Human parechovirus (HPeV) is a member of the picornovirus family with 19 subtypes identified to date.1 , 2 The HPeV genotype 3 (HPeV3) was first identified in Japan in 1999, in a 1 year old with transient paralysis, fever and diarrhea.3 In the last 10 years, HPeV3 has been implicated in outbreaks of sepsis-like infections and meningoencephalitis in neonates and infants younger than 3 months of age.4–7 Biannual epidemics have been described across the Northern hemisphere—Japan, Canada, Europe, and the United States, with initial outbreaks described in Australia in 2013/2014.7–13
Patients present with a constellation of symptoms including irritability, fevers, erythematous rash, tachycardia and abdominal distension.11 , 14–18 Younger infants tend to be more unwell and are more likely to require intensive care unit (ICU) admission for respiratory or inotropic support.10 , 11 , 14 , 19 , 20 The potential for long-term neurologic sequelae has more recently been recognized including gross motor delays, seizures and cerebral palsy in small numbers of children reviewed within 12 months of the HPeV infection.11 , 19–23
After 2 epidemics of HPeV infections in 2013 and then 2015, a state-wide survey of HPeV cases hospitalized in Queensland, Australia, was undertaken. Queensland is the second largest state in Australia with a population of 4,928,000.24 A centralized state-wide laboratory provided the opportunity for accurate case ascertainment using laboratory results.
All laboratory-proven cases of HPeV in Queensland from November 2013 to June 2016 were identified. Full ethical approval was obtained from Children’s Health Queensland Human Research Ethics Committee (HREC/16/QRCH/223). Retrospective medical record review was performed documenting presenting symptoms, preexisting morbidities, demographics, sick contacts, investigations, management and outpatient follow-up including any developmental and audiologic assessment.
Developmental delay was defined by pediatrician and allied health assessments of reported and examined developmental milestones compared with age-based normal milestones. Follow-up was not standardized for timing or mode of developmental assessment.
Descriptive statistical analysis was presented using medians and range for continuous variables and frequency and percentages for categorical data.
All requests for HPeV testing across Queensland are analyzed by Pathology Queensland Central Laboratory. The parechovirus polymerase chain reaction (PCR) assay used was an in-house real-time reverse transcription PCR assay using the method as previously described.25 All positive cerebrospinal fluid (CSF) and stool samples for HPeV were submitted for genotyping using Sanger sequencing of a typing fragment targeting the viral VP3/1 junction.26 , 27
A total of 202 children with laboratory-confirmed HPeV were identified across Queensland from 2013 to 2016. From October 2013 to April 2014 there were 16, with 190 from September 2015 to May 2016 (Fig. 1). The distribution throughout the state was in keeping with population density, with the vast majority attending hospitals in southeast Queensland, either in the capital city (Brisbane) or surrounding areas. All were hospitalized, in a total of 25 different hospitals. Forty children were transferred for tertiary-level medical care. Age, sex, length of admission and type of HPeV positive sample were available for all 202 children. Nine hospitals did not participate, resulting in detailed clinical information being available for 149, of whom 4 were excluded because of alternate diagnoses (Salmonella meningitis, hemodynamically significant ventricular septal defect (VSD) with congestive heart failure, minor upper respiratory infection and preexisting developmental delay and respiratory syncytial virus–positive bronchiolitis).
HPeV PCR positive samples are summarized in Table 1. CSF HPeV PCR was positive in 142 of the total cohort of 202, and 104 of the 145 (90.4%) where clinical information was available. Forty-one were diagnosed with a combination of characteristic clinical presentation and positive HPeV PCR on stool or respiratory samples. HPeV PCR was detected in 88.9% of the 63 stool samples tested and 86.2% of the 29 respiratory samples. HPeV was commonly detected across multiple sample types concurrently. Out of the 70 infants with follow-up available who had an LP performed during the initial illness, 52 had CSF HPeV PCR positive.
Genotyping was successful in 154 samples from 127 children out of the whole cohort of 202. Inadequate viral concentration in the sample was the main reason for unsuccessful genotyping. All 89 CSF samples successfully genotyped were identified as HPeV3. Forty-five of 47 stool samples and 17 of 18 respiratory samples were HPeV3, with the remainder identified as HPeV genotype 1 (HPeV1). No mixed HPeV3/HPeV1 infections were identified.
