Enteroviruses are small, single-stranded RNA-containing viruses within the Picornaviridae family. They have traditionally been divided into subgroups, including polioviruses, coxsackie A viruses, coxsackie B viruses, and echoviruses, based on replication properties in tissue culture and animal models, with newer enteroviruses designated by number rather than by subgroup designation.[1,2] More recently, the enteroviruses have been reclassified into five species (polioviruses and enteroviruses A–D), based on nucleotide and amino acid sequences.[3] The more than 60 serotypes within the genus enterovirus are distinguished by antigenic differences.[2]

Enteroviruses are common causes of human infection. Polioviruses cause paralytic poliomyelitis, which continues to be prevalent in some areas of the developing world. The nonpoliovirus enteroviruses, the focus of this article, cause a large number and a broad spectrum of diseases. These include mild conditions such as nonspecific febrile illnesses, herpangina, uncomplicated hand-foot-and-mouth disease, and respiratory tract infections, as well as potentially severe illnesses such as meningitis, encephalitis, paralytic disease, myocarditis, chronic or disseminated infection in immunocompromised hosts (e.g. patients with hypogammaglobulinemia or bone marrow transplant recipients), and neonatal sepsis. The incidence and severity of enterovirus infections are, in general, inversely related to age. In temperate climates, enterovirus infections have a distinct seasonality, with infections occurring predominantly in the summer and fall months.[1,2,4]

The objectives of this article are to describe the clinical and epidemiologic features of neonatal enterovirus infections, to discuss current diagnostic approaches, and to present the available information regarding potential therapies.

1. Clinical Overview

Infection by nonpoliovirus enteroviruses in the newborn period can be asymptomatic, manifest as a benign illness, or produce severe, life-threatening disease.[5,6] The majority of these infections are asymptomatic.[7] Most neonates who develop clinical illness were born at term following uncomplicated pregnancies and deliveries, and have had normal neonatal courses before onset of enterovirus disease.[5,8,9] History frequently (59–68%) includes a maternal viral illness preceding or immediately following delivery, with symptoms such as fever, respiratory findings, and/or abdominal pain. The latter may suggest a diagnosis of chorioamnionitis or abruptio placentae. Viral symptoms are also commonly present in other family members.[1,5,6,8–10] Newborns can present with symptoms throughout the neonatal period; some manifest illness as early as day 1 of life. Symptoms and signs include fever or hypothermia, irritability, lethargy, anorexia, decreased perfusion, jaundice, abdominal distension, emesis and, occasionally, diarrhea.[5,8,9] Although diarrhea may occasionally be bloody or severe,[9,11] in most reports it is not a dominant finding. Respiratory findings may include tachypnea, cough, grunting, retracting, wheezing, rhinorrhea, or apnea.[5,8,9] Rashes, frequently macular or maculopapular, and occasionally papulovesicular, nodular, or bullous, are often present and may suggest a viral diagnosis.[12,13]

Most affected neonates have mild illness without sequelae. Fever generally resolves in an average of 3 days and other symptoms regress in approximately 7 days.[5,8,9] Severe illness develops in a minority of infected newborns, particularly in the first 2 weeks of life.[14] A biphasic pattern, in which mild disease is followed by a short period of recovery followed by more severe illness, may occasionally occur. Severe disease consists of any combination of sepsis, meningoencephalitis, myocarditis, pneumonia, hepatitis, and coagulopathy. Encephalitis is suggested by extreme lethargy that may progress to depressed consciousness. Seizures or focal neurologic abnormalities may develop, and a bulging fontanelle or nuchal rigidity may occasionally be evident.[8,15–17] Myocarditis manifests as cardiomegaly, congestive heart failure, arrhythmias, and/or myocardial infarction; pericarditis may also occur.[18–20] Myocarditis may present as a biphasic illness.[21] Pneumonia can be rapidly progressive and severe.[22–24] Hepatitis is characterized by jaundice, hepatomegaly, elevated transaminases, and hyperbilirubinemia, and is frequently associated with thrombocytopenia and coagulopathy. Acute hepatic necrosis and endothelial injury, liver failure, bleeding complications, and renal failure may ensue.[8,10,25,26] Intracranial hemorrhage can be a life-threatening complication.[25,27] Renal and adrenal hemorrhagic necrosis may also develop.[28] Other more unusual complications of neonatal enterovirus infections include necrotizing enterocolitis, myositis, pancytopenia, hemophagocytic syndrome, and hyponatremia with inappropriate antidiuretic hormone secretion.[8,9,11,29,30]

