Seminars in Fetal & Neonatal Medicine 14 (2009) 222–227 Contents lists available at ScienceDirect Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny Enterovirus infections in neonates Marc Tebruegge a, b, c, Nigel Curtis a, b, c, * a Department of Paediatrics, The University of Melbourne, Royal Children’s Hospital Melbourne, Flemington Road, Parkville, VIC 3052, Australia Infectious Diseases Unit, Department of General Medicine, Royal Children’s Hospital Melbourne, Parkville, Victoria, Australia c Murdoch Children’s Research Institute, Royal Children’s Hospital Melbourne, Parkville, Victoria, Australia b s u m m a r y Keywords: Antiviral therapy Coxsackievirus Echovirus Enterovirus Neonate Treatment Enteroviruses, which include echoviruses, coxsackie A and B viruses, polioviruses and the ‘numbered’ enteroviruses, are among the most common viruses causing disease in humans. A large proportion of enteroviral infections occur in neonates and infants. There is a wide spectrum of clinical manifestations that can be caused by enterovirus infection with varying degrees of severity. In the neonatal age group, enteroviral infections are associated with significant morbidity and mortality, particularly when infection occurs antenatally. This review provides a detailed overview of the epidemiology and clinical features of enterovirus infections in the neonatal period. In addition, laboratory features and diagnostic investigations are discussed. A review of the currently available data for prophylactic and therapeutic interventions, including antiviral therapy, is also presented. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction The human enteroviruses belong to the family of picornaviridae and have historically been classified into echoviruses, coxsackie A and B viruses, and polioviruses. This traditional taxonomy is based on replication properties in culture, as well as the range of clinical symptoms caused by infection with these viruses in humans. Since the 1960s, rather than being assigned to one of the four major groups, newly identified enteroviruses have been given a numeric designation (‘numbered enteroviruses’, e.g. enterovirus 68 to 71). Further numbered enterovirus serotypes have been identified only in the last five years.1,2 Relatively recent molecular data suggest that the traditional groups are genetically quite diverse, which has led to the adoption of a new taxonomy.3,4 In this current taxonomy, enteroviruses are divided into five species: human enterovirus A, B, C and D, and polioviruses, with the traditional names retained for individual serotypes (Table 1). This review focuses primarily on non-polio enterovirus infections. Poliovirus infections and poliomyelitis have become exceedingly rare in most developed countries as a result of routine immunisation programmes, and are discussed in detail elsewhere.8,9 Also, parechoviruses, some of which were previously classified as echoviruses (echovirus 22 and 23), are not discussed in this review. Recent molecular sequencing data suggest that these * Corresponding author. Tel.: þ61 3 9345 5161; fax: þ61 3 9345 6667. E-mail address: nigel.curtis@rch.org.au (N. Curtis). 1744-165X/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2009.02.002 are a separate group of viruses.10 However, the clinical manifestations associated with parechovirus infection show a considerable overlap with those produced by enteroviruses and disease can be virtually indistinguishable.11 Non-polio enteroviruses can produce a wide spectrum of acute illnesses with clinical manifestations ranging from non-specific febrile illness, mild upper respiratory tract infection or self-limiting gastroenteritis, to more severe entities such as myocarditis, hepatitis and encephalitis. Some diseases or manifestations are typically associated with a particular enterovirus group or even a particular serotype, such as herpangina (coxsackie A viruses),12 hand-foot-and-mouth disease [coxsackie A viruses (frequently A16), enterovirus 71],13,14 pericarditis/myocarditis (coxsackie B viruses),15,16 pleurodynia (Bornholm’s disease; coxsackie B viruses)17 and haemorrhagic conjunctivitis (coxsackievirus A24, enterovirus 70).18,19 2. Epidemiology of enterovirus infections Enteroviruses are among the most common viruses causing disease in humans. It has been estimated that in the USA alone 10– 15 million symptomatic enterovirus infections occur each year.20 Enterovirus infections have a distinct seasonal pattern in temperate climates, with the majority of infections occurring during summer and fall,21–24 although this seasonality appears to be less pronounced in the neonatal population.20 In Europe the most commonly isolated enterovirus serotypes are echoviruses E6, E7, E9, E11, E13, E19, E30, coxsackie A viruses A9, A16 and coxsackie B viruses B2 to B5.21,25,26 A recent publication from the Centers for Disease Control and Prevention (CDC), M. Tebruegge, N. Curtis / Seminars in Fetal & Neonatal Medicine 14 (2009) 222–227 Table 1 Classification of enteroviruses. Traditional taxonomy Current taxonomy Echoviruses E1–7, 9, 11–21, 24–27, 29–33 Human