DOI: 10.1542/Pir.19-6-183 1998;19;183 Pediatrics in Review Theoklis Zaoutis and Joel D. Klein Enterovirus Infections

Enterovirus Infections Theoklis Zaoutis and Joel D. Klein Pediatrics in Review 1998;19;183 DOI: 10.1542/pir.19-6-183

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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1998 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.

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ARTICLE Enterovirus Infections Theoklis Zaoutis, MD* and Joel D. Klein, MD†

currently recognized to infect IMPORTANT POINTS humans are outlined in Table 1. 1. Enteroviral infections occur primarily during the summer and Enterovirus 72 is hepatitis A virus, fall months; the fecal-oral route is the most common mode of which differs from the other entero- transmission. viruses by having only one serotype 2. New polio vaccination regimens have been developed to reduce or and replicating only in liver cells. It eliminate the incidence of vaccine-associated paralytic poliomyelitis. will not be included in this review. 3. Neonates infected with enteroviruses can present with a sepsis-like The virion consists of an icoso- clinical picture indistinguishable from bacterial sepsis. hedron-shaped protein capsid and 4. Herpangina and hand-foot-mouth disease often can be distinguished an RNA core. Although the capsid from herpes simplex and varicella infections by the distribution of proteins determine antigenicity, the rash and the severity of constitutional symptoms. there are no significant antigens 5. Enteroviruses are the most common cause of aseptic meningitis, common to all members of this which usually presents with fever, meningeal signs, cerebrospinal 3 group of viruses. The virus can fluid pleocytosis (<500 white blood cells/mm ), and normal levels withstand the acidic pH of the of cerebrospinal fluid glucose and protein. human gastrointestinal tract and can survive at room temperature for several days. These features enable the fecal-oral mode of trans- Introduction History mission. Most enteroviruses can Enteroviruses (polioviruses, cox- In 1920, soon-to-be president grow in primate (human or non- sackieviruses, echoviruses) are Franklin Delano Roosevelt devel- human) cell cultures, exhibiting among the most common and sig- oped a febrile illness during his cytopathic effect in 3 to 7 days. nificant causes of infectious illness summer vacation that was followed in infants and children. They are by paralysis. Although this is one of associated with a broad spectrum the most publicly recognized cases Epidemiology of clinical syndromes, including of paralytic poliomyelitis, polio has Enteroviruses are commonly aseptic meningitis, herpangina, been described as early as 1580 referred to as “summer viruses” hand-foot-mouth disease, conjunc- B.C. An Egyptian stone tablet shows because resulting infections occur tivitis, pleurodynia, myopericarditis, a young priest who has a withered, primarily during the warmer, sum- poliomyelitis, various exanthems, shortened leg, the characteristic mer months (May through October) and nonspecific febrile illness. In deformity of poliomyelitis. The in temperate northern hemisphere the neonate, enteroviral infection virus was not isolated until 1949 climates such as in the United can cause a sepsis-like picture or when John Enders grew it in tissue States. In tropical climates, entero- meningoencephalitis, either of which culture. Following the isolation and viral infection is seen all year can be severe. Newer technologies identification of this prototypic without seasonal variation. such as polymerase chain reaction enterovirus, other members of the Humans are the only known (PCR) may provide rapid and sensi- enteroviral family were studied natural hosts for enteroviruses. tive testing methods for diagnosis and their properties elucidated. of enteroviral infections, which may expand the list of diseases attribut- TABLE 1. able to this group of pathogens. Characteristics of Human Enteroviruses Although treatment of enteroviral Enteroviruses GROUP SEROTYPES infections remains unsatisfactory, The enteroviruses are a subgroup immunization against poliovirus has of single-stranded RNA, non- Poliovirus 1Ð3 been remarkably successful, and enveloped viruses belonging to the new immunization regimens using Coxsackievirus 1Ð22, 24 Picornaviradae family (pico=small, group A live and killed virus vaccines have RNA=ribonucleic acid). They been developed. A role has been include the polioviruses, coxsackie- Coxsackievirus 1Ð6 postulated for enteroviruses in the viruses, echoviruses (echo=enteric group B pathogenesis of diabetes mellitus. cytopathogenic human orphan), Echovirus 1Ð9, 11Ð27, and unclassified enteroviruses. 29Ð33 Early classification of enteroviruses involved groupings based on cyto- Enterovirus 68Ð72* *Resident, Department of Pediatrics. pathologic effect in tissue culture. †Chief, Division of Pediatric Infectious *Hepatitis A virus was enterovirus type Diseases, duPont Hospital for Children, Newly discovered enteroviruses are 72, but recently has been reclassified Wilmington, DE; Jefferson Medical College, now simply assigned enterovirus as a Heparnavirus. Philadelphia, PA. type numbers. The enteroviruses

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INFECTIOUS DISEASE Enterovirus Infections