Retrospective reports and literature reviews suggest mortality rates of neonatal enterovirus infections ranging between 0% and 83%.[5,6,8,9] Myocarditis and hepatitis with coagulopathy are associated with the greatest mortality.[6,8,25] Thirty-one percent of neonates with hepatitis or coagulopathy died in one retrospective series; mortality was especially high when hepatitis and myocarditis occurred together.[25] Fortunately, the prognosis for survivors is generally favorable, even after severe disease. Most neonates who survive myocarditis do not have long-term cardiac sequelae, although residual myocardial dysfunction, chronic calcific myocarditis with chronic heart failure and dysrhythmias, and ventricular aneurysm have all been reported.[18,19,31,32] Hepatic dysfunction following hepatitis may persist into infancy and hepatic calcification may become evident; however, the majority of survivors eventually have return of normal liver function and maintain satisfactory growth.[25,33] The prognosis for neonates with central nervous system involvement is more difficult to predict. Some studies described long-term sequelae, for example delayed speech and language development, intellectual deficits, motor abnormalities (spasticity, hypotonicity, and weakness), seizure disorders, ocular defects, and microcephaly, while others did not identify long-term neurologic deficits.[8,16,34–39] Severe encephalitis may be associated with necrosis and subsequent neurologic compromise, including reduced intelligence, motor abnormalities, or hydrocephalus.[17,34,35]

2. Epidemiology

Enterovirus infections occur frequently during pregnancy. A 10-year seroepidemiologic survey revealed that 42% of 1794 pregnant women were infected with enteroviruses.[40] Another study found that 25% of pregnant women had serologic evidence of an enterovirus infection during the 3-month period surrounding delivery during peak enterovirus season. Additionally, 3–4% of pregnant women shed enteroviruses from the throat or rectum, near delivery, during enterovirus season, frequently with minimal or no symptoms.[41]

Nonpoliovirus enterovirus infections of neonates are also common. Thirteen percent of infants <1 month of age were infected by an enterovirus during the summer and fall months (July–October) in one study; 21% of the infected newborns were symptomatic. Enterovirus infections accounted for 65% of hospital admissions of infants <3 months of age with suspected sepsis in the summer and fall in the same community.[7,42] In another report, asymptomatic or symptomatic neonatal enterovirus infections were detected by culture in 5% of infants, and by serology in 7% of infants during enterovirus season.[41] In a study of neonates evaluated for possible sepsis during a 13-month period, 4% were found to have an enterovirus infection.[43] Enteroviruses were the most frequently identified etiology of meningitis, occurring between days 8 and 29 of life at one institution, and accounting for at least one-third of cases.[44] Application of the sensitive polymerase chain reaction (PCR) test has added to our understanding of the frequency of enterovirus infections in young infants. In one community, during a 1-year period enteroviruses were detected by PCR in 26% of hospitalized, febrile infants ≤90 days of age, peaking at 50% during the summer and fall (June–November).[45] Similarly, in a multicenter study, enteroviruses were responsible for 59% and 48% of hospital admissions in infants ≤90 days of age and ≤30 days of age, respectively, in the summer and fall (July–October), as determined by viral culture and PCR.[46] Overall, estimates suggest that neonatal enterovirus disease occurs at an incidence greater than or equal to that of Streptococcus agalactiae, herpes simplex virus, and cytomegalovirus.[6–8]

Most enterovirus-infected neonates are presumed to acquire infection either intrapartum by exposure to maternal blood or genital secretions, or after delivery by exposure to oropharyngeal secretions or stool of mothers or other contacts.[6,9,47] Enteroviruses have been grown from the throat, rectum, and cervical swabs from pregnant women and from mothers of infected, ill neonates.[41,48–51] High rates of viral illness in the peripartum period among siblings and fathers of enterovirus-infected newborns also suggest the possibility of transmission from these family members.[5] A modest number of cases of neonatal enterovirus disease with onset in the first few hours after birth have been reported, suggesting that some neonatal enterovirus infections are acquired in utero. Culture of enteroviruses from amniotic fluid and umbilical cord blood, detection of enterovirus antigens in myocardia hours after delivery, culture of enteroviruses from neonatal organs a few hours after birth, and detection of neutralizing immunoglobulin (Ig)M antibody in serum on day 1 of life all further support this possibility.[23,48,52–55] Identification of enteroviruses in placentas suggests that some in utero infections may occur via a transplacental route;[56–59] shedding of enteroviruses from the stool and cervix of pregnant women, and growth of enteroviruses from amniotic fluid, also indicate the potential for ascending infection.[8,41,49–51,53,57,60] Based on the presence of viremia or symptoms in the first 1–2 days after delivery, it has been estimated that approximately 22% of fatal neonatal coxsackie B virus infections and 11% of neonatal echovirus infections were acquired in utero.[6,8,15,22]

