- Email: [email protected]
Early Life Parechovirus Infection Neurodevelopmental Outcomes at 3 Years: A Cohort Study
ORIGINAL ARTICLES Early Life Parechovirus Infection Neurodevelopmental Outcomes at 3 Years: A Cohort Study Philip N. Britton, PhD1,2, Karen Walker, PhD1,3,4, Brendan McMullan, MBBS5,6, Claire Galea, PhD7, Rebecca Burrell, BSc1, Bronte Morgan, BSc1, Ingrid Honan, PhD1,7, Suzy Teutsch, PhD1, Hayley Smithers-Sheedy, PhD1,7, Natalie Fairbairn, BAppSco3, Richard Mattick, PhD8, Delyse Hutchinson, PhD8,9,10,11, and Cheryl A. Jones, PhD1,2,11 Objective To investigate the long-term developmental and behavioral outcomes in an established cohort of children hospitalized as infants with human parechovirus (HPeV) infection and sepsis-like illness.
Study design The HPeV cohort was composed of children 3 years of age after HPeV infection and hospitalization in early infancy that occurred during a well-documented HPeV genotype 3 outbreak in Australia. We assessed neurodevelopmental and behavioral outcomes using the Bayley Scales of Infant and Toddler Development-III and the Child Behavior Checklist. We compared their outcomes with a subsample of healthy control infants drawn from the independently sampled Triple B Pregnancy Cohort Study. Results Fifty children, with a mean age of 41 months, were followed for 3 years after hospital admission with HPeV infection. There were 47 children whose original illness was fever without source or sepsis-like illness and 3 who had encephalitis. All children in the HPeV cohort showed age-specific development within the population normal range on the Bayley Scales of Infant and Toddler Development-III. There was no difference in developmental attainment compared with 107 healthy control infants after adjusting for measured confounders. The HPeV cohort showed higher average scores on the Child Behavior Checklist and a higher frequency of clinical range scores compared with healthy controls. Conclusions Although HPeV sepsis-like illness did not result in neurodevelopmental delay at 3 years of age, it was associated with increased behavioral problems compared with healthy controls. The behavioral problems reached a clinical threshold in a minority of children. Results inform clinical management and planning for children after severe HPeV infection in infancy. (J Pediatr 2019;-:1-7).
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uman parechoviruses (HPeV) are an emerging cause of serious infections in children.1-4 HPeV genotype 3 in particular can cause sepsis and central nervous system (CNS) infections in young infants (<3 months of age).5-7 The neurologic outcomes after early life HPeV are poorly characterized. We and others have previously reported that, after HPeV encephalitis (brain inflammation with dysfunction), infants show a high frequency of severe neurologic morbidity.5,8-11 We have also shown that, at 12 months after HPeV sepsis and meningitis, 1 in 5 children show significant developmental concerns.12 In contrast, other studies report an uneventful outcome after HPeV genotype 3 infection, although most did not involve long-term follow-up or standardized assessment measures.3,4,13,14 Further, systematic study of the neurodevelopmental consequences of severe HPeV infection is required. We have an established cohort of children from an outbreak of HPeV infection that occurred in New South Wales, Australia, between October 2013 and January 2014.6,15 Infants admitted at the Children’s Hospital at Westmead and Sydney Children’s Hospital, Randwick, with confirmed HPeV infection were recruited. These infants were almost all very young at admisFrom the Discipline of Child and Adolescent Health and Marie Bashir Institute Faculty of Medicine and Health, sion (median age, 35 days). The frequency of developmental concerns previously University of Sydney; Department of Infectious Diseases reported, and the very young age of the infants in our previous follow-up study, and Microbiology, and Grace Centre for Newborn 12 Intensive Care, The Children’s Hospital at Westmead, supported the need for further detailed assessment. Sydney Children’s Hospitals Network; The George Institute for Global Health, Sydney; Department of In the present study, we aimed to determine neurodevelopmental and behavImmunology and Infectious Diseases, Sydney Children’s ioral outcomes using the Bayley Scales of Infant and Toddler Development-III Hospital, Randwick, Sydney Children’s Hospitals Network; School of Women’s and Children’s Health, (BSID-III), and the Child Behavior Checklist (CBCL) at 3 years of age among University of New South Wales; Cerebral Palsy Alliance, The University of Sydney; National Drug and Alcohol these infants with HPeV infection in early infancy. Research Centre, University of New South Wales, 1
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BSID-III CBCL CNS CSF HPeV
Bayley Scales of Infant and Toddler Development-III Child Behavior Checklist Central nervous system Cerebrospinal fluid Human parechovirus
Sydney; 9Deakin University, Centre for Social and Early Emotional Development, School of Psychology, Faculty of Health, Geelong; 10Murdoch Children’s Research Institute, Centre for Adolescent Health, Royal Children’s Hospital, Melbourne; and 11Department of Pediatrics, University of Melbourne, Melbourne, Australia Funding and conflict of interest disclosures are available at www.jpeds.com. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.12.026
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Methods Infants with laboratory confirmed HPeV from the 2013-2014 infection outbreak in Sydney, Australia, and who were hospitalized within the Sydney Children’s Hospitals Network were included. Seventy-nine eligible children were initially identified in the retrospective study of clinical data.6 None of these children had a known maternal history of substance abuse, a known developmental disorder, had been admitted to neonatal intensive care units before their illness, or underwent neonatal surgery/general anesthesia. Sepsis-like illness was defined as fever with clinical evidence of poor tissue perfusion; fever without source was defined as infants aged <12 months with fever and no clinical focus, and encephalitis was defined using the Brighton criteria and international encephalitis consortium definitions as described elsewhere.16 Where infants with sepsis-like illness or fever without source had HPeV detected in the cerebrospinal fluid (CSF), we gave the diagnosis of meningitis, although few infants showed CSF pleocytosis (white cell count of >5 106/L), which is typical for HPeV CSF infection. A convenience, control sample of healthy, term-born infant neurodevelopmental data was drawn from a subsample of the independently ascertained prospective Triple B Pregnancy Cohort Study.17 The Triple B Cohort Study is a longitudinal Australian birth cohort study of 1623 families identified prenatally from 2009 to 2013 in New South Wales and Western Australia. The project examines a wide range of biopsychosocial factors that relate to the health and development of Australian children and families. These infants were routinely assessed using the Bayley Scale of Infant and Toddler Development and a subset of families completed the CBCL. We arrived at eligible control cases after exclusion of those with a maternal history of substance abuse, or where the child had a known developmental disorder, neonatal surgery/general anesthesia, prematurity (£36 weeks of gestation), or neonatal intensive care unit admission. Procedures Demographic data were collected from parents/guardians. Socio-Economic Indexes for Areas (www.abs.gov.au) were determined from Australian postcodes of participating families; a standardized measure of socioeconomic advantage or disadvantage. Parental surveys were either mailed to participating families with a stamped addressed envelope for return or completed via a telephone interview with a member of the research team. The BSID-III was administered following standardized procedures by experienced developmental assessors. Assessments were conducted in hospital clinics or as home visits and took approximately 60 minutes to complete. Parents or a nominated medical practitioner were provided with a report of their child’s outcomes and were referred to a family doctor or pediatrician if they had concerns. The BSID-III is an objective, standardized pediatric neurodevelopmental assessment for children £42 months 15 days 2
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of age, consisting of 5 domains: cognition, receptive language, expressive language, fine motor, and gross motor.18 This assessment was validated and normed in the US, and is widely used as the gold standard in neonatal follow-up clinics across Australia.19,20 The BSID-III reports good psychometric properties with moderate to strong reliability and validity.21 Raw scores obtained on each BSID-III domain were converted to standardized scaled scores (mean, 10 3). We added the CBCL as an outcome measure after our experienced developmental assessors reporting unexpectedly difficult behavior during the assessment of the first few children from the HPeV cohort. Behavior is not adequately captured by the BSID-III, and we concluded that a systematic measurement tool was warranted as part of this study. The CBCL is a standardized parental report measure of emotional and behavioral difficulties in children aged 1.5 to 5.0 years of age.22,23 CBCL questionnaires were scored manually by a pediatric psychologist. The CBCL has 7 syndrome scales that make up total scales of internalizing problems, externalizing problems, and total problems. The 7 syndrome scales are emotionally reactive, anxious/depressed, somatic complaints, withdrawn, sleep problems, attention problems, and aggressive behavior. Raw scores are converted to Tscores (mean, 50 10). Higher scores reflect increased emotional and behavioral difficulties. Statistical Analyses Data were entered into SPSS version 22.0, 2014 (SPSS Inc, Chicago, Illinois). Descriptive statistics were compiled to characterize cohort demographics. Normality assumptions were tested using Shapiro-Wilks and visual inspection of box plots. Outliers were not removed for clinical interpretation. Independent t tests, c2 associations, and univariate and multivariate analysis were undertaken. When data assumptions were not met, nonparametric alternatives were used including the Mann-Whitney U test. Human Research Ethics Committee Approval All parents provided informed consent. Ethics approval for the HPeV cohort study was granted by the Sydney Children’s Hospitals Network (SCHN) Human Research Ethics Committee (reference number HREC/16/SCHN/410), University of Sydney and New South Wales Health Human Research Ethics Committees (lead approval numbers: HREC/11/ RPAH/153 and Protocol No X11-0111), the Cerebral Palsy Alliance HREC (HREC/16/SCHN/410), and by Deakin University, Victoria for access to the healthy controls from the Triple B cohort (HREC 2016-347).
