.⁸
• 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.
• 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 echocardiographs.

Other Tests

• Obtain 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.

Procedures

• 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.
  • Often, the WBC count is less than 500/mL, with an initial 2 days of polymorphonuclear cell predominance that is replaced by mononuclear cells. 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.

Treatment

Medical Care

Unfortunately, no specific antiviral medication or treatment is available for an enteroviral infection. The best care is provided through supportive measures. Fluid hydration and antipyretics 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. 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.
• Intravenous immune globulin (IVIG) has been suggested to be beneficial in the outcome of myocarditis because of immunoglobulin G (IgG) and T-cell modulation. Other indications include possible efficacy in infections in newborns and patients with agammaglobulinemia.
• Although not approved by the US Food and Drug Administration, (FDA), pleconaril may play a role in the treatment plan in the future.
• The best medical care involves continued efforts for worldwide poliovirus vaccination.

Consultations

• 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.

Medication

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.

Antipyretic and analgesic agents

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

Acetaminophen (Tylenol, FeverAll)

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

Dosing

Adult

325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d

Pediatric

<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d
>12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h

Interactions

Rifampin can reduce analgesic effects of acetaminophen; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity

Contraindications

Documented hypersensitivity; known G-6-PD deficiency

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hepatotoxicity is possible in people with chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate a serious illness; combined use with OTC products that contain acetaminophen may result in cumulative doses that exceed recommended maximum dose

Ibuprofen (Motrin, Advil)

One of the few NSAIDs indicated for reduction of fever.

Dosing

Adult

200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d

Pediatric

6 months to 12 years: 4-10 mg/kg/dose PO tid/qid
>12 years: Administer as in adults

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy

Immunoglobulins

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%).

Dosing

Adult

2 g/kg IV as a single infusion over 12 h; alternatively, 2 g/kg IV as a single dose infused over 4 d (ie, over 96 h); must gradually increase rate of infusion to avoid infusion-related toxicity

Pediatric

750 mg/kg IV as a single infusion over 12 h; alternatively, 750 mg/kg IV as a single dose infused over 4 d (ie, over 96 h); must gradually increase rate of infusion to avoid infusion-related toxicity

Interactions

Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)

Contraindications

Documented hypersensitivity; IgA deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum IgA before IVIG administration (obtain a low IgA product if necessary); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Antiviral agents

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)

Investigational in the United States. Low-molecular weight capsid-inhibitor fits into the hydrophobic pocket of the VP1 capsid protein and interferes with viral attachment and uncoating. Has shown efficacy against enterovirus species.
Several clinical trials in adults have shown good drug tolerability with low adverse effects. Drug distribution shows good penetration into the liver, CNS, and nasal mucosa. Efficacy demonstrated in terms of symptom scores, nasal mucus production, and length of illness in studies in which administration of the drug precedes or coincides with experimental enterococcus inoculation. Bioavailability increases more than 2-fold when administered with a fatty meal compared with administration in a fasting state. Treatment of subjects presenting with a "common cold" reduced the disease duration by about 1 d.
Several case reports document successful treatment of severe or life-threatening infections. Data in children is extremely limited. Studies are underway. Contact Schering-Plough for information regarding experimental protocols or compassionate need.

Dosing

Adult

200 mg PO bid for 5-7 d; administer with a fatty meal

Pediatric

1-5 mg/kg/dose PO qd/tid; dose and administration frequency varies depending on experimental protocol being followed
Pediatric doses are typically higher per kg, perhaps due to a greater volume of distribution in infants and neonates and/or lower bioavailability

Interactions

Mild CYP 3A4 isoenzyme inducer; reduces PO contraceptive serum concentrations, and users report a significantly higher rate of menstrual irregularities (69% in patients who use PO contraceptives and receive 400 mg bid vs about 25% in patients who do not use PO contraceptives and receive any pleconaril dose or patients who use PO contraceptives and do not receive pleconaril), long-term use (ie, >1 mo) may increase the rate of pregnancy because of these irregularities (suggest alternate birth control method); may increase theophylline serum concentrations

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Experimental drug; although current data show a generally good safety profile, administration is still limited to compassionate use in severe, life-threatening enterovirus infections; caution in renal or hepatic impairment due to limited data

Follow-up

Further Inpatient Care

• The course of enterovirus infection widely varies; therefore, each case must be individually handled. Neonatal meningitis and septic cases require careful observation for CNS changes. Cultures must be carefully obtained and monitored.
• Patients with paralytic poliovirus should be admitted to the 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 should be liberally offered 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.