Epidemic spread and sporadic transmission of enteroviruses in hospital nurseries have been reported.[6,8,11,48,55,61–66] Several outbreaks could be traced to vertically infected neonates, with subsequent spread by nursery staff, whereas adults were considered to have introduced enteroviruses into nurseries in other outbreaks.[6] Risk factors for acquiring enterovirus infection in the nursery include prematurity, low birth weight, intensive care, and nasopharyngeal or oropharyngeal instrumentation.[58,59,62] Nosocomially acquired infections tend to be associated with milder disease and lower mortality than vertically acquired infections.[6]

One of the major risk factors for the development of clinically significant enterovirus disease is the absence, or low titer, of maternally derived neutralizing antibody to the infecting enterovirus serotype.[10,63,64,67] Other risk factors and clinical features associated with severe neonatal disease include maternal illness prior to or at delivery, prematurity, onset of illness within the first few days of life, multiorgan involvement, severe hepatitis, positive serum viral culture, and certain infecting serotypes (e.g. group B coxsackieviruses and echovirus 11).[5,6,8–10,67–69]

3. Laboratory Evaluation and Diagnosis

The peripheral white blood cell count may be normal or elevated with enterovirus infection; elevated counts have been observed in 10–20% of infected neonates. The band count may also be increased.[5,9] Cerebrospinal fluid pleocytosis suggestive of viral meningitis may be present (usually <500 white blood cells/mm3) in 35–50% and, occasionally, may mimic bacterial meningitis, with up to several thousand white blood cells/mm3. A neutrophil predominance is frequently present, and increased protein or decreased glucose levels may sometimes occur.[5,9] Conversely, cerebrospinal fluid may be positive by culture or PCR despite normal cell counts and chemistries.[5,8,9] CNS imaging is advisable in the presence of profound lethargy, focal neurologic findings, or neurologic deterioration in the setting of significant thrombocytopenia or coagulopathy. If a newborn is systemically ill, or if findings suggestive of hepatic involvement (e.g. hepatomegaly or jaundice) or bleeding are present, transaminases and bilirubin should be assessed. If hepatic disease is severe, ammonia levels may need to be monitored, especially if profound lethargy is present. In an infant with hepatitis or bleeding, or in any newborn that is systemically ill, the platelet count and coagulation profile should be monitored. A chest radiograph is indicated if respiratory or cardiac symptoms are present. Infiltrates suggest pneumonia or heart failure; cardiac enlargement suggests myocarditis or pericarditis. If cardiac disease is suspected, echocardiography can define myocardial function, cardiac size, and presence of a pericardial effusion. An electrocardiogram may be useful to evaluate for dysrhythmias, decreased voltage (reduced amplitude), and/or evidence of myocardial infarction.[8,19,20] Scintigraphic imaging has also been used to detect neonatal myocarditis.[70]

The mainstay of specific diagnosis for enterovirus infections has traditionally been viral isolation in cell culture. A variety of cell lines support enteroviruses, for example monkey kidney cells and human fibroblast, epithelial, and rhabdomyosarcoma cell lines. No single line is optimal for all enteroviruses; therefore, diagnostic laboratories typically use a combination of cell types, such as a monkey kidney line and a fibroblast line.[1] Viral culture specimens with the highest yield in neonatal enterovirus infections are rectum or stool (91–93% positive), cerebrospinal fluid (62–83% positive), and nasopharynx or throat (52–67% positive). Cultures of serum and urine have lower yields (24–47%); however, serum specimens may grow virus more rapidly than other body fluids/sites.[5,9,71] Serum cultures are more likely to be positive with echoviruses, low serum neutralizing antibody titer, and onset of illness within the first 5 days of life.[69,71]