Results Of the 79 families identified with confirmed HPeV infection from the 2013-2014 outbreak, 74 parents had consented to be contacted for future research studies. Of those, 1 child was excluded because they were older than the 42-month limit of the BSID-III; thus, 73 families were contacted. Fifty Britton et al
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families (63%) gave consent for their children to participate in the 3-year neurodevelopmental assessment using the BSID-III. One additional child had a parent completed CBCL returned and provided demographic data, and so their child was included in appropriate analyses. Of the included cases, the median age at illness was 32 days (IQR, 18.0-46.5) the clinical illness during hospitalization was sepsis-like illness (n = 36), fever without source and irritability (n = 11), and encephalitis (n = 3). Two-thirds (34/51) had HPeV detected in CSF during hospitalization (meningitis, n = 31; encephalitis n = 3). Of the remaining 17, 2 had confirmed HPeV negative CSF samples and 14 were untested, and 1 did not have admission data available. None of the children had been diagnosed with neurologic impairments between hospitalization and follow-up. Of the New South Wales families in the Triple B Pregnancy Cohort Study, 107 children who completed a 3-year followup BSID-III developmental assessment and did not meet exclusion criteria were included in this study, 55 of whom had also a completed CBCL. Demographic data for both cohorts are shown in Table I. There was a statistically significant difference between the ages of the cohorts; children with HPeV were older than the healthy controls at the time of BSID-III completion (P < .001). Additionally, mother’s highest level of education also differed significantly, with healthy control parents more likely to have completed a bachelor’s degree or higher than parents of children with HPeV (P = .002). There were no other significant differences between the cohort demographic data. BSID-III Outcomes All children in the HPeV cohort showed age-appropriate development within the population normal range on the BSID-III 3 years after hospitalization with HPeV infection (Table II). The lowest subscale scores were in the gross
motor domain, yet scores still averaged within the normal range. When compared with healthy controls, children in the HPeV cohort scored lower on 4 of the BSID-III domains; however, only scores on the gross motor domain were significantly lower than healthy controls (mean, 9.83 1.74 vs mean, 10.50 2.17; P = .04). Conversely, children with HPeV scored significantly higher on the cognitive domain compared with the controls (mean, 10.18 2.18 vs mean, 9.57 1.33; P = .03). In a multiple regression analysis adjusting for mother’s education, the scores on the gross motor domain remained significantly lower and cognitive domains significantly higher than in controls (Table III). However, the statistical differences between the groups was not retained when age at time of assessment was added to the multiple regression model (Table III). CBCL Outcomes Among the HPeV cohort, 20% of children (8/40) showed scores in the clinically significant range (Table IV). By comparison, only 2 of the control participants (2/55; 4%) showed scores in the clinical range, both on the sleep problems scale. This frequency difference was statistically significant (relative risk, 5.5; 95% CI, 1.2-24.5; P = .02, Fisher exact test). Children in the HPeV cohort obtained higher average raw scores on all 7 syndrome scales of the CBCL except sleep problems. Additionally, the HPeV cohort obtained higher average t-scores on the aggregated scales: internalizing problems, externalizing problems, and total problems compared with controls. Independent t tests showed statistically significant differences on 3 scales: anxious/depressed, withdrawn and attention problems, and total problems (Table III). However, the average t-scores across these aggregated scales
Table II. Developmental and behavioral outcomes in the HPeV cohort and healthy controls from the Triple B Pregnancy Cohort Study Table I. Demographic characteristics of the HPeV cases and healthy controls from the Triple B Pregnancy Cohort Study HPeV Demographic characteristic Mean age at BSID-III, months Age Range at BSID-III, months Female sex English speaking Australian SEIFA* decile Maternal education: bachelor or higher
n
mean ± SD or n (%) or ranges
Controls
n
mean ± SD or n (%) or ranges
P value
50 41.1 1.64 107 36.0 1.18 <.001 36.6-42.4 51 51 50 49
26 (51) 48 (94) 7.4 2.80 20 (41)
33.0-42.0 107 89 107 97
57 (53) 77 (87) 7.8 2.24 66 (68)
NS NS NS .002
NS, not significant; SEIFA, Socio-Economic Index for Areas of Relative Socio-economic Advantage and Disadvantage. *Fifty-one children with HPeV as additional child data included from children who did not have a BSID-III assessment.
HPeV Domains/syndrome scales BSID-III Cognition Receptive language Expressive language Fine motor Gross motor CBCL Emotionally reactive* Anxious/depressed* Somatic complaints* Withdrawn* Sleep problems* Attention problems* Aggressive behavior* Internalizing problems Externalizing problems Total problems
Controls
n
Mean ± SD
n
Mean ± SD
50 49 49 50 47
10.18 2.18 11.04 2.14 10.84 2.58 11.52 2.31 9.83 1.74
107 107 107 107 107
9.57 1.33 11.12 2.22 11.37 1.96 11.68 2.28 10.50 2.17
40 40 40 40 40 40 40 40 40 40
53.8 6.77 52.2 4.58 53.6 5.98 54.6 7.22 53.3 5.35 54.8 7.67 53.3 6.32 45.73 12.69 46.35 11.98 45.98 12.24
55 55 55 55 55 55 55 55 55 55
51.2 2.58 50.9 1.96 51.8 3.15 51.0 2.49 53.5 5.42 50.5 1.22 50.9 2.08 41.13 7.85 43.36 6.85 34.05 3.62
*CBCL normality assumptions were not met for the raw scores for the 7 syndrome empirical scales, so no transformations were undertaken for clinical interpretation.
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Table III. Bivariate and multivariate statistical comparison of developmental and behavioral outcomes in the HPeV cohort and healthy controls from the Triple B Pregnancy Cohort Study Independent t test
R2
P value
.032 .832 .154 .680 .042
0.047 0.004 0.013 0.004 0.042
.006 .960 .283 .905 .018
0.041 0.009 0.010 0.004 0.035
.198 .323 .853 .356 .292
.054 .039 .196 .006 .611 .007 .189 .047 .162 <.001
0.029 0.016 0.015 0.078 0.014 0.097 0.003 0.021 0.008 0.302
.079 .159 .648 .004 .613 .021 .162 .114 .117 <.001
0.020 0.079 0.007 0.089 0.018 0.095 0.002 0.038 0.002 0.296
.179 .951 .901 .056 .414 .015 .116 .504 .132 <.001
P value
Domains/syndrome scales BSID-III Cognition Receptive language Expressive language Fine motor Gross motor CBCL Emotionally reactive Anxious/depressed Somatic complaints Withdrawn Sleep problems Attention problems Aggressive behavior Internalizing problems Externalizing problems Total problems
Regression adjusting for maternal education and infant age
Regression adjusting for maternal education
P value
R2
Bold P values show significance at P < .05.
were within the population normal range for both cases and controls. Statistical differences across all domains remained significant after adjustment for mother’s education, with the exception of the anxious/depressed domain, which was no longer statistically significant. After adjusting for age at follow-up, differences in attention problems (P = .015) and total problems (P < .001) remained statistically significant (Table III).