The fecal-oral route is the most not included the polioviruses since monly described in enteroviral infec- common mode of transmission, the use of vaccination virtually tions (Fig 1). but oral-oral and respiratory spread eliminated paralytic poliomyelitis Viremia is the most common also are possible. Risk factors for from developed nations. source of CNS infection, with some infection include poor sanitation, enteroviral serotypes exhibiting crowded living conditions, and Pathogenesis increased neurotropism or neuro- low socioeconomic class. Children virulence. These include all three younger than 5 years of age are The incubation period for most serotypes of poliovirus, numerous the most susceptible to infection, enteroviral infections ranges from echovirus strains, and coxsackie- due in part to a lack of prior immu- 3 to 10 days. The virus enters the viruses B3 through B5. In paralytic nity and to the poor hygienic habits host via the oral cavity and/or respi- associated with this age group. ratory tract, then invades and repli- Sixty-eight enteroviral serotypes cates in the upper respiratory tract TABLE 2. Pathogenesis have been identified, but most infec- and small intestine, with a predilec- of Enteroviruses tions are caused by a small number tion for lymphoid tissues in these of these. During annual epidemics regions (Peyer patches, mesenteric ¥ Entry of virus via oral and/or of clinical disease, certain serotypes nodes, tonsils, and cervical nodes). respiratory route predominate. In the past 25 years, Virus then enters the bloodstream, approximately 15 serotypes have resulting in a minor viremia and ¥ Viral replication in regional been responsible for the majority of dissemination to a variety of target lymph nodes of upper infections and include echoviruses 4, organs, including the central nervous respiratory and gastrointestinal 6, 9, 11, and 30; coxsackieviruses system (CNS), heart, liver, pancreas, tracts A9, A16, and B2 through B5; and adrenal glands, skin, and mucous ¥ Minor viremia; onset of enteroviruses 70 and 71. A given membranes. A major viremia results symptoms serotype may decrease in prevalence from viral replication at and dissem- following an epidemic only to re- ination from these secondary sites, ¥ Viral replication in heart, liver, emerge in subsequent outbreaks, which provide additional opportuni- skin, and other organs when a new group of susceptible ties for seeding the CNS (Table 2). ¥ Major viremia with secondary hosts becomes available. The minor and major viremia may seeding of central nervous The pattern of enteroviral epi- correlate with the biphasic appear- system demics occurring each season has ance of fever and symptoms com-

FIGURE 1. Clinical course, viral isolation, and antibody response in enteroviral infection. Reproduced with permission from Sherris J, ed. Medical Microbiology. An Introduction to Infectious Diseases. New York, NY: Simon and Schuster, Inc; 1984.

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INFECTIOUS DISEASE Enterovirus Infections polio infection, the virus replicates It is believed that approximately Findings on the physical examina- in the motor neurons in the anterior 50% of nonpolio enterovirus infec- tion are usually unremarkable, but horn of the spinal cord and brain- tions are asymptomatic. The more mild conjunctivitis, lymphadenitis, stem, leading to death of the neu- common syndromes include non- or pharyngeal erythema may be ronal cells and paralysis of the specific febrile illness, aseptic present. If a white blood cell count innervated muscles. meningitis, herpangina, hand-foot- is obtained, there is usually little to The immune response in entero- mouth syndrome, and exanthems. no elevation and no shift in the dif- viral infections involves an early The clinical manifestations of infec- ferential. Knowledge that the fever immunoglobulin M (IgM) antibody tion in the neonate can be distinct can last for up to 1 week may pre- response at 7 to 10 days, followed and will be discussed separately. vent unnecessary diagnostic evalua- by a rise in IgG and intestinal IgA tions and ease parental fears. neutralizing antibodies. There is rel- NONSPECIFIC FEBRILE ILLNESS ative immunity to reinfection with The most common clinical presenta- ASEPTIC MENINGITIS the same serotype, but if reinfection tion of nonpolio enterovirus infec- Nonpolio enteroviruses are the lead- does occur, the symptoms are ame- tion is a nonspecific febrile illness. ing causes of aseptic meningitis, liorated and the illness may be sub- Typically, fever develops suddenly, accounting for 80% to 90% of all clinical. without a prodrome, and tempera- cases from which an etiologic agent tures range from 38.5û to 40ûC is identified. The most common Clinical Presentations of (101û to 104ûF) and last for an enterovirus types associated with average of 3 days. Occasionally, aseptic meningitis are coxsackievirus Infection With Nonpolio a biphasic pattern of symptoms can B5 and echoviruses 4, 6, 9, and 11. Enteroviruses be seen, with an initial fever for These have occurred in epidemic Nonpolio enteroviruses are estimated 1 day, followed by 2 to 3 days outbreaks as well as sporadic cases. to cause 10 to 15 million sympto- of normal temperatures and recur- The initial presentation is similar matic infections in the United States rence of fever for an additional 2 to to that of nonspecific febrile illness. annually. They cause a wide spec- 4 days. Accompanying symptoms Commonly, a biphasic pattern of trum of disease that can involve are nonspecific and include malaise, symptoms is seen, with signs of almost any organ system (Table 3). myalgia, headache, and sore throat, CNS involvement developing in Disease severity can range from as well as gastrointestinal symptoms addition to recurrence of fever. life-threatening with significant of nausea, vomiting, mild abdominal Evidence for meningeal irritation morbidity to mild or subclinical. discomfort, and mildly loose stools. commonly includes headache and