enterovirus A (HEV-A) CAV2-8, 10, 12, 14, 16, EV71 Coxsackie A viruses CAV1–22, 24 Human enterovirus B (HEV-B) CAV9, CBV1–6, E1–7, 9, 11–21, 24–27, 29–33, EV69 Coxsackie B viruses CBV1–6 Human enterovirus C (HEV-C) CAV1, 11, 13, 17, 19–22, 24, PV1–3 Polioviruses PV1–3 Human enterovirus D (HEV-D) EV68, 70 Numbered enteroviruses EV68–71 Table adapted from Khetsuriani et al.27 Gaps in the numbering are partly due to the finding that some viruses were in fact identical (e.g. coxsackievirus A15 and A11); others have been reclassified as part of another genus or virus family (e.g. echovirus 28 is now human rhinovirus 1A). Notably, echoviruses 22 and 23 are now considered to be part of a different genus, and have been renamed as parechovirus 1 and 2, respectively. Not included in the table are the four new enterovirus serotypes described in 2005 (EV76, EV89, EV90, EV91; likely subgroup of HEV-A)1 and 13 new serotypes reported in 2007(EV79-88, EV97, EV100, EV101; likely members of HEV-B).2 Other reports have described additional serotypes.5–7 summarising the epidemiological data in the USA accumulated over a 35-year period, reported that the five most common enterovirus serotypes were echoviruses E6, E9, E11, E30 and coxsackievirus B5, which accounted for almost half of all enteroviruses detected.27 In contrast to Europe, echovirus E13 and E19 played only a relatively minor role in the USA (1.2% and 0.2% of the reported cases respectively). The same report also showed that the predominant serotypes and ranking of individual enteroviruses change considerably over time. Another recent publication from the CDC reported that coxsackievirus B1 had become the most commonly identified enterovirus serotype in the USA in 2007, accounting for 25% of all enterovirus infections with known serotypes.28 Worryingly, an unusually large proportion of babies infected with this serotype developed severe disease – including myocarditis, severe hepatitis and coagulopathy – resulting in the death of five of these neonates. National surveillance data collected over a five-year period in France has shown that the vast majority of enterovirus infections occur in young children, with infants below the age of one year accounting for about a third of all cases.25 Similar observations have been reported by other national enterovirus surveillance programmes, including those in the USA,27 the UK26 and Taiwan.15 Enterovirus infections in the neonatal period are not rare. One study in the USA, conducted during a typical enterovirus season, found that the incidence of non-polio enterovirus infection in neonates, who were followed until one month of life, was as high as 12%.29 Interestingly, the majority (79%) of babies infected with enteroviruses in this report were asymptomatic, while only 4% required admission to the hospital. More recent data from the CDC National Enterovirus Surveillance System indicate that enteroviral infections in the neonatal period account for about 10% of the total number of reported cases of enterovirus infection in the USA.20 Notably, this report also revealed that the relative frequency and predominant serotypes of enteroviruses affecting neonates differed from the pattern observed in the general population (described above). During the 20-year period described in this report, echoviruses E6, E9, E11 and coxsackieviruses B2, B4 and B5 were the most commonly identified serotypes in neonates. 223 Enterovirus infections are not an uncommon cause of sepsis-like illness in the neonatal period. A prospective, population-based survey of neonates (up to day 29 of life) presenting with suspected systemic infection found that at least 3% of these episodes had been caused by enteroviruses.24 To put this number into context: only 3% of infants were diagnosed with microbiologically confirmed bacterial sepsis during the same period. 3. Enterovirus transmission in neonates There is evidence suggesting that enterovirus infections can be acquired antenatally, intrapartum and postnatally. In-utero transmission in late gestation has been demonstrated in animal models,30 and a number of observations in humans also support the concept that enteroviruses can be transmitted antenatally – either transplacentally or potentially via ascending infection. One prospective study during a community outbreak of echovirus 11 suggests that vertical transmission is relatively common when the maternal enterovirus infection is acquired during late pregnancy.31 In this report, 57% of the neonates born to mothers with echovirus 11 infection were found to be infected with the same serotype; in all neonatal cases the virus could be isolated from the throat and/or rectum at three days of age, suggesting that the virus had been transmitted antenatally. Further evidence for antenatal transmission comes from the fact that specific neutralising immunoglobulin M (IgM) antibodies have been detected on the first day of life in a number of neonates.32 Other publications have reported the isolation of enterovirus from amniotic fluid and umbilical cord blood.22,33,34 In addition, a number of postmortem studies have identified