Discussion Here, we report the 3-year neurodevelopmental and behavioral outcomes of a cohort of children with confirmed HPeV in early infancy and compared their outcomes with a cohort of healthy control children. Our results show that children at 3 years of age who had hospitalized HPeV infection in early infancy—predominantly febrile illness and
Table IV. CBCL clinical interpretation in the HPeV and control cohorts HPeV (n = 40) Scales Empirical Emotionally reactive Anxious/depressed Somatic complaints Withdrawn Sleep problems Attention problems Aggressive behavior Internalizing problems Externalizing problems Total problems DSM-V oriented Depressive disorders Anxiety disorders Autism spectrum disorder ADHD Oppositional defiant disorder Any concern
Normal range
Borderline clinical range
35 (88) 39 (98) 37 (93) 36 (90) 38 (95) 36 (90) 37 (93) 34 (85) 34 (85) 33 (83)
3 (8) 1 (3) 2 (5) 1 (3) 1 (3) 2 (5) 1 (3) 1 (3) 2 (5) 2 (5)
37 (93) 38 (95) 34 (85) 37 (93) 37 (93) 30 (75)
1 (3) 1 (3) 2 (5) 1 (3) 2 (5) 2 (5)
Controls (n = 55) Clinical range
Normal range
Borderline clinical range
Clinical range
2 (5) 0 1 (3) 3 (8) 1 (3) 2 (5) 2 (5) 5 (13) 4 (10) 5 (13)
54 (98) 55 (100) 55 (100) 55 (100) 51 (93) 55 (100) 55 (100) 54 (98) 54 (98) 55 (100)
1 (2) 0 0 0 2 (4) 0 0 1 (2) 1 (2) 0
0 0 0 0 2 (4) 0 0 0 0 0
2 (5) 1 (3) 4 (10) 2 (5) 1 (3) 8 (20)
55 (100) 55 (100) 55 (100) 55 (100) 55 (100) 50 (93)
0 0 0 0 0 3 (6)
0 0 0 0 0 2 (4)
P value*
1.0
.02
Bold P values show significance at P < .05. ADHD, attention deficit hyperactivity disorder; DSM-V, Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Values are number (%). *Fisher exact test comparing frequency of clinical range CBCL interpretation in the HPeV and control cohorts.
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- 2019 sepsis-like illness with or without CNS infection—show developmental outcomes in the normal range on all domains of the BSID-III and in keeping with developmental attainment in healthy controls. However, we have shown a difference in the frequency of clinically significant behavioral problems and higher average scores on the CBCL compared with controls. The overall favorable developmental outcome of HPeV sepsis-like illness and meningitis is consistent with reports from both Dutch and Spanish cohorts where no significant developmental concern or gross motor delay was found at 24 months follow-up.24,25 Other observational cohorts for Europe and the United Kingdom have also shown favorable recovery among cases of HPeV meningitis and sepsis-like illness, albeit over shorter follow-up periods.3,4,26 We emphasize that these results should not be generalized to cases of early childhood HPeV encephalitis. We have previously reported a series of infants with HPeV encephalitis where adverse neurologic outcomes occurred in 5 of 8 children followed.5 Among these cases, seizures, apnea, and abnormal magnetic resonance finding defined their illness. In contrast, all infants but 3 included in this study did not show evidence of brain parenchymal involvement, namely, encephalitis (seizures, apnea, focal neurologic findings, or changes on neuroimaging). Further, the 3 children with encephalitis showed lower BSID-III scores in cognition and motor domains compared with those with fever or sepsis-like illness, which scored similarly (Table V; available at www. jpeds.com). HPeV was, however, detected from the CNS in two-thirds of these cases, most often considered to represent meningitis notwithstanding absent CSF pleocytosis. It seems, therefore, that HPeV CNS infection may result in neurologic morbidity in some children where clinical or radiologic evidence of acute brain parenchymal involvement (encephalitis) is evident; however, in many children, CNS infection (meningitis) resolves without leaving sequelae identifiable in terms of neurologic function or developmental outcomes over the long term.5,8,13,27-29 The longitudinal progress of such cases warrants additional consideration. Several cases from our HPeV cohort showed developmental concern on the Ages and Stages Questionnaire at 12 months of age, most frequently in motor domains.12 The majority of these children had been enrolled in preschool in the intervening period and some had received specific allied health (occupational/physio/speech therapy) intervention (results not shown). In the Dutch cohort, children who showed gross motor functional concerns at 6 months improved by 24 months in the absence of any specific intervention.24,30 In the Spanish cohort, developmental concern indicated at first screening, again mainly in motor domains, resolved in the majority of infants 12 months later after in-home physical therapy.25 It cannot be determined whether this specific intervention modified child outcomes. It may be that early delays/concerns resolve naturally as children develop; however, monitoring of development in cases of infant HPeV sepsis-like illness or meningitis appears warranted; particularly in the motor domain.
ORIGINAL ARTICLES Importantly, we have shown that children with early HPeV infection who required hospitalization in infancy are characterized by more behavioral difficulties as reported by parents on the CBCL at 3 years of age. Although the effect size is relatively small, this association has not been previously reported. Clinically it is also notable that the CBCL was added after multiple reports from parents expressing concern about their children’s behavior, in addition to assessors’ observations of behavioral difficulties at the follow-up assessments. Although this result requires replication in future studies with larger samples, it does suggest that assessment of behavioral problems is warranted as part of clinical management and follow-up of children hospitalized in infancy owing to early HPeV infection. We note emerging evidence regarding more subtle, and less well characterized neurocognitive and psychiatric impairments after central nervous system infection in adults.31 Long-term outcomes of CNS viral infections in children have not been well-studied, especially among very young children whose neurocognitive function emerges progressively throughout childhood. The results of this study suggest that possible subtle deficits may be present in children with nonencephalitic HPeV CNS infection, despite showing normal overall neurodevelopment progress. With respect to possible mechanisms for such an effect, we have previously emphasized that the imaging findings in cases of HPeV encephalitis are reminiscent of perinatal white matter injury from other causes, in particular hypoxic ischemic encephalopathy.5 We also note limited autopsy evidence that the pathogenesis of severe HPeV infection may be vasculopathic.32 Taken together, it is possible that HPeV infection may compromise circulation to the developing brain of young infants, and we hypothesize that this may occur in a spectrum. To whatever extent the neonatal hypoxic-encephalopathy literature may be considered analogous, we note animal evidence regarding the specific vulnerability of structures such as the hippocampus, striatum, and parasagittal cortex that may lead to deficits in cognition and may manifest behaviorally.33,34 We also note evidence that milder forms of hypoxic-encephalopathy in humans have been associated with deficits in cognition in the absence of functional motor deficits.33,34 Understanding the potential association of nonencephalitic HPeV infection with increased behavioral difficulties is important for clinicians and parents. The results of this study suggest that cognitive, language, and motor outcomes are age appropriate compared with healthy peers. Importantly, however, we identified a higher frequency of behavioral problems in children with early HPeV infection who required hospitalization in infancy. Behavioral issues can have significant implications for school readiness, social interactions, and academic achievement. Poor attentional control is associated with learning and executive functioning difficulties and long term poor school performance.35,36 Disruptive behaviors can also negatively impact how a child is perceived and treated by parents, teachers, and friends.37,38 Taken together, early detection of behavioral difficulties and the implementation of effective behavioral interventions in children hospitalized