Of the 145 where clinical information was available, 127 (87.5%) were under the age of 3 months at time of admission, 54 (37.2%) were neonates (< 28 days of age) (Table 2). Thirty-three children (22.7%) were admitted to ICU. The most common presenting symptoms were irritability (94.5%), tachycardia (88%), poor feeding (87.6%), fevers (82.1%) and rash (74.5%). Fourteen (9.7%) patients presented with seizures or developed seizures by day 3 of their illness. Limited clinical information was available for the 3 children with HPeV1 infection. One was the oldest child in the cohort at 18 months (567 days) of age. The others were 6 months (211 days) and 1 month (40 days), respectively. The child who was 18 months of age had a febrile convulsion but no lumbar puncture and was only admitted for 1 day. The child of 40 days of age had a CSF negative for HPeV PCR.
Seventy-seven of 145 children (53.1%) had planned initial general pediatric follow-up at intervals of 4–12 weeks from acute illness. The remainder appeared to have full recovery with no anticipated sequelae before expansion of our knowledge of adverse outcomes. The longest duration of follow-up recorded for a child was 2 years of age. Of those assessed, 11 were identified to have neurodevelopmental concerns (Table, Supplemental Digital Content 1, http://links.lww.com/INF/D216). Of these, 2 were diagnosed with cerebral palsy, 2 had developed seizure disorders, 1 in the absence of developmental concerns. Five children with longer term concerns had normal early developmental follow-up at 6–16 weeks. Sixty-seven (46.2%) children were referred for audiology review; none had sensorineural hearing loss. None of the 3 children with HPeV1 had pediatric follow-up documented.
Infants with abnormal neurologic outcome appeared more likely to be neonates, to present with seizures, fever (>38°C) or apneas and to have a history of prematurity. In addition, they appeared more likely to have required pediatric ICU (PICU) admission (72.7% vs 24.2%), invasive ventilatory support (72.7% vs 19.6%) and to have received inotropes (36.4% vs 7.6%) in comparison to those with recorded normal development. Although similar proportions of infants who had normal or abnormal development required intravenous fluid (59% vs 54.5%), the mean volume of resuscitation fluid per kilogram appeared to be greater for infants with poor outcome (35 mL/kg vs 19.5 mL/kg).
Within the cohort of children admitted to PICU (n = 33), 25% had documented neurodevelopmental concerns and 48% did not. Nine children were lost to follow-up. Twenty-three were neonates.
Twenty children had magnetic resonance imagings (MRIs) performed during admission of which 15 were abnormal. The most common finding was restricted diffusion in deep white matter.
In contrast, 14 had cranial ultrasound (USS) performed with only 1 abnormal showing mild right parietal deep white matter flare, and subsequent MRI showed extensive abnormalities. Of the 13 with normal cranial USS, 8 had subsequent cranial MRIs, of which 7 were abnormal.
Of the 15 with initial abnormal MRIs, 7 had neurodevelopmental concerns at follow-up, and 8 had clinically normal development at early follow-up (between 6 and 15 months). Five of those with abnormal development had subsequent persisting abnormalities on MRI. Four of the 5 patients with normal MRIs had normal developmental follow-up. Two of these were followed up to 6 months, and 2 to 12 months. The fifth patient had no long-term follow-up available for review.
Long-term neurologic sequelae have been previously described in HPeV infection (Table 3); however, the proportion of cases successfully documenting follow-up in published case series remains relatively small, and the lack of standardized assessments makes comparative analysis difficult.
To our knowledge, this is the largest pediatric cohort of laboratory-confirmed HPeV3 cases described to date, with documented pediatric follow-up and developmental progress in 53.1% of cases. Although the developmental outcome for 129 children without documented follow-up is unknown, 14% (n = 11) of children with follow-up had identified neurodevelopmental sequelae. This is comparable with that of the next largest study to date,19 which found neurodevelopmental sequelae in nearly 16% of their study population. A recent prospective follow-up study in the Netherlands reported no neurodevelopmental concerns; however, again the data interpretation is hampered by low numbers, with only 5 of 11 HPeV cases completing 12 months follow-up and 9 completing 24 months.33
Epidemiologic studies conducting HPeV surveillance report a broader range of genotypes and generally a lower incidence of sepsis-like illness than hospitalized cohorts, reflective of the variability in colonization and infection that can be seen with HPeV.6 , 34 Similar to others’ findings, the few children in this cohort with HPeV1 infection seemed to be older,6 , 35 although numbers are too small for any meaningful comparison.