the presence of enteroviruses in the organs of aborted fetuses using immunohistochemical and molecular methods.35,36 Furthermore, several publications have reported neonates with symptomatic enterovirus infection on day 1 of life, indicating that the infection must have been acquired antenatally.22,23,33,37–40 Other modes of transmission include intrapartum exposure to maternal blood, genital secretions and stool, as well as postnatal exposure to oropharyngeal secretions from the mother and other individuals who have close contact with the baby.22,37,41 Given the relatively high rates of ‘viral illness’ observed in siblings and fathers of neonates with confirmed enterovirus infection it appears likely that transmission from family members is relatively common.38–40 Both epidemic outbreaks and sporadic transmission of enteroviruses in neonatal units and hospital nurseries have been described, with echovirus 11 and coxsackie B viruses as the most commonly implicated serotypes in the majority of reports.22,37,42–45 In some of these instances the enterovirus had been introduced by personnel working in the unit, while other outbreaks were traced back to neonates in the unit who had been vertically infected. The attack rate for infants at risk has been estimated to range from 22% to 53% in this setting.37 Notably, nosocomially acquired enterovirus infections are generally associated with less severe disease and lower mortality rates than vertically acquired infections.16,37 4. Clinical features of neonatal enterovirus infection Enterovirus infections in the neonate are associated with a wide spectrum of signs and symptoms, which range from a non-specific febrile illness to potentially fatal multisystem disease, frequently referred to as ‘neonatal enterovirus sepsis’ or ‘enteroviral sepsis syndrome’. The most common presenting features associated with neonatal enterovirus infection are fever, irritability, poor feeding and lethargy.22,38–40 A non-specific rash, which is frequently macular or 224 M. Tebruegge, N. Curtis / Seminars in Fetal & Neonatal Medicine 14 (2009) 222–227 maculo-papular in nature, is observed in around half of infants during the course of the illness.38,39 A similar proportion of patients develop respiratory symptoms, including nasal discharge, cough, apnoeas, tachypnoea, recessions, grunting and nasal flaring. Gastrointestinal symptoms, comprising vomiting, abdominal distension and diarrhoea, are less common, but still occur in about 20% of cases.39 Other potential manifestations include pancreatitis, adrenal haemorrhage and necrotising enterocolitis.22 Approximately half of the infants with neonatal enterovirus infection have evidence of hepatitis or jaundice during the course of the illness, while hepatomegaly is detected in around 20%.22,38 The hepatic inflammation may progress to acute hepatic necrosis, associated with marked elevation of transaminases and jaundice, liver failure and coagulopathy.23,39 Splenomegaly is a relatively uncommon feature.39 Some neonatal cases develop signs of myocarditis, such as cardiac arrhythmias, cardiomegaly, poor ventricular function, systemic hypotension, congestive heart failure, pulmonary oedema and myocardial ischaemia.16,22,23,39,40 Central nervous system disease may manifest as meningitis or encephalitis, or a combination of the two.22,23,39,46 Neonates with enteroviral meningitis may present with irritability, poor feeding, or less commonly a prominent anterior fontanelle.22,39 Encephalitis can manifest with seizures, depressed level of consciousness or focal neurological symptoms. 5. Diagnosis of enterovirus infection The detection of enteroviruses is traditionally based on viral isolation in cell culture, followed by immunofluorescence staining or typing with the use of antisera, which allows identification of the infecting serotype. Previous reports suggest that the highest isolation yields are achieved with samples from the upper respiratory tract (throat swabs/nasopharyngeal aspirates), gastrointestinal samples (rectal swabs/stool samples) and cerebrospinal fluid. Isolation from blood and urine is less common.15,23,38 Serology, which relies on the detection of IgM antibodies or the detection of a significant rise in IgG antibody titre, is generally less useful in the diagnosis of enterovirus infections. All currently available serological techniques have significant limitations. Notably, there is no single antigen that is present in all enterovirus serotypes, and consequently no truly ‘universal’ antibody or antigen assay exists. Various serological methods, including enzyme immunoassays (EIA) and complement fixation tests, have been developed.47,48 Although the specificity of these tests is often good, their sensitivity is generally rather poor (below 80%). Reverse transcriptase polymerase chain reaction (RT-PCR) may increase the detection rate in enterovirus infections and is particularly useful in the analysis of cerebrospinal fluid (CSF) samples in patients with evidence of meningitis.40,49 In this setting, RT-PCR has been shown to have greater sensitivity than culture methods. In