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with early HPeV infection may confer significant benefit to parents and children, and help support children’s development more generally. Strengths of our study include the longitudinal study design, including children with early life HPeV infection and a comparison control group of healthy children. We acknowledge that the BSID-III is recognized to underestimate neurodevelopmental delay; the more limited sensitivity of the test to detect mild impairment means that the results of this study may represent an underestimate of developmental impacts identified.39,40 Further, the age of the HPeV cohort was clustered at the upper age limit for the BSID-III, and these children were older than the controls. A possible ceiling effect of the tool may have further contributed to an underestimate of neurodevelopmental delay in this cohort. Although it would have been advantageous to have had contemporaneous controls more closely matched in age at BSID-III completion and to maternal education level, age was adjusted for in the direct assessment of outcome measures. Furthermore, the BSID-III assessment is age standardized, including calculation of standardized scale scores, which further adjust for age at assessment. Furthermore, we controlled for both age and maternal education in the regression analyses. We acknowledge it is possible that unmeasured confounders may be present and have influenced outcomes. We have reported all relevant known characteristics of the cohorts which were similar apart from age and maternal education. The developmental and behavioral (CBCL) assessments were completed by different observers for each cohort and were not blinded; we cannot completely exclude an observer bias in the assessment of the HPeV cohort. We emphasize that both the observers are experienced assessors of childhood development. We acknowledge that HPeV infection occurs frequently in children and may be mild or asymptomatic. As such, and in the absence of serological testing, we cannot exclude the possibility that the control group may have had HPeV infection in early life although none were hospitalized with HPeV infection. Although children with early, predominantly nonencephalitic HPeV infection showed age-appropriate cognitive, language, and motor development at 3 years of age, they demonstrated increased behavioral problems relative to their healthy peers. The impact of these early behavioral problems, such as attention, may potentially compound and contribute to difficulties in learning and with later socialization. This finding warrants further investigation and we suggest that further long-term follow-up studies are warranted with a focus on learning, academic achievement, behavior, and cognitive function. Children with early childhood hospitalized HPeV infection should be monitored clinically across the preschool period to identify problems early, allowing for intervention to optimize outcomes. n We thank Dr Ameneh Khatami, who provided access to the original hospitalization data on the HPeV cases. We gratefully acknowledge
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the research staff and students who assisted with collection of the data, study investigators not included as authors, the hospitals and antenatal clinics for their assistance with recruitment, and the study participants and their families. Submitted for publication Aug 15, 2019; last revision received Oct 30, 2019; accepted Dec 12, 2019. Reprint requests: Philip N. Britton, PhD, C/o Discipline of Pediatrics and Child Heath, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia 2145. E-mail: [email protected]
References 1. Britton PN, Jones CA, Macartney K, Cheng AC. Parechovirus: an important emerging infection in young infants. Med J Aust 2018;208:365-9. 2. Benschop KS, Schinkel J, Minnaar RP, Pajkrt D, Spanjerberg L, Kraakman HC, et al. Human parechovirus infections in Dutch children and the association between serotype and disease severity. Clin Infect Dis 2006;42:204-10. 3. Skram MK, Skanke LH, Krokstad S, Nordbo SA, Nietsch L, Dollner H. Severe parechovirus infection in Norwegian infants. Pediatr Infect Dis J 2014;33:1222-5. 4. Kadambari S, Braccio S, Ribeiro S, Allen DJ, Pebody R, Brown D, et al. Enterovirus and parechovirus meningitis in infants younger than 90 days old in the UK and Republic of Ireland: a British Paediatric Surveillance Unit study. Arch Dis Child 2019;104:552-7. 5. Britton PN, Dale RC, Nissen MD, Crawford N, Elliot E, Macartney K, et al. Parechovirus encephalitis and neurodevelopmental outcomes. Pediatrics 2016;137:e20152848. 6. Khatami A, McMullan BJ, Webber M, Stewart P, Francis S, Timmers KJ, et al. Sepsis-like disease in infants due to human parechovirus type 3 during an outbreak in Australia. Clin Infect Dis 2015;60:228-36. 7. Walters B, Penaranda S, Nix WA, Oberste MS, Todd KM, Katz BZ, et al. Detection of human parechovirus (HPeV)-3 in spinal fluid specimens from pediatric patients in the Chicago area. J Clin Virol 2011;52:187-91. 8. Verboon-Maciolek MA, Groenendaal F, Hahn CD, Hellmann J, van Loon AM, Boivin G, et al. Human parechovirus causes encephalitis with white matter injury in neonates. Ann Neurol 2008;64:266-73. 9. Gupta S, Fernandez D, Siddiqui A, Tong WC, Pohl K, Jungbluth H. Extensive white matter abnormalities associated with neonatal Parechovirus (HPeV) infection. Eur J Paediatr Neurol 2010;14:531-4. 10. Brownell AD, Reynolds TQ, Livingston B, McCarthy CA. Human parechovirus-3 encephalitis in two neonates: acute and follow-up magnetic resonance imaging and evaluation of central nervous system markers of inflammation. Pediatr Neurol 2015;52:245-9. 11. Vergnano S, Kadambari S, Whalley K, Menson EN, Martinez-Alier N, Cooper M, et al. Characteristics and outcomes of human parechovirus infection in infants (2008-2012). Eur J Pediatr 2015;174:919-24. 12. Britton PN, Khandaker G, Khatami A, Teutsch S, Francis S, McMullan BJ, et al. High prevalence of developmental concern amongst infants at 12 months following hospitalised parechovirus infection. J Paediatr Child Health 2018;54:289-95. 13. Joseph L, May M, Thomas M, Smerdon C, Tozer S, Bialasiewicz S, et al. Human Parechovirus 3 in Infants: expanding our knowledge of adverse outcomes. Pediatr Infect Dis J 2019;38:1-5. 14. Felsenstein S, Yang S, Eubanks N, Sobrera E, Grimm JP, Aldrovandi G. Human parechovirus central nervous system infections in southern California children. Pediatr Infect Dis J 2014;33:e87-91. 15. Cumming G, Khatami A, McMullan BJ, Musto J, Leung K, Nguyen O, et al. Parechovirus genotype 3 outbreak among infants, New South Wales, Australia, 2013–2014. Emerg Infect Dis 2015;21:1144-52. 16. Britton PN, Dale RC, Elliott E, Festa M, Macartney K, Booy R, et al. Pilot surveillance for childhood encephalitis in Australia using the Paediatric Active Enhanced Disease Surveillance (PAEDS) network. Epidemiol Infect 2016;144:1-11.
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- 2019 17. Hutchinson D, Wilson J, Allsop S, Elliott E, Najman J, Burns L, et al. Cohort profile: the Triple B Pregnancy Cohort Study: a longitudinal study of the relationship between alcohol, tobacco and other substance use during pregnancy and the health and well-being of Australian children and families. Int J Epidemiol 2018;47:26-7. 18. Bayley N. Bayley scales of infant and Toddler development. London (UK): PsychCorp, Pearson; 2006. 19. Walker K, Loughran-Fowlds A, Halliday R, Holland AJ, Stewart J, Sholler GF, et al. Developmental outcomes at 3 years of age following major non-cardiac and cardiac surgery in term infants: a populationbased study. J Paediatr Child Health 2015;51:1221-5. 20. Walker K, Badawi N, Halliday R, Stewart J, Sholler GF, Winlaw DS, et al. Early developmental outcomes following major noncardiac and cardiac surgery in term infants: a population-based study. J Pediatr 2012;161: 748-52. 21. Albers CA, Grieve AJ. Test review: Bayley, N.(2006). Bayley Scales of Infant and Toddler Development–third edition. San Antonio (TX): Harcourt assessment. J Psychoeduc Assess 2007;25:180-90. 22. Achenbach TM, Rescorla LA. Manual for the ASEBA preschool forms and profiles. Burlington: University of Vermont, Research Center for Children, Youth; 2000. 23. Achenbach TM, Rescorla LA. Child Behavior Checklist for ages 1 1/2-5: ASEBA. Burlington: University of Vermont; 2000. 24. van Hinsbergh TMT, Elbers RG, van Furth MAM, Obihara CCC. Longitudinal association between human parechovirus central nervous system infection and gross-motor neurodevelopment in young children. Pediatr Infect Dis J 2019;38:110-4. 25. Martin Del Valle F, Menasalvas Ruiz A, Cilla A, Gonzalez AV, de Ceano Vivas M, Cabrerizo Sanz M, et al. Neurodevelopment mediumterm outcome after parechovirus infection. Early Human Dev 2019;132:1-5. 26. de Jong EP, Holscher HC, Steggerda SJ, Van Klink JMM, van Elzakker EPM, Lopriore E, et al. Cerebral imaging and neurodevelopmental outcome after entero- and human parechovirus sepsis in young infants. Eur J Pediatr 2017;176:1595-602. 27. Berk MC, Bruning AHL, van Wassenaer-Leemhuis AG, Wolthers KC, Pajkrt D. Human Parechovirus meningitis with adverse neurodevelopmental outcome: a case report. Pediatr Infect Dis J 2018;37:e256-7. 28. Belcastro V, Bini P, Barachetti R, Barbarini M. Teaching neuroimages: neonatal parechovirus encephalitis: typical MRI findings. Neurology 2014;82:e23.