TABLE 3. Clinical Syndromes and Associated Enteroviruses

SYNDROME PREDOMINANT VIRUS CLINICAL FEATURES Nonspecific febrile illness All types Febrile illness (occasionally biphasic), with non- specific upper respiratory and gastrointestinal tract symptoms Aseptic meningitis Echovirus and group B Fever, meningeal signs with mild cerebrospinal (CSF) coxsackieviruses pleocytosis, usually normal CSF glucose and pro- tein, and absence of bacteria Herpangina Group A coxsackieviruses Fever, painful oral vesicles on tonsils and posterior pharynx Hand-foot-mouth disease Coxsackievirus A16 Fever, vesicles on buccal mucosa and tongue and on interdigital surfaces of hands and feet Nonspecific exanthem Echoviruses Variable rash (usually rubelliform but may be petechial or vesicular), +/Ð fever Pleurodynia Coxsackievirus B3, B5 Uncommon, epidemic, fever, and severe muscle pain of chest and abdomen Carditis Group B coxsackievirus Uncommon, myocarditis/pericarditis, which can present with heart failure or dysrhythmia Acute hemorrhagic Enterovirus 70 Epidemic cause of conjunctivitis with lid swelling, conjunctivitis subconjunctival hemorrhage, and eye pain without systemic symptoms Neonatal disease Group B coxsackieviruses Sepsis-like picture, meningoencephalitis, hepatitis, and echoviruses myocarditis

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INFECTIOUS DISEASE Enterovirus Infections photophobia, with 50% of children term sequelae. Recent large studies the oral lesions, which are tiny, firm, older than 1 to 2 years of age also have shown that there are no long- white nodules (packed with lympho- developing nuchal rigidity. Approxi- term neurologic, cognitive, or devel- cytes) in the same distribution. mately one third of these older chil- opmental abnormalities from this The differential diagnosis for dren will have a positive Kernig infection in older children. How- herpangina is discussed in the next and/or Brudzinski sign. Children ever, several investigations have section. younger than 1 year of age usually documented that 10% of children have no specific meningeal signs, younger than 3 months of age who HAND-FOOT-MOUTH but exhibit increased irritability. have aseptic meningitis may suffer (HFM) DISEASE Rash is often present and is usually long-term sequelae, especially HFM disease is characterized clini- nonspecific. However, on occasion speech and language delay. cally by a vesicular eruption on the it is petechial and may be confused CNS infection by nonpolio hands and feet and in the oral cavity. with the rash of meningococcemia. enteroviruses less commonly is Toddlers and school-age children are Examination of the cerebrospinal manifested as encephalitis, which is affected most commonly. Coxsackie- fluid (CSF) reveals a mildly ele- often severe and, unlike meningitis, virus A16 is the primary etiologic vated white blood cell count that can result in long-term sequelae. agent, but other enteroviruses have typically is less than 500/mm3 but The encephalitis is typically global, been implicated as well. can be as high as 2,000/mm3. In the which can differentiate it from the Patients present with fever of first 1 to 2 days of the illness, poly- focal presentation often seen with 38û to 39ûC (100.4û to 102.2ûF) morphonuclear cells predominate, herpes simplex encephalitis. that lasts 1 to 2 days, sore mouth but they are replaced rapidly by or throat, and the characteristic mononuclear cells. Because bacterial HERPANGINA exanthem/enanthem. The oral meningitis usually produces a per- Herpangina is an enanthemous vesicles usually are located on sistent granulocytosis in the CSF, (mucous membrane) disease charac- the buccal mucosa and tongue sequential lumbar punctures can be terized by a painful vesicular erup- and are only mildly painful. They useful in differentiating bacterial tion of the oral mucosa associated are surrounded by erythematous from viral infection. The CSF glu- with fever, sore throat, and pain rings and eventually ulcerate cose level tends to be normal, but it on swallowing. It is seen most (Fig 2). The exanthem involves has been reported to be low in some commonly in children ages 3 to vesicles on the palms, soles, and patients, and the CSF protein con- 10 years. Group A coxsackieviruses interdigital surfaces of the hands centration may be normal or mildly are the most common etiologic and feet (Fig 3). Less commonly, elevated (80 to 100 mg/dL). agents, but group B coxsackie- lesions (nonvesicular) can be seen The differential diagnosis for viruses and echoviruses also have on the buttocks, proximal extremi- aseptic meningitis is extremely been isolated from patients. broad and includes the tick-borne Fever, usually mild, develops illnesses (ie, Rocky Mountain suddenly, but higher temperatures spotted fever, Lyme disease, up to 41ûC (105.8ûF) can be seen, and ehrlichiosis) as well as particularly in younger patients. arbovirus infections. These all Nonspecific early symptoms may occur more commonly during the include headache, vomiting, and summer/autumn months, which myalgia. Sore throat and pain with corresponds to the peak season for swallowing are the most prominent enteroviral infection. The distribu- symptoms and precede the charac- tion and character of the rash and teristic enanthem by approximately blood count findings may help dis- 1 day. The enanthem consists of tinguish these different entities. Par- punctate macules that vesiculate and tially treated bacterial meningitis ulcerate. The vesicles and ulcers are may present with similar clinical surrounded by an erythematous ring and CSF findings; this possibility and are found on the anterior tonsil- should be considered in every lar pillars, soft palate, and posterior patient presenting with aseptic pharynx. There are typically two to meningitis. The presence of other six lesions, but there can be as many identifiable enteroviral syndromes as 12 to 16. The posterior orophar- in the community, such as herpan- ynx usually is minimally erythema- gina and hand-foot-mouth disease, tous. Herpangina is self-limited, and can be useful in diagnosis because symptoms resolve within 1 week. outbreaks tend to be epidemic and Young children are at risk for dehy- FIGURE 2. Characteristic distribution of oral ulcers in hand-foot-mouth disease seasonal. dration because of refusal to eat (top); lesions occasionally occur on pos- The course of enteroviral menin- or drink. terior soft palate (bottom). Reproduced gitis usually is self-limited and be- Lymphonodular pharyngitis, a with permission from Slide Atlas of Pedi- nign, but there has been ongoing variant of herpangina, presents simi- atric Physical Diagnosis. New York, NY: debate about the occurrence of long- larly but differs in the appearance of Gower Medical Publishing Ltd; 1987.