Tissue culture has some significant limitations. It requires expertise and is relatively expensive. Not all enterovirus serotypes grow in culture; coxsackie A viruses, in particular, grow poorly in culture. Sensitivity of culture is further limited by neutralizing antibody in diagnostic specimens, inadequate specimen collection or handling, and insensitivity of some cell lines for some serotypes. Additionally, growth in culture can be slow, ranging from 3 to >8 days. Methods more rapid than culture would be desirable to reduce unneeded diagnostic evaluations and treatments, and initiate potential therapies.[1] Antibody and antigen detection assays have been developed, but their sensitivity is suboptimal because an antigen shared by the majority of enteroviruses is lacking.[1] Enzyme immunoassay, counterimmunoelectrophoresis, and neutralization assays to detect IgG, IgM, and/or IgA antibodies to a variety of enteroviruses have been developed.[72,73] In general, their utility has been restricted by limited sensitivity; moreover, serologic assays are generally not useful for acute diagnosis unless the likely infecting serotype is known from epidemiologic circumstances and an IgM assay for that serotype is available. Antigen detection assays for stool samples and tissues have generally had suboptimal sensitivity.[74,75]

In contrast with antigen detection, application of the PCR to diagnosis of enterovirus infections has been very rewarding. Several sets of PCR primers and probes that detect the majority of enterovirus serotypes have been described. These are directed at highly conserved regions of the 5′ noncoding region of the enterovirus genome and are designed for reverse transcription combined with PCR (RT-PCR).[76] Enterovirus PCR assays detect most enterovirus serotypes implicated in neonatal disease. These tests are more sensitive than culture, and they approach 100% specificity in the absence of laboratory contamination.[76,77] Rapid formats that produce results in as little as 5 hours have been developed. PCR has been shown to be useful for diagnosis of pediatric enterovirus meningitis, nonspecific fever illnesses, and neonatal infections.[1] In these studies, PCR testing of cerebrospinal fluid, serum, and throat specimens from children with acute illnesses had sensitivities of >90% and high specificity; urine testing was somewhat less sensitive.[78,79] Rapid diagnosis afforded by PCR allows the possibility of significant cost savings and fewer interventions for infected infants.[80–82] In neonates, PCR of serum and urine specimens has been demonstrated to be more sensitive than culture of these specimens, with a yield approaching 90%. High sensitivity was maintained for the first several days of illness and provided more rapid diagnosis than culture.[5,9,83] Sensitivity also appears high with PCR assay of cerebrospinal fluid from neonates,[84] and PCR has been used to detect enterovirus in neonatal tissue.[85] PCR and nucleotide sequencing have assisted with the detection of viral spread in neonatal units and with infection control interventions.[86–91]

In general, positive cultures and PCR assays of mucosal sites such as the throat or rectum may reflect asymptomatic infection or presence of disease-causing virus. In contrast, positive culture and PCR tests of body fluids such as serum and cerebrospinal fluid more specifically suggest disease causation.[7,71] Nevertheless, a positive culture or PCR assay of a mucosal site in the first month of life (even without a positive assay of normally sterile body fluids), in the presence of an enterovirus-compatible illness, and in the absence of evidence of infection by another virus (e.g. herpes simplex virus, cytomegalovirus, or adenovirus) or a bacterial pathogen (e.g. group B streptococcus or Escherichia coli) or a noninfectious condition (e.g. metabolic disorder or structural cardiac disease) that can produce similar clinical findings, implicates an enterovirus as the likely etiologic agent. Viral culture or PCR of maternal rectal or cervical specimens may yield the same virus as that causing neonatal illness. Maternal serum may also have a significant titer of neutralizing antibody to the causative viral serotype;[9,15,69] however, diagnosis of a neonatal infection can usually be made directly from neonatal specimens.

The majority of neonatal enterovirus infections are caused by coxsackie B viruses and echoviruses; coxsackie A virus infections occur less frequently.[9] Coxsackieviruses B2–5 and echoviruses 6, 11, and 19 are frequent causes of severe neonatal disease,[6,8–10] although many other enterovirus serotypes have also been implicated. Associations between enterovirus subgroup and disease pattern have been observed, such as coxsackie B viruses with meningoencephalitis and myocarditis, and echoviruses with hepatitis and coagulopathy; however, significant overlap occurs.[6,8,10] For example, coxsackie B virus-associated hepatitis and coagulopathy has been increasingly reported in recent years.[92,93] In the absence of an epidemic, unique disease manifestations, or poliovirus circulation, identification of the enterovirus subgroup and serotype is generally unnecessary and does not affect diagnostic evaluation or therapy.