ORIGINAL ARTICLES 29. Verboon-Maciolek MA, Krediet TG, Gerards LJ, de Vries LS, Groenendaal F, van Loon AM. Severe neonatal parechovirus infection and similarity with enterovirus infection. Pediatr Infect Dis J 2008;27: 241-5. 30. van Hinsbergh TMT, de Crom SCM, Lindeboom R, van Furth MAM, Obihara CC. Human parechovirus meningitis and gross-motor neurodevelopment in young children. Eur J Pediatr 2019;178:473-81. 31. Granerod J, Davies NW, Ramanuj PP, Easton A, Brown DW, Thomas SL. Increased rates of sequelae post-encephalitis in individuals attending primary care practices in the United Kingdom: a population-based retrospective cohort study. J Neurol 2017;264:407-15. 32. Bissel SJ, Auer RN, Chiang CH, Kofler J, Murdoch GH, Nix WA, et al. Human parechovirus 3 meningitis and fatal leukoencephalopathy. J Neuropathol Exp Neurol 2015;74:767-77. 33. de Vries LS, Jongmans MJ. Long-term outcome after neonatal hypoxicischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2010;95: F220-4. 34. Gonzalez FF, Miller SP. Does perinatal asphyxia impair cognitive function without cerebral palsy? Arch Dis Child Fetal Neonatal Ed 2006;91: F454-9. 35. McClelland MM, Cameron CE. Developing together: the role of executive function and motor skills in children’s early academic lives. Early Childhood Res Q 2019;46:142-51. 36. Brennan LM, Shaw DS, Dishion TJ, Wilson MN. The predictive utility of early childhood disruptive behaviors for school-age social functioning. J Abnormal Child Psychol 2015;43:1187-99. 37. ten Braak D, Kleemans T, Størksen I, Verhoeven L, Segers E. Domain-specific effects of attentional and behavioral control in early literacy and numeracy development. Learning Individ Differ 2018;68:61-71. 38. Vandenbroucke L, Verschueren K, Baeyens D. The development of executive functioning across the transition to first grade and its predictive value for academic achievement. Learn Instr 2017;49:103-12. 39. Chinta S, Walker K, Halliday R, Loughran-Fowlds A, Badawi N. A comparison of the performance of healthy Australian 3-year-olds with the standardised norms of the Bayley Scales of Infant and Toddler Development (version-III). Arch Dis Child 2014;99:621-4. 40. Anderson PJ, De Luca CR, Hutchinson E, Roberts G, Doyle LW. Victorian Infant Collaborative Group. Underestimation of developmental delay by the new Bayley-III Scale. Arch Pediatr Adolesc Med 2010;164: 352-6.
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Funding and Conflicts of Interest Disclosure Funded in part by the Cerebral Palsy Alliance Grant (PG5616 [to C.J., P.B., K.W., H.S-S.]), Australian National Health and Medical Research Council (NHMRC) Centre for Research Excellence in Emerging Infectious Diseases (1079575 [to C.J. and P.B.]), NHMRC Early Career Fellowship (ECF) (1145817 [to P.B.]), NHMRC ECF (1144566 [to H.S-S.]), funding from the NHMRC Australasian Cerebral Palsy Clinical Trials Network (to H.S-S.), and Sydney Children’s Hospital Foundation Research Starter Grant (to B.M.). The Triple B Pregnancy Cohort Study was funded by NHMRC Project Grant (630517), and was financially supported by the National Drug and Alcohol Research Centre (NDARC), University of New South Wales (UNSW). The cohort is led by the National Drug and Alcohol Research Centre (NDARC) at UNSW Australia, the National Drug Research
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Institute (NDRI) at Curtin University, and the School of Psychology at Deakin University, in collaboration with the University of Sydney, the University of Queensland, the University of Canterbury, Christchurch, and the Murdoch Children’s Research Institute. NDARC and the National Drug Research Institute (NDRI), Curtin University of Technology are funded by the Australian Government under the Substance Misuse Prevention and Service Improvements Grants Fund. The study has also been supported by Australian Rotary Health (ARH; 2012-2013; 2018-2020), the Foundation for Alcohol Research and Education (FARE; 20102011), and the Financial Markets Foundation for Children (Australia) (2015-2016). Additionally, PhD candidates on the project have been funded through ARH; the NDARC Education Trust (NET) and the Australian Centre for Perinatal Science and NDARC, UNSW. The authors declare no conflicts of interest.
Table V. Developmental and behavioral outcomes in the HPeV cohort stratified by clinical syndrome at presentation and the presence of Central Nervous System (CNS) infection (HPeV detected in Cerebrospinal Fluid) Variables
Fever (n = 11)
Sepsis-like illness (n = 36)
Encephalitis (n = 3)
BSID-III Cognition Receptive language Expressive language Fine motor Gross motor CBCL Emotionally reactive Anxious/depressed Somatic complaints Withdrawn Sleep problems Attention problems Aggressive behavior Internalizing problems Externalizing problems Total problems Depressive disorders Anxiety disorders Autism spectrum disorder ADHD Oppositional defiant disorder
n = 10† 10.7 1.42 11.3 1.25 10.8 1.87 11.7 2.06 9.9 1.36 n=9 58.3 10.27 54.3 7.05 55.4 6.80 57.9 7.90 56.3 8.15 57.6 8.38 56.9 9.93 52.1 15.36 49 17.58 51.1 17.09 56.7 10.25 54.9 6.31 59.6 10.04 56.4 8.00 56.9 8.24
n = 36‡ 10.1 2.44 10.9 2.44 10.9 2.86 11.6 2.48 9.9 1.85 n = 27 52.1 4.02 51.7 3.72 53.0 5.60 53.3 6.19 51.9 2.98 53.5 7.26 52.2 4.58 43.8 10.72 45.3 10.04 44.0 9.75 53.3 4.58 51.4 3.25 53.4 5.88 52.8 5.54 52.5 4.64
n=3 9.3 0.58 11.0 1.00 10.7 2.08 10.3 1.53 9.0 2.00 n=3 56.3 10.97 50.7 1.15 55.0 8.66 57.7 13.28 57.7 8.62 59.7 8.74 53.3 5.77 43.3 21.46 49.3 13.58 49.3 17.90 57.3 11.02 57.7 13.28 59.7 16.74 53.0 3.61 52.3 2.52
P value Welch ANOVA*–fever/SLI 0.318 0.537 0.912 0.854 0.991 0.113 0.305 0.350 0.139 0.145 0.220 0.206 0.162 0.562 0.266 0.369 0.146 0.111 0.229 0.159
Confirmed CNS infection (n = 35) n = 33§ 10.4 2.00 11.3 1.71 10.9 2.44 11.7 1.98 9.7 1.98 n = 27 54.3 7.62 52.3 4.84 54 6.37 54.3 7.06 53.9 5.98 55.9 8.65 54.1 7.10 45.9 13.36 47.1 13.46 46.6 13.17 55.1 7.74 52.9 5.99 55.5 8.91 54.3 6.87 54.1 6.44
Values are mean SD unless otherwise noted. *Between-group differences were calculated for children with HPeV who had a clinical classification of fever and SLI, a Welch ANOVA was used owing to unequal sample sizes and violation of homogeneity of variances. †n = 9 in gross motor domain. ‡n = 35 in both receptive and expressive language domains, n = 34 in gross motor domain. §n = 32 in receptive and expressive language domains, and gross motor domain.