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enteroviral exanthem they can last up to several hours. consists of a pink, During spasms patients may develop macular, blanching, signs of respiratory distress or rubelliform rash. Unlike appear shock-like with diaphoresis rubella, this rash usually and pallor. Pain localized to the is not associated with abdomen in young children may adenopathy. Less com- falsely suggest intussusception or monly, the rash can appendicitis. The illness usually appear maculopapular, lasts 1 to 2 days, but frequently a vesicular, roseola-like, biphasic pattern is seen, with recur- urticarial, or petechial. rences possible several weeks after The rash may be the the initial episode. Associated signs sole manifestation of and symptoms include anorexia, FIGURE 3. Characteristic distribution and appear- infection or may present headache, nausea, and vomiting. ance of hand-foot-mouth disease lesions on the hand. in association with The affected muscles are tender Reproduced with permission from Slide Atlas of febrile illness or aseptic to palpation, and occasionally a Pediatric Physical Diagnosis. New York, NY: Gower meningitis. It also can Medical Publishing Ltd; 1987. pleural friction rub is heard on be seen after fever dis- auscultation. In contrast to many appears, thus mimicking other enteroviral syndromes, pleuro- ties, and genitalia. Most children roseola. Enteroviral exanthems are dynia is more common in older recover within 1 week. seen most commonly in children children and adolescents. The differential diagnosis for younger than 5 years of age and HFM disease includes infection by decrease in prevalence with age. MYOCARDITIS/PERICARDITIS herpes simplex or varicella-zoster The rash is self-limited and disap- Enteroviral myocarditis and/or peri- virus, herpangina, and aphthous pears in 3 to 5 days. carditis is associated with group B stomatitis. In contrast to HFM, coxsackievirus (B5 most commonly) varicella lesions are located more ADDITIONAL CLINICAL in up to 50% of cases. Patients pre- centrally, are more extensive, and MANIFESTATIONS sent with fatigue, dyspnea on exer- usually spare the palms and soles. Nonpolio enterovirus can cause a tion, or more fulminant symptoms of Additionally, resolution of varicella wide range of symptoms that are heart failure or dysrhythmia. Cardiac lesions involves crusting, whereas clinically indistinguishable from involvement is usually self-limited, HFM vesicles resolve by resorption those of other viral syndromes. with complete recovery, but overall of fluid. In herpetic gingivostomati- These include upper or lower mortality associated with myocardi- tis, patients usually appear more ill, respiratory tract infections, arthritis, tis is significant. may have gingival erythema or orchitis, nephritis, and gastroenteri- Recent evidence indicates that bleeding, present with higher tem- tis. Of note, gastrointestinal symp- toms such as vomiting, diarrhea, coxsackievirus cardiac infection can peratures, and exhibit significant be chronic. Viral-specific IgM anti- cervical lymphadenopathy and and abdominal pain are common in children who have enteroviral bodies have been found in patients lesions confined to the oral cavity who have chronic pericarditis, and without extremity involvement. infections, but rarely are the sole complaints. enteroviral genetic material has been These findings may help distinguish detected from biopsy specimens of herpetic stomatitis from HFM. patients who have dilated cardio- Herpangina also may resemble myopathy. Several studies also have HFM, but the herpangina oral Other Relevant Syndromes described an association between lesions usually are located in the Several illnesses, although relatively group B coxsackievirus infection posterior aspects of the pharynx; uncommon, are classically associ- and myocardial infarction in adults. the extremities are spared. Aphthous ated with enteroviral infection. stomatitis is characterized by larger, ACUTE HEMORRHAGIC ulcerative lesions of the lips, tongue, PLEURODYNIA CONJUNCTIVITIS (AHC) and buccal mucosa that are exquis- (BORNHOLM DISEASE) This explosive epidemic conjunctivi- itely painful. It is seen most com- Pleurodynia or epidemic myalgia is tis, first described in 1969 in Africa monly in older children and adults, characterized by an acute onset of and Asia, is now found worldwide. has multiple recurrences, and gener- severe muscular pain in the chest It is more common in tropical and ally is not associated with constitu- and abdomen accompanied by fever. densely populated regions. The tional symptoms. Coxsackieviruses B3 and B5 are the majority of outbreaks have been major causes of epidemic disease; caused by enterovirus serotype 70, NONSPECIFIC EXANTHEM rare sporadic cases have been but recently coxsackievirus A24 Nonpolio enteroviruses are the lead- described with other nonpolio has been isolated during outbreaks. ing cause of exanthems in children enteroviruses. AHC is characterized by sudden during the summer and fall months. The muscular pain is sharp and onset of severe eye pain, photopho- The most common serotype causing spasmodic, with episodes typically bia, and blurred vision. Subconjunc- exanthem is echovirus 9. The classic lasting 15 to 30 minutes, although tival hemorrhages, erythema, edema