Further 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 pediatrician in 1-2 days.

Inpatient & Outpatient Medications

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

Transfer

• No specific indications for transfer are recognized in patients with enteroviral infections.
  • Transfer may be needed for lack of intensive care setting, in such cases as 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 prior to transfer.

Deterrence/Prevention

• 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 OPV, developed by Sabin, consists of live-attenuated poliovirus. Oral polio vaccine (OPV) creates local community and herd immunity through viral shedding by the intestinal tract and is less invasive.
  • 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.⁹

Complications

• Both coxsackievirus and enterovirus have been associated with the development of Guillain-Barré syndrome.
• Coxsackieviruses have been hypothesized to play a role in the development of insulin-dependent diabetes mellitus. Rodent models have demonstrated enteroviral destruction of pancreatic beta-islet cells, but no definitive link has been established. In a 1995 study in Finland, Hyoty et al demonstrated elevated blood levels of enteroviral immunoglobulins in the mothers of children with insulin-dependent diabetes mellitus as compared with pregnant mothers of nondiabetic children.¹⁰
• Several studies have investigated a possible link between enteroviral infections and increased risk of myocardial infarction, but no definite conclusions have been proven.

Prognosis

• The prognosis for nonpolio enteroviral infections is excellent. Bad 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.

Patient Education

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

Miscellaneous

Medicolegal Pitfalls

• Although diagnosing enteroviral infections is quite useful, it does not exclude the possibility of a concomitant bacterial infection.

Special Concerns

• Pregnant females should theoretically not receive polio vaccination, although no bad outcomes have been documented. If vaccine is required for necessary protection, both inactivated polio vaccine and oral polio vaccine (OPV) are safe. Also, breastfeeding can continue without concerns.
• OPV vaccine is contraindicated in immunocompromised patients and household members of these patients because it contains live-attenuated virus. The Sabin vaccine was developed through long-term passage of virus, but genetic analysis shows that a single RNA base change in the transcription initiation site can restore near–wild-type replication kinetics.

Multimedia

Media file 1: Erosions on the base of the tongue.

Media file 2: A red halo surrounds several vesicles on the finger flexures and palms.

Media file 3: Small linear vesicle on the thumb.

Media file 4: Vesicle on the dorsal hand of a young adult.

References

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2. Picornaviridae Study Group. New and Re-classified TypesGenus Parechovirus, species Human parechovirus. Available at http://www.picornastudygroup.com/types/parechovirus/hpev.htm. Accessed 3/14/09.

3. CDC. Enterovirus surveillance--United States, 1997-1999. MMWR Morb Mortal Wkly Rep. Oct 13 2000;49(40):913-6. [Medline].

4. Global Polio Eradication Initiative. Wild Poliovirus Weekly Update. Global Polio Eradication. Available at http://www.polioeradication.org/casecount.asp. Accessed 3/14/09.

5. Ooi MH, Wong SC, Mohan A, Podin Y, Perera D, Clear D, et al. Identification and validation of clinical predictors for the risk of neurological involvement in children with hand, foot, and mouth disease in Sarawak. BMC Infect Dis. Jan 19 2009;9:3. [Medline].

6. Chonmaitree T, Menegus MA, Powell KR. The clinical relevance of 'CSF viral culture'. A two-year experience with aseptic meningitis in Rochester, NY. JAMA. Apr 2 1982;247(13):1843-7. [Medline].

7. Singer JI, Maur PR, Riley JP, Smith PB. Management of central nervous system infections during an epidemic of enteroviral aseptic meningitis. J Pediatr. Mar 1980;96(3 Pt 2):559-63. [Medline].

8. Ahmed A, Brito F, Goto C, et al. Clinical utility of the polymerase chain reaction for diagnosis of enteroviral meningitis in infancy. J Pediatr. Sep 1997;131(3):393-7. [Medline].

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10. Hyoty H, Hiltunen M, Knip M, et al. A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes. Jun 1995;44(6):652-7. [Medline].

11. Abzug MJ, Keyserling HL, Lee ML, et al. Neonatal enterovirus infection: virology, serology, and effects of intravenous immune globulin. Clin Infect Dis. May 1995;20(5):1201-6. [Medline].

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13. Andrus JK, Strebel PM, de Quadros CA, Olive JM. Risk of vaccine-associated paralytic poliomyelitis in Latin America, 1989-91. Bull World Health Organ. 1995;73(1):33-40. [Medline].