Currently, there is no published data regarding rates of HpeV seropositivity in Australian population, but it has been speculated that low rates of maternal antibody may contribute to periodic outbreaks of clinical infection in vulnerable infants.36 , 37 Figure 1 demonstrates that the 2 outbreaks described in this cohort cannot currently be explained by seasonal change, as has been described in some countries.6 A recent report from Australia38 identified a novel genomic recombination in the implicated HPeV3 virus associated with 16 infections in 2013; however, the relationship between this phenomenon and clinical phenotype or virulence remains unknown. Full sequence analysis of isolates and correlation to clinical outcome would be required to investigate this further, which is beyond the scope of this study.
Children less than 3 months of age are documented to have more acute presentations, more frequent ICU admission and longer hospitalization. In the current cohort, all infants with abnormal development at follow-up were <3 months of age at the time of the initial infection. A higher proportion were neonates or premature than those infants with normal development, suggesting that these factors are not only associated with more severe acute infection but also possibly a higher risk of subsequent developmental delay. While prematurity may be a confounder for later neurologic sequelae, only 1 infant with poor outcome was <36 weeks of gestation, and this child (28 weeks of gestation) had no previously documented developmental concerns.
It remains uncertain exactly why younger children are most commonly and severely affected. Regardless of outcome, the majority of infants had positive HPeV3 PCR in CSF, indicating that central nervous system infection is common in clinical HPeV3 infections, and is not predictive of poor outcome per se. Although occasional similar presentations with other serotypes including HPeV1 have been described,6 , 35 HPeV3 infection seems to have the strongest correlation with acute sepsis-like illness or encephalitis.4 , 6 , 13 , 17 , 28 , 36 Early in vitro research has suggested that neutralizing antibodies may be less effective for HPeV3 than HPeV1 and that HPeV3 may demonstrate a higher level of neurotrophism than HPeV1.37
Neurodevelopmental impairment is potentially due directly to virus exposure, the secondary hemodynamic or respiratory consequences or an adverse effect of the management and intervention. A larger proportion (72.7% vs 19.6%) of those with neurologic sequelae required invasive ventilatory support and intravenous inotropes to maintain circulation. The presence of hypotension was also frequent in these infants (36.4% vs 10.6%) (P = 0.02) Because of the retrospective nature of this study, it is not possible to determine if the level of invasive care required is a result of severe infection or is possibly contributory to poorer outcome.
When performed, cranial MRIs had a high yield of typical findings in those with evidence of cerebral irritation or seizures in contrast to USS, which was not sufficiently sensitive to detect abnormalities. This is consistent with previous published findings indicating low sensitivity of head USS.10 Data from this cohort and previous studies suggest that at a minimum, cranial MRI be performed in infants with apneas, seizures and those admitted to PICU.18 , 19 , 22 The precise timing of imaging has not been defined to date. Those with developmental concerns appear to have persistent MRI changes, although early white matter changes may not necessarily predict long-term sequelae. Only half of the children with abnormal MRIs acutely had subsequent developmental delay. However, of the 11 children with long-term neurodevelopmental concerns, all that underwent MRIs initially (7/11) had initial abnormal scans. The 5 children who had repeat scans displayed persistent and evolving changes (Table 2). Cranial MRI is likely to have been performed only in more severe clinical cases, and the role of MRI in clinically mild infection or in children without neurologic symptoms such as seizures or irritability is not clear.
In addition to the retrospective nature of these data, a weakness of this study is that neurodevelopmental follow-up assessments for this cohort of children were extremely variable in timing across multiple centers and involved multiple different clinicians. In addition, the lack of a standardized evaluation means that patients with more minor issues may have been missed or conversely that other factors influencing neurodevelopmental outcome were not identified. While it could be assumed that many of those patients who did not have further follow-up were developmentally normal, this cannot be known for certain. Despite these limitations, the children who were identified as having abnormal development clearly have significant impairment. Routine audiology post HPeV3 meningitis to date has not revealed a high incidence of sensorineural deficits, but data remain incomplete.
In conclusion, while the pathogenesis of poor outcome in a proportion of cases remains unclear, criteria for inclusion in long-term follow-up need to remain broad. Relatively normal reviews in the weeks and months after infection may not exclude longer term issues. Conversely, early neurodevelopmental concerns have in some cases been shown to resolve.28 , 33 Additional investigations using prospective long-term monitoring using standardized neurodevelopmental assessment methods are needed to further elucidate the role HPeV3 infection may play in poor neurologic outcomes.
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