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Study design The HPeV cohort was composed of children 3 years of age after HPeV infection and hospitalization in early infancy that occurred during a well-documented HPeV genotype 3 outbreak in Australia. We assessed neurodevelopmental and behavioral outcomes using the Bayley Scales of Infant and Toddler Development-III and the Child Behavior Checklist. We compared their outcomes with a subsample of healthy control infants drawn from the independently sampled Triple B Pregnancy Cohort Study. Results Fifty children, with a mean age of 41 months, were followed for 3 years after hospital admission with HPeV infection. There were 47 children whose original illness was fever without source or sepsis-like illness and 3 who had encephalitis. All children in the HPeV cohort showed age-specific development within the population normal range on the Bayley Scales of Infant and Toddler Development-III. There was no difference in developmental attainment compared with 107 healthy control infants after adjusting for measured confounders. The HPeV cohort showed higher average scores on the Child Behavior Checklist and a higher frequency of clinical range scores compared with healthy controls. Conclusions Although HPeV sepsis-like illness did not result in neurodevelopmental delay at 3 years of age, it was associated with increased behavioral problems compared with healthy controls. The behavioral problems reached a clinical threshold in a minority of children. Results inform clinical management and planning for children after severe HPeV infection in infancy. (J Pediatr 2019;-:1-7).
H
uman parechoviruses (HPeV) are an emerging cause of serious infections in children.1-4 HPeV genotype 3 in particular can cause sepsis and central nervous system (CNS) infections in young infants (<3 months of age).5-7 The neurologic outcomes after early life HPeV are poorly characterized. We and others have previously reported that, after HPeV encephalitis (brain inflammation with dysfunction), infants show a high frequency of severe neurologic morbidity.5,8-11 We have also shown that, at 12 months after HPeV sepsis and meningitis, 1 in 5 children show significant developmental concerns.12 In contrast, other studies report an uneventful outcome after HPeV genotype 3 infection, although most did not involve long-term follow-up or standardized assessment measures.3,4,13,14 Further, systematic study of the neurodevelopmental consequences of severe HPeV infection is required. We have an established cohort of children from an outbreak of HPeV infection that occurred in New South Wales, Australia, between October 2013 and January 2014.6,15 Infants admitted at the Children’s Hospital at Westmead and Sydney Children’s Hospital, Randwick, with confirmed HPeV infection were recruited. These infants were almost all very young at admisFrom the Discipline of Child and Adolescent Health and Marie Bashir Institute Faculty of Medicine and Health, sion (median age, 35 days). The frequency of developmental concerns previously University of Sydney; Department of Infectious Diseases reported, and the very young age of the infants in our previous follow-up study, and Microbiology, and Grace Centre for Newborn 12 Intensive Care, The Children’s Hospital at Westmead, supported the need for further detailed assessment. Sydney Children’s Hospitals Network; The George Institute for Global Health, Sydney; Department of In the present study, we aimed to determine neurodevelopmental and behavImmunology and Infectious Diseases, Sydney Children’s ioral outcomes using the Bayley Scales of Infant and Toddler Development-III Hospital, Randwick, Sydney Children’s Hospitals Network; School of Women’s and Children’s Health, (BSID-III), and the Child Behavior Checklist (CBCL) at 3 years of age among University of New South Wales; Cerebral Palsy Alliance, The University of Sydney; National Drug and Alcohol these infants with HPeV infection in early infancy. Research Centre, University of New South Wales, 1
2
3
4
5
6
7
8
BSID-III CBCL CNS CSF HPeV
Bayley Scales of Infant and Toddler Development-III Child Behavior Checklist Central nervous system Cerebrospinal fluid Human parechovirus
Sydney; 9Deakin University, Centre for Social and Early Emotional Development, School of Psychology, Faculty of Health, Geelong; 10Murdoch Children’s Research Institute, Centre for Adolescent Health, Royal Children’s Hospital, Melbourne; and 11Department of Pediatrics, University of Melbourne, Melbourne, Australia Funding and conflict of interest disclosures are available at www.jpeds.com. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.12.026
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Methods Infants with laboratory confirmed HPeV from the 2013-2014 infection outbreak in Sydney, Australia, and who were hospitalized within the Sydney Children’s Hospitals Network were included. Seventy-nine eligible children were initially identified in the retrospective study of clinical data.6 None of these children had a known maternal history of substance abuse, a known developmental disorder, had been admitted to neonatal intensive care units before their illness, or underwent neonatal surgery/general anesthesia. Sepsis-like illness was defined as fever with clinical evidence of poor tissue perfusion; fever without source was defined as infants aged <12 months with fever and no clinical focus, and encephalitis was defined using the Brighton criteria and international encephalitis consortium definitions as described elsewhere.16 Where infants with sepsis-like illness or fever without source had HPeV detected in the cerebrospinal fluid (CSF), we gave the diagnosis of meningitis, although few infants showed CSF pleocytosis (white cell count of >5 106/L), which is typical for HPeV CSF infection. A convenience, control sample of healthy, term-born infant neurodevelopmental data was drawn from a subsample of the independently ascertained prospective Triple B Pregnancy Cohort Study.17 The Triple B Cohort Study is a longitudinal Australian birth cohort study of 1623 families identified prenatally from 2009 to 2013 in New South Wales and Western Australia. The project examines a wide range of biopsychosocial factors that relate to the health and development of Australian children and families. These infants were routinely assessed using the Bayley Scale of Infant and Toddler Development and a subset of families completed the CBCL. We arrived at eligible control cases after exclusion of those with a maternal history of substance abuse, or where the child had a known developmental disorder, neonatal surgery/general anesthesia, prematurity (£36 weeks of gestation), or neonatal intensive care unit admission. Procedures Demographic data were collected from parents/guardians. Socio-Economic Indexes for Areas (www.abs.gov.au) were determined from Australian postcodes of participating families; a standardized measure of socioeconomic advantage or disadvantage. Parental surveys were either mailed to participating families with a stamped addressed envelope for return or completed via a telephone interview with a member of the research team. The BSID-III was administered following standardized procedures by experienced developmental assessors. Assessments were conducted in hospital clinics or as home visits and took approximately 60 minutes to complete. Parents or a nominated medical practitioner were provided with a report of their child’s outcomes and were referred to a family doctor or pediatrician if they had concerns. The BSID-III is an objective, standardized pediatric neurodevelopmental assessment for children £42 months 15 days 2
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of age, consisting of 5 domains: cognition, receptive language, expressive language, fine motor, and gross motor.18 This assessment was validated and normed in the US, and is widely used as the gold standard in neonatal follow-up clinics across Australia.19,20 The BSID-III reports good psychometric properties with moderate to strong reliability and validity.21 Raw scores obtained on each BSID-III domain were converted to standardized scaled scores (mean, 10 3). We added the CBCL as an outcome measure after our experienced developmental assessors reporting unexpectedly difficult behavior during the assessment of the first few children from the HPeV cohort. Behavior is not adequately captured by the BSID-III, and we concluded that a systematic measurement tool was warranted as part of this study. The CBCL is a standardized parental report measure of emotional and behavioral difficulties in children aged 1.5 to 5.0 years of age.22,23 CBCL questionnaires were scored manually by a pediatric psychologist. The CBCL has 7 syndrome scales that make up total scales of internalizing problems, externalizing problems, and total problems. The 7 syndrome scales are emotionally reactive, anxious/depressed, somatic complaints, withdrawn, sleep problems, attention problems, and aggressive behavior. Raw scores are converted to Tscores (mean, 50 10). Higher scores reflect increased emotional and behavioral difficulties. Statistical Analyses Data were entered into SPSS version 22.0, 2014 (SPSS Inc, Chicago, Illinois). Descriptive statistics were compiled to characterize cohort demographics. Normality assumptions were tested using Shapiro-Wilks and visual inspection of box plots. Outliers were not removed for clinical interpretation. Independent t tests, c2 associations, and univariate and multivariate analysis were undertaken. When data assumptions were not met, nonparametric alternatives were used including the Mann-Whitney U test. Human Research Ethics Committee Approval All parents provided informed consent. Ethics approval for the HPeV cohort study was granted by the Sydney Children’s Hospitals Network (SCHN) Human Research Ethics Committee (reference number HREC/16/SCHN/410), University of Sydney and New South Wales Health Human Research Ethics Committees (lead approval numbers: HREC/11/ RPAH/153 and Protocol No X11-0111), the Cerebral Palsy Alliance HREC (HREC/16/SCHN/410), and by Deakin University, Victoria for access to the healthy controls from the Triple B cohort (HREC 2016-347).
