Enterovirus infections in neonates

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Summary

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.

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 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

Section snippets

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, *22, *23, 24 although this seasonality appears to be less pronounced in the neonatal population.20

In Europe the most commonly isolated enterovirus serotypes are

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

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, 39, *40 A non-specific rash, which is frequently macular or maculo-papular in

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

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

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.

Conflict of interest statement

None declared.

Funding sources

M.T. is supported by a Fellowship from the European Society of Paediatric Infectious Diseases and an International Research Scholarship from the University of Melbourne.

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