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INFECTIOUS DISEASE Enterovirus Infections of the lids, eye discharge, and preau- and, at times, fatal disease manifests from virus shed from recent OPV ricular lymphadenopathy are seen. as pneumonitis, hepatitis, dissemi- recipients. Secondary bacterial infection is nated intravascular coagulation, and common. Systemic symptoms are meningoencephalitis. In a recent usually absent, and recovery occurs study profiling enterovirus infection Clinical Manifestations of within 7 to 10 days. Spread is by the in the first 2 weeks of life, 17% of Infection With Poliovirus eye-hand-fomite route in contrast to infected infants developed severe, Most infections caused by poliovirus the fecal-oral route seen with most multisystem disease. Although 100% are asymptomatic or subclinical; enteroviral infections. Overall, it is survival was reported, other studies only about 1% become clinically more common in adults, but it also have indicated that CNS deficits apparent. Of the three serotypes of does affect school-age children. may be a long-term sequela. poliovirus, type 1 causes the major- ity of epidemics. Three clinical syn- dromes are attributed to poliovirus Neonatal Disease Special Clinical infection—abortive poliomyelitis, Neonates infected with nonpolio Considerations aseptic meningitis, and paralytic enteroviruses are at high risk for Enteroviral infections also pose sig- poliomyelitis. Abortive poliomyelitis developing significant illness, nificant risk to children who have is characterized by a nonspecific including a sepsis-like condition, defects in B-lymphocyte function, febrile illness that includes head- meningoencephalitis, myocarditis, the most common of which is ache, sore throat, and no CNS and/or hepatitis. Echoviruses and X-linked agammaglobulinemia. involvement. These symptoms last group B coxsackieviruses account Unlike other viruses that are com- 2 to 3 days before resolving. Polio- virus infection also can be mani- fested as aseptic meningitis, indistin- guishable from the same syndrome Infants younger than 10 days of age are at higher risk caused by other enteroviruses. for severe enterovirus infections because of their relative Paralytic poliomyelitis begins inability to mount a significant immune response. with a minor febrile illness that is followed by a short asymptomatic period of 2 to 3 days. A sudden for the majority of neonatal entero- bated by cellular immune mecha- onset of asymmetric flaccid paraly- virus infections. Infection is usually nisms, enteroviruses are eliminated sis with no significant sensory loss acquired during birth or by postnatal from the host by humoral immune is the characteristic finding of para- contact with an infected caretaker. mechanisms. An intact B-cell lytic disease. Maximum neurologic Transplacental transmission is response is believed to be necessary damage occurs within a few days. possible but less likely. Nosoco- to block viral entry into the CNS. Motor neuron damage is permanent, mial transmission has accounted Children who have agamma- but some recovery results from other for multiple outbreaks in nurseries. globulinemia may develop chronic nerve cells taking over some of the Infection occurs in 20% to 50% enteroviral infection, most com- function. The most substantial por- of infants in whom there is a mater- monly meningoencephalitis. Patients tion of functional recovery occurs nal history of illness in the week present with headache, lethargy, within the first 6 months; little or preceding delivery. The severity of seizures, motor dysfunction, and no recovery is noted after 1 year. the neonatal illness is related to the altered sensorium. Symptoms may Bulbar poliomyelitis affects the severity of maternal illness at the wax and wane for years, but there is sensory, speech, and cardiorespira- time of delivery as well as to the an overall progressive deterioration tory centers of the brainstem and age of the infant at onset of infec- in CNS function. Pleocytosis and can cause death by paralysis of the tion. Infants younger than 10 days elevation of protein concentration respiratory muscles. of age are at higher risk for severe persist in CSF, and virus can be disease because of their relative recovered from the CSF for months inability to mount a significant to years. A late manifestation of Emerging Roles Of immune response and their lack of chronic enteroviral infection is a Enteroviruses serotype-specific maternal antibody. dermatomyositis-like syndrome in The role of enteroviruses, specifi- Asymptomatic infection is common, which virus is present in many body cally group B coxsackieviruses, but one study documented that up to tissues. Infection is fatal in most in the pathogenesis of type 1 dia- 20% of infected infants developed children who are immunodeficient. betes mellitus has been studied symptomatic disease during an Echovirus 11 has been the most extensively. A growing amount of enterovirus season. Presenting common cause of chronic infection, epidemiologic and experimental symptoms include fever, irritability, but cases caused by other echo- research suggests a strong associa- lethargy, poor feeding, hypoper- viruses and coxsackieviruses have tion. For example, new-onset type 1 fusion, abdominal distention, and been reported. Children who have diabetes mellitus occurs in clusters, jaundice. The sepsis-like clinical agammaglobulinemia are at risk for with a seasonal pattern that peaks 1 picture often is indistinguishable developing paralytic poliomyelitis to 2 months after the enteroviral from bacterial sepsis. Fulminant from oral polio vaccine (OPV) or season.