The differential diagnosis of neonatal enterovirus infections includes infections by other viruses (e.g. herpes simplex virus, cytomegalovirus, adenovirus, and rubella virus), and by bacteria (e.g. S. agalactiae and Gram-negative enterics). Additionally, noninfectious conditions such as metabolic disorders and congenital heart disease can mimic neonatal enterovirus disease.[1]

4. Therapy

Neonates with enterovirus disease generally require hospitalization for diagnostic evaluation and empiric treatment of possible bacterial or herpes simplex virus infection, because the symptoms of enterovirus infection are nonspecific. In addition, supportive care such as respiratory support, cardiovascular pharmacotherapy, and blood product administration may be required for severe disease.[5,9,63,94] Fulminant hepatic failure has been treated with selective gut decontamination,[95] peritoneovenous shunting,[96] and orthotopic liver transplantation.[26,94]

Immunoglobulin has been used as a therapeutic agent for neonates with enterovirus disease, for several reasons. Lack of type-specific serum antibody is a risk factor for symptomatic neonatal enterovirus infection. Ig products contain neutralizing antibodies to commonly circulating serotypes. Ig has been used successfully for patients with hypogammaglobulinemia with severe or chronic enterovirus infections.[67,69,97–99] Intramuscular or intravenous Ig has been administered to numerous neonates with severe enterovirus disease.[100–104] The combination of intravenous Ig and human leukocyte interferon has also been tried.[92] No clear conclusions can be made from these uncontrolled experiences. In the only randomized trial in neonates, administration of intravenous Ig (750 mg/kg) was associated with modest boosts of serum neutralizing antibody titers to viral isolates of patients, subtle clinical benefits, and faster cessation of viremia and viruria in patients who received a high titer (≥1 : 800) of neutralizing antibody to their own viral isolates;[69] however, the study population was too small for definitive conclusions. Infusion of maternal convalescent plasma has also been occasionally described and remains another potential, but unproven, treatment option.[105]

Specific antiviral therapy for enterovirus infections is currently in development. Agents that act at several key steps in the enterovirus life cycle, including attachment, uncoating, protease activity, and replication, are being evaluated. The investigational agent that has advanced furthest for the treatment of enteroviruses is pleconaril. This agent fits within a pocket beneath the floor of a canyon at the junctions of VP1 and VP3 on the viral capsid, and inhibits viral attachment to host cell receptors and uncoating of viral nucleic acid.[106,107] It has broad-spectrum and potent anti-enterovirus and anti-rhinovirus activity; it inhibits replication of more than 96% of the most commonly isolated enterovirus serotypes at achievable concentrations.[108] It is highly bioavailable (approaching 70%) after oral administration (the only route for which there is currently a preparation), achieving serum levels >0.1 μg/mL, the concentration required to inhibit >90% of commonly circulating enterovirus serotypes.[107,109] Preclinical data indicate that it concentrates 2- to 6-fold in the meninges, brain, and spinal cord. Experience to date suggests that pleconaril is well tolerated, with adverse events occurring at a frequency similar to, or slightly greater than, that observed with placebo.[106] Nausea, diarrhea, and headache are the most commonly reported adverse effects. Enterovirus isolates induced in vitro to become pleconaril-resistant were shown to have amino acid substitution in the pocket in which the drug binds within VP1 and, importantly, to be less stable and to have reduced replicative capacity and lethality in mice.[108]

Randomized, controlled clinical trials evaluating pleconaril in adults and children are summarized in table I.[110–115] These studies have generally utilized doses of 200–400mg three times daily in adults, and 2.5–5.0 mg/kg three times daily in children, usually for 5 to 7-day courses. Pediatric studies of pleconaril for enterovirus meningitis have had inconsistent results.[112,113] Results of pediatric studies of the treatment and prevention of upper respiratory tract infections are pending. An additional category for which pleconaril has been evaluated is severe enterovirus disease treated via a compassionate use mechanism. In a summary of this program between 1996 and 1998, 38 patients had received pleconaril for chronic enterovirus meningoencephalitis complicating agammaglobulinemia, neonatal enterovirus sepsis, enterovirus myocarditis, severe infection in bone marrow transplant recipients, acute enterovirus encephalitis, and poliomyelitis caused by wild-type poliovirus or live poliovirus vaccine. Clinical, laboratory, virologic, and radiologic responses were seen in 78%, 88%, 92%, and 60%, respectively, of patients evaluable for each category. Although these are uncontrolled, observational data, the response rates may be greater than what would be expected in untreated patients with similar diagnoses.[116]