Results Of the 79 families identified with confirmed HPeV infection from the 2013-2014 outbreak, 74 parents had consented to be contacted for future research studies. Of those, 1 child was excluded because they were older than the 42-month limit of the BSID-III; thus, 73 families were contacted. Fifty Britton et al
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ORIGINAL ARTICLES
families (63%) gave consent for their children to participate in the 3-year neurodevelopmental assessment using the BSID-III. One additional child had a parent completed CBCL returned and provided demographic data, and so their child was included in appropriate analyses. Of the included cases, the median age at illness was 32 days (IQR, 18.0-46.5) the clinical illness during hospitalization was sepsis-like illness (n = 36), fever without source and irritability (n = 11), and encephalitis (n = 3). Two-thirds (34/51) had HPeV detected in CSF during hospitalization (meningitis, n = 31; encephalitis n = 3). Of the remaining 17, 2 had confirmed HPeV negative CSF samples and 14 were untested, and 1 did not have admission data available. None of the children had been diagnosed with neurologic impairments between hospitalization and follow-up. Of the New South Wales families in the Triple B Pregnancy Cohort Study, 107 children who completed a 3-year followup BSID-III developmental assessment and did not meet exclusion criteria were included in this study, 55 of whom had also a completed CBCL. Demographic data for both cohorts are shown in Table I. There was a statistically significant difference between the ages of the cohorts; children with HPeV were older than the healthy controls at the time of BSID-III completion (P < .001). Additionally, mother’s highest level of education also differed significantly, with healthy control parents more likely to have completed a bachelor’s degree or higher than parents of children with HPeV (P = .002). There were no other significant differences between the cohort demographic data. BSID-III Outcomes All children in the HPeV cohort showed age-appropriate development within the population normal range on the BSID-III 3 years after hospitalization with HPeV infection (Table II). The lowest subscale scores were in the gross
motor domain, yet scores still averaged within the normal range. When compared with healthy controls, children in the HPeV cohort scored lower on 4 of the BSID-III domains; however, only scores on the gross motor domain were significantly lower than healthy controls (mean, 9.83 1.74 vs mean, 10.50 2.17; P = .04). Conversely, children with HPeV scored significantly higher on the cognitive domain compared with the controls (mean, 10.18 2.18 vs mean, 9.57 1.33; P = .03). In a multiple regression analysis adjusting for mother’s education, the scores on the gross motor domain remained significantly lower and cognitive domains significantly higher than in controls (Table III). However, the statistical differences between the groups was not retained when age at time of assessment was added to the multiple regression model (Table III). CBCL Outcomes Among the HPeV cohort, 20% of children (8/40) showed scores in the clinically significant range (Table IV). By comparison, only 2 of the control participants (2/55; 4%) showed scores in the clinical range, both on the sleep problems scale. This frequency difference was statistically significant (relative risk, 5.5; 95% CI, 1.2-24.5; P = .02, Fisher exact test). Children in the HPeV cohort obtained higher average raw scores on all 7 syndrome scales of the CBCL except sleep problems. Additionally, the HPeV cohort obtained higher average t-scores on the aggregated scales: internalizing problems, externalizing problems, and total problems compared with controls. Independent t tests showed statistically significant differences on 3 scales: anxious/depressed, withdrawn and attention problems, and total problems (Table III). However, the average t-scores across these aggregated scales
Table II. Developmental and behavioral outcomes in the HPeV cohort and healthy controls from the Triple B Pregnancy Cohort Study Table I. Demographic characteristics of the HPeV cases and healthy controls from the Triple B Pregnancy Cohort Study HPeV Demographic characteristic Mean age at BSID-III, months Age Range at BSID-III, months Female sex English speaking Australian SEIFA* decile Maternal education: bachelor or higher
n
mean ± SD or n (%) or ranges
Controls
n
mean ± SD or n (%) or ranges
P value
50 41.1 1.64 107 36.0 1.18 <.001 36.6-42.4 51 51 50 49
26 (51) 48 (94) 7.4 2.80 20 (41)
33.0-42.0 107 89 107 97
57 (53) 77 (87) 7.8 2.24 66 (68)
NS NS NS .002
NS, not significant; SEIFA, Socio-Economic Index for Areas of Relative Socio-economic Advantage and Disadvantage. *Fifty-one children with HPeV as additional child data included from children who did not have a BSID-III assessment.
HPeV Domains/syndrome scales BSID-III Cognition Receptive language Expressive language Fine motor Gross motor CBCL Emotionally reactive* Anxious/depressed* Somatic complaints* Withdrawn* Sleep problems* Attention problems* Aggressive behavior* Internalizing problems Externalizing problems Total problems
Controls
n
Mean ± SD
n
Mean ± SD
50 49 49 50 47
10.18 2.18 11.04 2.14 10.84 2.58 11.52 2.31 9.83 1.74
107 107 107 107 107
9.57 1.33 11.12 2.22 11.37 1.96 11.68 2.28 10.50 2.17
40 40 40 40 40 40 40 40 40 40
53.8 6.77 52.2 4.58 53.6 5.98 54.6 7.22 53.3 5.35 54.8 7.67 53.3 6.32 45.73 12.69 46.35 11.98 45.98 12.24
55 55 55 55 55 55 55 55 55 55
51.2 2.58 50.9 1.96 51.8 3.15 51.0 2.49 53.5 5.42 50.5 1.22 50.9 2.08 41.13 7.85 43.36 6.85 34.05 3.62
*CBCL normality assumptions were not met for the raw scores for the 7 syndrome empirical scales, so no transformations were undertaken for clinical interpretation.
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Table III. Bivariate and multivariate statistical comparison of developmental and behavioral outcomes in the HPeV cohort and healthy controls from the Triple B Pregnancy Cohort Study Independent t test
R2
P value
.032 .832 .154 .680 .042
0.047 0.004 0.013 0.004 0.042
.006 .960 .283 .905 .018
0.041 0.009 0.010 0.004 0.035
.198 .323 .853 .356 .292
.054 .039 .196 .006 .611 .007 .189 .047 .162 <.001
0.029 0.016 0.015 0.078 0.014 0.097 0.003 0.021 0.008 0.302
.079 .159 .648 .004 .613 .021 .162 .114 .117 <.001
0.020 0.079 0.007 0.089 0.018 0.095 0.002 0.038 0.002 0.296
.179 .951 .901 .056 .414 .015 .116 .504 .132 <.001
P value
Domains/syndrome scales BSID-III Cognition Receptive language Expressive language Fine motor Gross motor CBCL Emotionally reactive Anxious/depressed Somatic complaints Withdrawn Sleep problems Attention problems Aggressive behavior Internalizing problems Externalizing problems Total problems
Regression adjusting for maternal education and infant age
Regression adjusting for maternal education
P value
R2
Bold P values show significance at P < .05.
were within the population normal range for both cases and controls. Statistical differences across all domains remained significant after adjustment for mother’s education, with the exception of the anxious/depressed domain, which was no longer statistically significant. After adjusting for age at follow-up, differences in attention problems (P = .015) and total problems (P < .001) remained statistically significant (Table III).