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Numerous studies have investi- sample is not useful because there was associated with faster cessation gated the presence of IgM antibod- is a wide range of titers to different of viremia and viruria (commonly ies to coxsackieviruses in patients serotypes in healthy individuals. seen in neonatal infection). The who have type 1 diabetes and con- The more than 60 antigenically efficacy of IVIG in children who trols; most have demonstrated an different serotypes that have no have agammaglobulinemia has been increased prevalence of the antibod- common group antigens makes inconsistent. ies in patients compared with con- serologic techniques both cumber- trols. Coxsackieviruses have been some and impractical. isolated from pancreatic tissue of The most promising development Prophylaxis children who have died of diabetic in diagnostic techniques for entero- The only enterovirus for which a ketoacidosis, and injury to pancre- viral infections is PCR. The genetic vaccine is available is poliovirus. atic beta cells by coxsackievirus probe is directed against a region Use of poliovirus vaccines has has been duplicated in cell culture that is conserved among almost all eradicated polio from the Western models. The process by which viral enteroviral serotypes. One such PCR Hemisphere and dramatically infection could cause type 1 diabetes test has been evaluated against 66 decreased the incidence worldwide. mellitus is not clear. Among the the- serotypes and found to detect 60 of The first poliovirus vaccine, devel- ories are an autoimmune response them. The PCR technique has been oped by Salk in 1955, was an inacti- due to cross-reacting antigens found tested almost exclusively in CSF vated poliovirus vaccine (IPV). In in the pancreas and the virus, direct samples and found to be more sensi- 1962, Sabin developed an oral, live viral injury, genetic predisposition, tive than cell culture and 100% spe- attenuated poliovirus vaccine (OPV) or a combination of these and other cific. Colorometric assays using that contains all three serotypes. yet unknown factors.

Enteroviral infection usually is diagnosed clinically, using Diagnosis seasonality, exposure, and characteristic physical findings Enteroviral infection usually is diag- and symptoms. nosed clinically without isolation and identification of the specific virus. Factors that aid in diagnosis PCR methods that can be performed Both vaccines are highly immuno- include seasonality, knowledge of in 5 hours have been shown to be genic, with greater than 95% sero- exposure, and characteristic con- 90% sensitive and 97% specific. conversion rates among recipients. stellation of physical findings and PCR testing of serum and urine After its introduction, OPV was symptoms. In certain clinical situa- samples from neonates in whom adopted rapidly worldwide as the tions, such as meningitis or neonatal infection was suspected was twice vaccine of choice. Its advantages disease, isolation and/or identifica- as sensitive as cell culture and 100% over IPV include ease of administra- tion of the virus may be indicated. specific. PCR technology soon may tion, secondary immunization of Laboratory methods for diagnos- allow sensitive and rapid diagnosis. vaccinee contacts, and stimulation of ing enterovirus infections include local immunity in the gastrointesti- cell culture, serology, and newly nal tract. Because the pathogenesis developed PCR techniques. The Treatment of polio infection depends on intesti- gold standard for diagnosis has No effective antiviral therapy cur- nal entry, high levels of neutralizing been isolation of enterovirus in rently is available for enteroviral antibodies locally (ie, in intestinal cell culture. Virus can be isolated infections; treatment is symptomatic mucosa) are optimal for protection. from stool, throat, blood, and CSF and supportive. Corticosteroids have With OPV, live virus replicates in of infected individuals, but most been of some benefit in the treat- the small intestine, thereby inducing clinical specimens are CSF. Isolation ment of myocarditis, but their use high titers of secretory IgA at this from blood is not common because is generally not recommended location. In addition, the presence viremia is usually undetectable by because administration in experi- of intestinal immunity may help the time symptoms appear. Virus mental animal models has had prevent spread of wild poliovirus can be isolated from the throat for deleterious effects. within an incompletely immunized 2 days to approximately 2 weeks Because clearance of enteroviral population. This is believed to occur after infection. Isolation of virus infections depends on humoral im- by binding of the wild poliovirus from stool must be interpreted with mune factors, intravenous immune within the intestines of vaccinated caution because asymptomatic indi- globulin (IVIG) has been used in individuals. As previously men- viduals can shed virus for up to 4 to neonates and immmunodeficient tioned, secondary immunization 8 weeks. children. Most available data on (herd immunity) may represent Serologic diagnosis is made by successful outcomes are from anec- an additional advantage of OPV. demonstrating a fourfold or greater dotal reports. A recent, small, ran- It has been estimated that 10% to increase in neutralizing antibody domized study in infected newborns 20% of unvaccinated children in titers between paired acute and con- revealed that administration of IVIG inner cities are effectively vaccinated valescent serum samples. Quantita- containing high neutralizing titers to by contact with virus shed by vac- tive interpretation of a single serum the patient’s specific viral isolate cine recipients.