addition, RT-PCR on blood can be a useful tool for the diagnosis of enterovirus infection in infants presenting with sepsis-like illness.50,51 More recently, enteroviral real-time RT-PCR assays, which allow shorter turnover times, have been developed and demonstrated to have high sensitivity and specificity.50,52 Cerebrospinal fluid abnormalities are common in neonates with enterovirus infection. One study reported that abnormal CSF results were observed in 70% of neonatal cases, with CSF pleocytosis occurring in 53%.38 CSF pleocytosis in these patients most commonly shows a predominantly lymphocytic pattern.22 However, CSF pleocytosis with polymorphonuclear predominance (i.e. more than 50% polymorphs; usually suggestive of bacterial meningitis) has been reported to occur in up to one-third of patients.22,38,39 The majority of patients with enterovirus meningitis have only mild to moderately elevated CSF white blood cell counts, but cases with counts above 1000/mm3 have been described.16,22,38–40,46 CSF protein levels are frequently elevated.22 CSF glucose concentrations are generally within normal range,39,46 as would be expected in a viral infection, although several neonates with CSF glucose levels below 30 mg/ dL and abnormally low CSF glucose:blood glucose ratios have been reported.22 6. Prognosis of enterovirus infection in the neonatal period The majority of infants who present with enterovirus infection in the neonatal period have a benign course and make a full recovery. Pyrexia generally resolves within three to five days, whereas resolution of symptoms occurs on average within four to seven days after onset.22,38,39 Previous studies have reported overall mortality rates ranging between 0 and 42%.16,22,38,39,41 Risk factors for severe infection include prematurity,31,39,53 presence of maternal ‘viral symptoms’ at delivery,38 onset of symptoms in the first week of life23,38,40,53 and absence of specific antibodies (acquired by placental transfer) to the infecting serotype in the neonate.31,44,53,54 There is some evidence that certain enterovirus serotypes are associated with more severe disease in the neonatal period. In one population-based study, the highest mortality rate by far (40%) was observed in neonates infected with coxsackievirus B4.20 Another serotype associated with a high mortality rate was echovirus E11. By contrast, despite the fact that a considerable number (n ¼ 28) of neonatal infections with coxsackie B5 virus were documented during the study period, none had a fatal outcome. In addition to the specific serotype involved, the clinical manifestation of neonatal enterovirus infection is also an important determinant of prognosis, with the highest mortality rates being reported in neonates with sepsis-like illness, myocarditis and hepatitis.23,38,39,55 In one large study, all neonates who presented with a non-specific illness or aseptic meningitis (n ¼ 103) survived without long-term sequelae.23 By contrast, 24% of the neonates who developed hepatic necrosis and coagulopathy (n ¼ 42) had a fatal outcome. In this cohort the highest mortality (71%) was recorded in patients with hepatic necrosis and concurrent myocarditis. A different, retrospective study reported that the mortality rate of neonates with hepatitis and coexisting coagulopathy was 31%.55 Long-term sequelae following neonatal enterovirus infection are relatively rare. However, residual hepatic dysfunction in some infants who had originally presented with acute hepatic failure and coagulopathy has been described.38 Most patients with enteroviral myocarditis who survive have no persisting cardiac problems; a minority have residual ventricular dysfunction, ventricular aneurysms or rhythm abnormalities or develop dilated cardiomyopathy.56–58 Several reports have also described persisting neurological deficits in patients who had enteroviral meningitis or encephalitis, including spasticity, seizure disorders, learning difficulties and language disorders.59–61 One report also described the presence of white matter changes in several neonates with enterovirus meningoencephalitis, which resembled periventricular leukomalacia on imaging.62 7. Prophylaxis and treatment of enterovirus infection in neonates As enteroviral infection is a self-limiting infection in immunocompetent individuals and most neonates have a benign course, the treatment of neonatal enterovirus infections predominately consists of supportive therapy. M. Tebruegge, N. Curtis / Seminars in Fetal & Neonatal Medicine 14 (2009) 222–227 7.1. The role of immunoglobulin in enterovirus infections There is some anecdotal evidence suggesting that prophylactic immunoglobulin containing sufficiently high levels of specific neutralising antibodies may prevent enterovirus infection in infants at risk during outbreaks on neonatal units. In one report all patients in a neonatal unit were given immunoglobulin following the diagnosis of meningitis caused by echovirus 11 in an index case, and infection control measures were instigated simultaneously.54 None of the babies that had received prophylactic immunoglobulin soon after delivery