Table I
figure Tab1

Summary of randomized, placebo-controlled clinical trials of pleconaril in adults and children

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Experience with pleconaril in infants and neonates is limited. In a small trial of pleconaril (5 mg/kg three times daily) in infants with enterovirus meningitis, 90% of peak and trough pleconaril levels exceeded the concentration required to inhibit 90% of clinical enterovirus isolates in vitro. A median 3.5-fold accumulation was observed during the 1-week treatment period, greater than the approximately 2-fold accumulation observed in adults.[117] In this study, pleconaril was well tolerated, although twice as many adverse events per patient were observed in the pleconaril group compared with the placebo group. Virologic and clinical efficacy were not demonstrable in this small trial. Data from a single-dose, phase I study in neonates suggest that potentially therapeutic concentrations of pleconaril are achievable in plasma with weight-adjusted doses similar to those used in older children; however, pharmacokinetics have not been established in critically ill newborns.[118] Uncontrolled, anecdotal reports of the use of pleconaril in neonates with severe enterovirus disease suggest that the medication is well tolerated in this population and may offer possible benefit.[119,120] A multicenter, placebo-controlled, randomized trial of pleconaril for neonatal enterovirus sepsis characterized by hepatitis, coagulopathy, and/or myocarditis is currently being conducted under the sponsorship of the National Institute of Allergy and Infectious Disease Collaborative Antiviral Study Group of the US National Institutes of Health. This study is examining pharmacokinetics, safety, and efficacy.[117]

Currently, pleconaril remains an experimental agent. Concerns regarding the induction of cytochrome P3A4 causing menstrual disorders in women taking oral contraceptives have held up licensure by the US FDA.[121]

5. Prevention

Vaccines for the nonpoliovirus enteroviruses are not available. The primary defense against transmission of enteroviruses is good hygiene, particularly hand washing to prevent fecal-oral and respiratory spread within families, preschool and school settings, and hospital nurseries. Infection control strategies such as cohorting have been effective in limiting nursery outbreaks. Ig or convalescent plasma has been administered intramuscularly or intravenously prophylactically in some nursery epidemics to prevent infection or ameliorate symptomatic disease. Simultaneous infection control interventions make it difficult to determine the efficacy of these approaches.[62,63,66,97,122–124]

Pregnant women near term should avoid contact with individuals who are ill with probable enterovirus infections. If a pregnant woman develops an illness likely to be caused by an enterovirus, it is advisable not to proceed with emergent delivery unless there is concern for fetal compromise or obstetric emergencies cannot be excluded. Rather, it may be advantageous to extend pregnancy, allowing the fetus time to passively acquire protective antibodies.[67] A strategy of prophylactically administering Ig to neonates born to mothers with enterovirus infections near delivery is a logical but untested approach.[31]

6. Conclusions

Enteroviruses can cause severe disease in newborns, including life-threatening manifestations such as hepatitis, coagulopathy, and myocarditis. Additionally, meningoencephalitis can be associated with long-term neurologic sequelae. The PCR is a significant diagnostic advance that provides accurate and rapid results. The current approach to therapy of neonates with severe enterovirus disease is supportive care, including respiratory and cardiovascular support and blood product administration. Ig has been used anecdotally and in small case series based on theoretical rationale and limited supportive clinical trial evidence; however, proof of efficacy is lacking. Specific antiviral therapy for enterovirus infections is needed, particularly for neonatal infections, and is in development. Pleconaril offers promise for neonatal enterovirus disease, based on demonstration of benefit in some studies in children and adults with enterovirus meningitis or picornavirus (rhinovirus and enterovirus)-associated upper respiratory disease and on positive compassionate use experience. Limited pharmacokinetic data are currently available in infants and neonates. The multicenter, placebo-controlled, randomized trial of pleconaril for neonatal enterovirus hepatitis, coagulopathy, and/or myocarditis currently being conducted will provide more definitive information regarding pharmacokinetics, safety, and efficacy of pleconaril in sick neonates.