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INFECTIOUS DISEASE Enterovirus Infections

OPV in developing countries is The initial IPV was replaced in currently recommends any one of less immunogenic, as measured by the 1980s by an enhanced potency three polio vaccination schedules: seroconversion rates. Several factors inactivated poliovirus vaccine an all-OPV regimen, a mixed are probably responsible for this (eIPV), which exhibits even higher eIPV/OPV regimen, or an all-eIPV phenomenon, including inadequate seroconversion rates with fewer regimen (Table 4). The Centers for refrigeration of the vaccine, poor doses. It has been used success- Disease Control and Prevention and nutrition among recipients, and fully in several European countries the Advisory Committee for Immu- coinfection of the gastrointestinal (Finland, Netherlands, Norway, nization Practices recommend the tract with other enteroviruses, all and Sweden) as the sole mode of mixed schedule of eIPV followed by of which may cause diminished polio immunization. No serious OPV, which maintains the benefits immunogenicity. adverse reactions have been of intestinal and herd immunity The primary risk associated with reported, although it contains associated with OPV while reducing OPV administration is development trace amounts of streptomycin the risk of VAPP by initially immu- of vaccine-associated paralytic and neomycin and, therefore, hyper- nizing with eIPV. poliomyelitis (VAPP). The last case sensitivity reactions are a possi- Recent studies comparing all- of wild-type poliomyelitis in the bility in patients who are sensitive OPV, all-eIPV, and eIPV/OPV com- United States was seen in 1979. to these antibiotics. binations reveal excellent systemic Since then, there have been 8 to Prior to 1996, the OPV regimen immunity and nasopharyngeal neu- 10 cases per year of paralytic was employed in routine childhood tralizing antibodies with all regi- poliomyelitis, all attributed to the immunization. However, with the mens, but higher nasopharyngeal live virus vaccine. This corresponds eradication of wild-type polio from IgA titers with the all-OPV regimen. to approximately 4 cases per the United States and many other The authors concluded that OPV 10 million doses of vaccine adminis- developed countries and the ongoing and eIPV are highly effective in tered. The greatest risk for VAPP concern about the small number of stimulating protective levels of (>75% of cases) is seen after the VAPP each year, other options for immunity against poliovirus. initial dose of OPV, with about dosing were established. The Ameri- Each regimen has advantages and 1 in 700,000 American children or can Academy of Pediatrics (AAP) disadvantages regarding ease of contacts developing paralytic dis- ease. Vaccine virus can undergo reverse mutation in the intestinal TABLE 4. Polio Vaccination Schedule Options tract of vaccinees, and these rever- tant strains have a selective advan- DOSE OPV ONLY eIPV/OPV eIPV ONLY tage for replication in the intestine 1 2 months 2 months (eIPV) 2 months and may possess increased viru- lence. Poliovirus serotype 3 2 4 months 4 months (eIPV) 4 months accounts for 92% of VAPP because 3 6 to 18 months 6 to 18 months (OPV) 6 to 18 months it is genetically more unstable, fol- lowed by serotype 2 and then 1. 4 4 to 6 years 4 to 6 years (OPV) 4 to 6 years Because OPV is a live virus vaccine and live virus is excreted by vaccinees, it never should be TABLE 5. Comparison of Polio Vaccination Regimens administered to immunocompro- REGIMEN ADVANTAGES DISADVANTAGES mised recipients or to those living in households that contain immuno- All-OPV ¥ Induces intestinal immunity ¥ Can cause VAPP compromised people. This includes ¥ Administration is easy ¥ Requires refrigeration those who have human immunodefi- ¥ Provides herd immunity ciency virus infection, lymphoma, elPV/OPV ¥ Should reduce VAPP in ¥ May not eliminate leukemia, solid tumors, abnormal healthy individuals VAPP in contacts immunoglobulin synthesis, or ¥ Delays OPV use in children ¥ Increased number of immunosuppresion due to medica- who have undiagnosed injections needed tions prescribed for other diseases. immunodeficiencies IPV should be administered in these ¥ Maintains mucosal immunity situations because there is no live ¥ Maintains herd immunity virus and, therefore, no risk of VAPP. It is theoretically prudent All-elPV ¥ Eliminates risk of VAPP ¥ Minimal mucosal not to vaccinate pregnant women, immunity but if immediate protection against ¥ No herd immunity polio is required, OPV, not IPV, is ¥ Increased number of recommended. Breastfeeding, con- injections needed current antimicrobial use, or diar- Note: All three vaccination regimens are considered highly effective in preventing paralytic rhea are not contraindications to poliomyelitis. OPV administration.