developed signs suggestive of echovirus infection. Subsequent studies in similar settings reported less favourable results, although it appears that prophylactic immunoglobulin at least mitigates disease severity in some exposed neonates.63–65 Immunoglobulin has also been used for the treatment of symptomatic infants with enterovirus infection in several reports.16,23,66 While some groups believe that the use of immunoglobulin was potentially beneficial,16 others did not observe any impact on clinical outcome.23 In the only randomised controlled trial of immunoglobulin in the context of neonatal enterovirus infection, intravenously administered immunoglobulin was associated with subtle clinical benefits and faster resolution of viraemia.67 However, the study group was small (n ¼ 16), and therefore firm conclusions cannot be made. 7.2. Antiviral treatment options in enterovirus infection Over the last three decades a large variety of compounds with activity against picornaviruses, including enteroviruses, have been developed. These compounds either: (a) target the attachment, entry and uncoating of enteroviruses (e.g. pleconaril, BPROZ-194,68 MDL-86069), (b) inhibit the replication of the virus (e.g. enviroxime, enviradone,70 TBZE-02971), (c) interfere with viral proteases (e.g. rupintrivir,72 MPCMK73) or (d) prevent viral assembly and release (e.g. 5-(3,4-dichlorophenyl)methylhydantoin74). Many of these antiviral agents have been assessed in vitro and in animal models, and some have been evaluated in human trials (mainly phase I and II). A detailed review of these agents is beyond the scope of this chapter, but can be found elsewhere.75 At present, pleconaril is the most advanced antiviral treatment option for enterovirus infections. A report by Rotbart et al., describing the early experience with pleconaril in human enterovirus infection, showed some encouraging results.76 The majority of cases in this report were patients with congenital immunodeficiencies who suffered from chronic enterovirus infection. In this subgroup, treatment with pleconaril was associated with clinical improvement in 75% and virological response in 86% of cases. Notably, this report also included six neonates with enteroviral sepsis syndrome, five of whom survived. Viral clearance was achieved in all four neonates in whom the virological response was assessed. The largest study of pleconaril in the context of enteroviral disease reported to date is a randomised controlled trial conducted in adults with meningitis (n ¼ 240).77 Disappointingly, the clinical benefit of pleconaril treatment was only modest and primarily apparent in patients who presented with the most severe disease. To date there are only very limited data regarding pleconaril as treatment for enterovirus infections in neonates or infants.40,78–82 In this age group, reports consist almost exclusively of single case reports and small case series. Some of the respective authors believed that treatment with pleconaril had a positive impact on outcome; however, without untreated control patients for comparison, none of these anecdotal observations allow firm conclusions. Notably, some reports have described neonates with a fatal outcome despite treatment with pleconaril, although in most instances these patients already had severe disease manifestations 225 before treatment was started.40,79,82 A small randomised controlled trial in infants failed to show a significant difference in viral persistence, symptoms or duration of hospitalisation between the pleconaril-treated and the placebo groups.78 However, the majority of patients in this study had only mild disease and the size of the study population (n ¼ 20) would have limited the ability to detect even moderate treatment effects. A phase II double-blind, placebo-controlled trial of pleconaril for the treatment of neonatal enteroviral sepsis syndrome is currently underway.83 However, the results of this trial are unlikely to be available before the year 2010, highlighting the need for the development and investigation of further effective anti-enteroviral compounds. Practice points Enterovirus infections in neonates are associated with a wide spectrum of clinical manifestations resulting in significant morbidity and mortality. The seasonality of enterovirus infections is less pronounced in the neonatal population and infections may be encountered throughout the year. Neonatal enterovirus infection resulting from antenatal transmission is associated with the most severe disease and poorest outcome. Prognosis depends on the causative serotype and the clinical manifestations. The use of molecular diagnostic methods can improve detection rates. The potential benefit of currently available antivirals in neonatal enterovirus infection remains uncertain. Research directions The epidemiology and clinical manifestations of recently identified enterovirus serotypes. The role of existing antiviral agents in the treatment of neonatal enterovirus infections. The development of new antiviral agents with antienteroviral activity. 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