14. Ballow M. Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory diseases. J Allergy Clin Immunol. Aug 1997;100(2):151-7. [Medline].

15. Gaspar BG, Kinnon C. Humoral Immunodeficiency: X-linked agammaglobulinemia. Immunol Allergy Clin North Am. 2001;21(1).

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18. Kohler KA, Banerjee K, Gary Hlady W, Andrus JK, Sutter RW. Vaccine-associated paralytic poliomyelitis in India during 1999: decreased risk despite massive use of oral polio vaccine. Bull World Health Organ. 2002;80(3):210-6. [Medline].

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20. Norris CM, Danis PG, Gardner TD. Aseptic meningitis in the newborn and young infant. Am Fam Physician. May 15 1999;59(10):2761-70. [Medline].

21. Prager P, Nolan M, Andrews IP, Williams GD. Neurogenic pulmonary edema in enterovirus 71 encephalitis is not uniformly fatal but causes severe morbidity in survivors. Pediatr Crit Care Med. Jul 2003;4(3):377-81. [Medline].

22. Prevots DR, Burr RK, Sutter RW, Murphy TV,. Poliomyelitis prevention in the United States. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. May 9 2000;49(RR-5):1-22; quiz CE1-7. [Medline]. [Full Text].

23. Roivainen M. Enteroviruses and myocardial infarction. Am Heart J. Nov 1999;138(5 Pt 2):S479-83. [Medline].

24. Rotbart HA, Sawyer MH, Fast S, et al. Diagnosis of enteroviral meningitis by using PCR with a colorimetric microwell detection assay. J Clin Microbiol. Oct 1994;32(10):2590-2. [Medline]. [Full Text].

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Keywords

enteroviral infections, enterovirus, poliovirus, echovirus, coxsackie virus, coxsackievirus, oral polio vaccine, OPV, inactivated polio vaccine, IPV, hand-foot-and-mouth disease, HFM, herpangina, myocarditis, pleurodynia, aseptic meningitis, neonatal sepsis, viremia, biphasic prodromal illness, hepatic necrosis, viral exanthems, vaccine-associated paralytic polio, VAPP, Sabin vaccine, monovalent oral polio vaccine, mOPV, global encephalitis, rhombencephalitis, myoclonus, acute hemorrhagic conjunctivitis, myalgia, orchitis, epididymitis, meningococcemia, neurogenic pulmonary edema, pleurodynia, Bornholm disease, devil’s grippe, bulbar poliomyelitis, auscultatory fiction rub, Hamman crunch, coryza, X-linked agammaglobulinemia, Guillain-Barré syndrome, treatment, diagnosis

Contributor Information and Disclosures

Author

Nicholas John Bennett, MB, BCh, PhD, Fellow in Pediatric Infectious Disease, Department of Pediatrics, State University of New York Upstate Medical University
Nicholas John Bennett, MB, BCh, PhD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Pediatrics
Disclosure: Nothing to disclose.

Coauthor(s)

Joseph Domachowske, MD, Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York-Upstate Medical University
Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Mobeen H Rathore, MD, CPE, FAAP, FIDSA, Chief of Division of Pediatric Infectious Diseases/Immunology, Associate Chairman of Department of Pediatrics, University of Florida College of Medicine at Jacksonville; Hospital Epidemiologist and Section Chief of Infectious Disease and Immunology, Wolfson Children's Hospital; Director of University of Florida Center for HIV/AIDS Research, Education and Service (UF CARES)
Mobeen H Rathore, MD, CPE, FAAP, FIDSA is a member of the following medical societies: American Academy of Pediatrics, American Society for Microbiology, European Society for Paediatric Infectious Diseases, Florida Medical Association, Florida Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Society for Healthcare Epidemiology of America, Society for Pediatric Research, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Leonard R Krilov, MD, Chief of Pediatric Infectious Diseases, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital
Leonard R Krilov, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Medimmune Grant/research funds Cliinical trials; Medimmune Honoraria Speaking and teaching; Medimmune Consulting fee Consulting

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School
Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Robert W Tolan Jr, MD, Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine
Robert W Tolan Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility
Disclosure: GlaxoSmithKline Honoraria Speaking and teaching; MedImmune Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; sanofi pasteur Honoraria Speaking and teaching; Baxter Healthcare Honoraria Speaking and teaching

Chief Editor

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association
Disclosure: None None None

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Michelle Mowad, MD, to the original writing and development of this article.

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