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INFECTIOUS DISEASE Enterovirus Infections administration, population immunity, of novel antiviral compounds to Faden H. Poliovirus vaccination: a trilogy. and risk of VAPP (Table 5). treat enteroviral infections. J Infect Dis. 1993;168:25Ð28 Modlin JF. Update on enterovirus infections in infants and children. Adv Pediatr Infect Conclusion SUGGESTED READING Dis. 1997;12:155Ð179 Abzug MJ, Keyserling HL, Lee ML, Levin Plotkin SA. Inactivated polio vaccine for Because multiple nonpolio entero- MJ, Rothbart HA. Neonatal enterovirus the United States: a missed vaccination viral serotypes are responsible for infection: virology, serology, and effects of opportunity. Pediatr Infect Dis J. 1995; intravenous immune globulin. Clin Infect 14:835Ð839 clinical illness, prevention by vacci- 1997 Red Book: Report of the Committee on nation probably will not be possible Dis. 1995;20:1201Ð1206 Abzug MJ, Levin MJ, Rothbart HA. Profile Infectious Diseases. 24th ed. Elk Grove Village, Ill: American Academy of Pedi- in the near future. High-risk popu- of enterovirus disease in the first two atrics; 1997 lations, such as those who have weeks of life. Pediatr Infect Dis J. 1993; Rothbart HA. Enteroviral infections of the immunodeficiencies and neonates, 12:820Ð824 central nervous system. Clin Infect Dis. would benefit greatly from effective Cherry JD. Enteroviruses: polioviruses 1995;20:971Ð981 treatments because infection among (poliomyelitis), coxsackieviruses, echo- Wilfert CM, Nusinoff Lehrman S, Katz SL. these children carries significant viruses and enteroviruses. Textbook of Enteroviruses and meningitis. Pediatr Pediatric Infectious Diseases. 3rd ed. Infect Dis. 1983;2:333Ð341 morbidity and mortality. Current Philadelphia, Penn: WB Saunders Co; efforts are focused on development 1992:1705Ð1753

PIR QUIZ 1. A febrile illness associated with severe 4. A previously healthy 4-year-old headache and an acral rash assumes boy presents with a 2-day history epidemic proportions in your New of sore throat and fever. The find- England town during August. The ings on physical examination feature most atypical for an entero- that predict an enteroviral explana- viral origin would be: tion with highest confidence are: A. Aseptic meningitis. A. Bilateral tonsillar enlargement, B. Biphasic course. diffuse erythematous rash. C. Herpangina. B. Bilateral tonsillar exudate, soft D. Mid-summer occurrence. palate petechiae. E. Sparing of infants. C. Friable gingiva, multiple ulcers of gums and tongue. 2. The most important benefit derived D. Hoarse voice, mild stridor. from replacing oral polio vaccine E. Ulceration on anterior tonsillar with enhanced potency inactivated pillars and adjoining soft poliovirus vaccine is: palate. A. Elimination of vaccine-associated paralytic poliomyelitis. 5. Three days after recovering B. Greater ease of administration. uneventfully from a transient fever C. Greater overall effectiveness. and mild irritability, a 2-year-old D. Higher levels of intestinal boy begins to complain of a severe secretory IgA. headache, and fever recurs. He E. Strengthened herd immunity. previously has been well and is appropriately immunized. On 3. A previously healthy 6-day-old examination, abnormal findings girl suddenly becomes febrile and include a rectal temperature of lethargic. Vaginal delivery of this 39ûC (102.2ûF), irritability, nuchal term infant was uneventful, and rigidity, and a diffuse maculo- the nursery stay was unremarkable. papular rash. Cerebrospinal fluid The mother had been in excellent findings most consistent with an health throughout the pregnancy enteroviral meningitis are: until early July when, 3 days before A. 20 cells/mm3, 70% granulo- delivery, she developed a moderate cytes, glucose 0, protein 100. headache, photophobia, and low- B. 200 cells/mm3, 100% lympho- grade fever that resisted diagnosis. cytes, glucose 20, protein 250. All symptoms resolved 12 hours C. 200 cells/mm3, 70% granulo- after delivery. While appropriately cytes, glucose 65, protein 45. entertaining and exploring the possi- D. 3,500 cells/mm3, 70% granulo- bility of bacterial sepsis in the infant, cytes, glucose 20, protein 150. you suspect enteroviral infection, E. 3,500 cells/mm3, 70% lympho- given the clinical setting, The cytes, glucose 40, protein 100. most sensitive diagnostic test for enterovirus in this circumstance is: A. Blood culture. B. Cerebrospinal fluid (CSF) cell count. C. CSF cell culture. D. CSF polymerase chain reaction. E. Virus-specific serum IgM.

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Downloaded from http://pedsinreview.aappublications.org/ at UNIV OF CHICAGO on March 28, 2013 Enterovirus Infections Theoklis Zaoutis and Joel D. Klein Pediatrics in Review 1998;19;183 DOI: 10.1542/pir.19-6-183

Updated Information & including high resolution figures, can be found at: Services http://pedsinreview.aappublications.org/content/19/6/183 References This article cites 7 articles, 3 of which you can access for free at: http://pedsinreview.aappublications.org/content/19/6/183#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Diseases http://pedsinreview.aappublications.org/cgi/collection/infectious_diseases Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: /site/misc/reprints.xhtml

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