Introduction
Human parechoviruses (HPeV) are RNA viruses belonging to the family of
Picornaviridae. Formerly described as echovirus 22 and 23 in the
Enterovirus genus, HPeV were reclassified into their own genus,
Parechovirus, in the 1990s based on genetic differences and biological properties. Then, they were renamed as HPeV-1 and HPeV-2, respectively [
13,
25]. Recently, additional types of HPeV have been reported, and a total of 16 different types have been recognized to date (HPeV-1 to 16). The most common genotype detected worldwide is HPeV-1 followed by HPeV-3. Other types such as HPeV-2 and HPeV-4 are less common.
Infections with HPeV are prevalent in young children and have been associated with mild diseases of the respiratory and gastrointestinal tract but also with serious diseases such as meningitis, encephalitis and sepsis in young infants [
3,
12,
13]. According to recent studies, HPeV-3 might be one of the main agents causing severe neonatal neurological infections in Europe [
5,
14,
17], although its real incidence is unknown since HPeV detection is not routinely performed in the majority of clinical microbiology laboratories. Clinical data specific for neonates are also scarce.
This study describes the results obtained about the prevalence of HPeV infections in children up to 1 month of age in Spain and the clinical and epidemiological characteristics of the infected patients over a 1-year period. Furthermore, HPeV and enterovirus (EV) infections were compared.
Discussion
We present a prospective, multicentre study performed during 1 year in Spanish infants up to 1 month of age with suspected sepsis or meningo-encephalitis or fever without source. EV was detected in 38 % of the patients and HPeV in 11 %. With respect to EV infections, other authors found EV incidences in neonates between 9.5 and 24 % [
2,
16,
18,
26]. The high detection frequency observed in our series might be due to the study being performed in clinically ill infants with a high suspicion of viral infection and not as active surveillance. Besides, not all EV-negative samples collected by the hospitals could be included in the final study, due to absence of available samples or signed consent forms.
On the other hand, few HPeV epidemiological studies focused on newborns (infants <30 days) have been published. Most of them were performed in children (<18 years), and the presence of the virus in CSF varies from 2.3 to 7 %, whereas in the general population the percentage decreases to 0.5–0.8 % [
9‐
11,
23]. As far as we know, there is only one study from Italy in which 7 (11.6 %) cases of EV and 3 (5 %) cases of HPeV infections were detected out of 60 neonates with suspected sepsis or neurological infection [
18]. Our higher HPeV prevalence in the same type of patients (11 %) might be due to the fact that the Italian study [
18] was conducted at the NICU, reducing the study population and leaving out the analysis of children who do not require admission to the NICU (56 % in our series).
In most of the previous studies, HPeV-3 infections have been described as clearly associated with central nervous system infections and sepsis-like illness in neonates and young infants [
4,
15,
22]. Our data supported these findings, as HPeV-3 was also the predominant genotype identified, representing 89 % of the total HPeV detected. Only one strain was identified as HPeV-5, which is an infrequent type reported in the literature [
9‐
11,
18,
23]. In this study, this type was detected in a case with FWS, so we cannot conclude that HPeV type 5 has a proved association with neurological or systemic diseases in newborns.
Regarding seasonal distribution, in Europe, HPeV infections are more common in spring and summer, similar to the EV infections [
9‐
11,
23]. In our series, there is also a predominance of HPeV detection in spring and summer, although we have only 1 year of enrollment period. Besides, HPeV has been described to present in biannual cycles in Europe [
9,
11,
15]. Previous data in Spain (not published) are consistent with those findings as the detection frequency was significantly higher in 2011 and 2013 than in 2012, but further longer surveillance studies are necessary to confirm the seasonality and periodicity of the HPeV-3 infections. This circulation pattern might also explain the high HPeV incidence found in this study, in comparison with the previously mentioned Italian one [
18].
Recently, Sharp et al [
23], in Kansas, found that up to 17 % of the CSF-positive samples of children (<18 years) tested between June and October 2009 were positive for HPeV, with HPeV-3 being the predominant type. Clinically, they described HPeV infections with irritability and longer fever, lower peripheral leucocytes, absence of pleocytosis, lower CSF protein and higher CSF glucose compared to EV infections. In our series, some of these clinical characteristics were also observed as HPeV-infected patients had lower blood leucocytes, CSF protein and CSF cells values than those with EV infection. Furthermore, several studies including the American one mentioned above reported that admission to intensive care units were more frequent in HPeV-positive cases than in those infected by EV, but the prognosis was generally good [
9,
22,
23]. We observed the same in our series. The higher proportion of HPeV-infected children who required admission to NICU was probably determined by the low age in an infant with an unwell appearance rather than by the clinical severity, as there was only one patient with encephalitis who had sequelae. In the literature, however, some fatal cases were described [
19,
20], encephalitis being the major complication that caused sequelae and deaths.
Another recent study reported that between 50 and 100 % of HPeV-positive cases had been associated with erythematous rash on the extremities, especially palms and soles, not always present in the first hours but during evolution [
24]. This dermatologic manifestation would be very suspicious data of HPeV infection in neonates and very young infants with febrile syndrome. However, these data are not consistent in the literature; the rash might have gone unnoticed or showed a different prevalence depending on the area. In the present study, only 12.5 % of patients showed rash.
In summary, HPeV-3 infections should be suspected in infants younger than 1 month, with fever but without leucocytosis and pleocytosis in CSF. In these cases, HPeV screening in CSF or blood should be incorporated in the routine viral diagnosis to prevent unnecessary antibiotic treatment and prolonged hospitalization. The low number of samples included in this study was a limitation that affects the incidence data of the EV and HPeV infections, but not the results obtained in relation to the clinical and epidemiological differences found between both infections. Further studies could provide more information about the burden of HPeV infections in newborns.
Acknowledgments
This study was partially supported by a grant from the Spanish National Health Institute PI12-00904.
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