Discussion Here, we report the 3-year neurodevelopmental and behavioral outcomes of a cohort of children with confirmed HPeV in early infancy and compared their outcomes with a cohort of healthy control children. Our results show that children at 3 years of age who had hospitalized HPeV infection in early infancy—predominantly febrile illness and
Table IV. CBCL clinical interpretation in the HPeV and control cohorts HPeV (n = 40) Scales Empirical Emotionally reactive Anxious/depressed Somatic complaints Withdrawn Sleep problems Attention problems Aggressive behavior Internalizing problems Externalizing problems Total problems DSM-V oriented Depressive disorders Anxiety disorders Autism spectrum disorder ADHD Oppositional defiant disorder Any concern
Normal range
Borderline clinical range
35 (88) 39 (98) 37 (93) 36 (90) 38 (95) 36 (90) 37 (93) 34 (85) 34 (85) 33 (83)
3 (8) 1 (3) 2 (5) 1 (3) 1 (3) 2 (5) 1 (3) 1 (3) 2 (5) 2 (5)
37 (93) 38 (95) 34 (85) 37 (93) 37 (93) 30 (75)
1 (3) 1 (3) 2 (5) 1 (3) 2 (5) 2 (5)
Controls (n = 55) Clinical range
Normal range
Borderline clinical range
Clinical range
2 (5) 0 1 (3) 3 (8) 1 (3) 2 (5) 2 (5) 5 (13) 4 (10) 5 (13)
54 (98) 55 (100) 55 (100) 55 (100) 51 (93) 55 (100) 55 (100) 54 (98) 54 (98) 55 (100)
1 (2) 0 0 0 2 (4) 0 0 1 (2) 1 (2) 0
0 0 0 0 2 (4) 0 0 0 0 0
2 (5) 1 (3) 4 (10) 2 (5) 1 (3) 8 (20)
55 (100) 55 (100) 55 (100) 55 (100) 55 (100) 50 (93)
0 0 0 0 0 3 (6)
0 0 0 0 0 2 (4)
P value*
1.0
.02
Bold P values show significance at P < .05. ADHD, attention deficit hyperactivity disorder; DSM-V, Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Values are number (%). *Fisher exact test comparing frequency of clinical range CBCL interpretation in the HPeV and control cohorts.
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- 2019 sepsis-like illness with or without CNS infection—show developmental outcomes in the normal range on all domains of the BSID-III and in keeping with developmental attainment in healthy controls. However, we have shown a difference in the frequency of clinically significant behavioral problems and higher average scores on the CBCL compared with controls. The overall favorable developmental outcome of HPeV sepsis-like illness and meningitis is consistent with reports from both Dutch and Spanish cohorts where no significant developmental concern or gross motor delay was found at 24 months follow-up.24,25 Other observational cohorts for Europe and the United Kingdom have also shown favorable recovery among cases of HPeV meningitis and sepsis-like illness, albeit over shorter follow-up periods.3,4,26 We emphasize that these results should not be generalized to cases of early childhood HPeV encephalitis. We have previously reported a series of infants with HPeV encephalitis where adverse neurologic outcomes occurred in 5 of 8 children followed.5 Among these cases, seizures, apnea, and abnormal magnetic resonance finding defined their illness. In contrast, all infants but 3 included in this study did not show evidence of brain parenchymal involvement, namely, encephalitis (seizures, apnea, focal neurologic findings, or changes on neuroimaging). Further, the 3 children with encephalitis showed lower BSID-III scores in cognition and motor domains compared with those with fever or sepsis-like illness, which scored similarly (Table V; available at www. jpeds.com). HPeV was, however, detected from the CNS in two-thirds of these cases, most often considered to represent meningitis notwithstanding absent CSF pleocytosis. It seems, therefore, that HPeV CNS infection may result in neurologic morbidity in some children where clinical or radiologic evidence of acute brain parenchymal involvement (encephalitis) is evident; however, in many children, CNS infection (meningitis) resolves without leaving sequelae identifiable in terms of neurologic function or developmental outcomes over the long term.5,8,13,27-29 The longitudinal progress of such cases warrants additional consideration. Several cases from our HPeV cohort showed developmental concern on the Ages and Stages Questionnaire at 12 months of age, most frequently in motor domains.12 The majority of these children had been enrolled in preschool in the intervening period and some had received specific allied health (occupational/physio/speech therapy) intervention (results not shown). In the Dutch cohort, children who showed gross motor functional concerns at 6 months improved by 24 months in the absence of any specific intervention.24,30 In the Spanish cohort, developmental concern indicated at first screening, again mainly in motor domains, resolved in the majority of infants 12 months later after in-home physical therapy.25 It cannot be determined whether this specific intervention modified child outcomes. It may be that early delays/concerns resolve naturally as children develop; however, monitoring of development in cases of infant HPeV sepsis-like illness or meningitis appears warranted; particularly in the motor domain.
ORIGINAL ARTICLES Importantly, we have shown that children with early HPeV infection who required hospitalization in infancy are characterized by more behavioral difficulties as reported by parents on the CBCL at 3 years of age. Although the effect size is relatively small, this association has not been previously reported. Clinically it is also notable that the CBCL was added after multiple reports from parents expressing concern about their children’s behavior, in addition to assessors’ observations of behavioral difficulties at the follow-up assessments. Although this result requires replication in future studies with larger samples, it does suggest that assessment of behavioral problems is warranted as part of clinical management and follow-up of children hospitalized in infancy owing to early HPeV infection. We note emerging evidence regarding more subtle, and less well characterized neurocognitive and psychiatric impairments after central nervous system infection in adults.31 Long-term outcomes of CNS viral infections in children have not been well-studied, especially among very young children whose neurocognitive function emerges progressively throughout childhood. The results of this study suggest that possible subtle deficits may be present in children with nonencephalitic HPeV CNS infection, despite showing normal overall neurodevelopment progress. With respect to possible mechanisms for such an effect, we have previously emphasized that the imaging findings in cases of HPeV encephalitis are reminiscent of perinatal white matter injury from other causes, in particular hypoxic ischemic encephalopathy.5 We also note limited autopsy evidence that the pathogenesis of severe HPeV infection may be vasculopathic.32 Taken together, it is possible that HPeV infection may compromise circulation to the developing brain of young infants, and we hypothesize that this may occur in a spectrum. To whatever extent the neonatal hypoxic-encephalopathy literature may be considered analogous, we note animal evidence regarding the specific vulnerability of structures such as the hippocampus, striatum, and parasagittal cortex that may lead to deficits in cognition and may manifest behaviorally.33,34 We also note evidence that milder forms of hypoxic-encephalopathy in humans have been associated with deficits in cognition in the absence of functional motor deficits.33,34 Understanding the potential association of nonencephalitic HPeV infection with increased behavioral difficulties is important for clinicians and parents. The results of this study suggest that cognitive, language, and motor outcomes are age appropriate compared with healthy peers. Importantly, however, we identified a higher frequency of behavioral problems in children with early HPeV infection who required hospitalization in infancy. Behavioral issues can have significant implications for school readiness, social interactions, and academic achievement. Poor attentional control is associated with learning and executive functioning difficulties and long term poor school performance.35,36 Disruptive behaviors can also negatively impact how a child is perceived and treated by parents, teachers, and friends.37,38 Taken together, early detection of behavioral difficulties and the implementation of effective behavioral interventions in children hospitalized
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with early HPeV infection may confer significant benefit to parents and children, and help support children’s development more generally. Strengths of our study include the longitudinal study design, including children with early life HPeV infection and a comparison control group of healthy children. We acknowledge that the BSID-III is recognized to underestimate neurodevelopmental delay; the more limited sensitivity of the test to detect mild impairment means that the results of this study may represent an underestimate of developmental impacts identified.39,40 Further, the age of the HPeV cohort was clustered at the upper age limit for the BSID-III, and these children were older than the controls. A possible ceiling effect of the tool may have further contributed to an underestimate of neurodevelopmental delay in this cohort. Although it would have been advantageous to have had contemporaneous controls more closely matched in age at BSID-III completion and to maternal education level, age was adjusted for in the direct assessment of outcome measures. Furthermore, the BSID-III assessment is age standardized, including calculation of standardized scale scores, which further adjust for age at assessment. Furthermore, we controlled for both age and maternal education in the regression analyses. We acknowledge it is possible that unmeasured confounders may be present and have influenced outcomes. We have reported all relevant known characteristics of the cohorts which were similar apart from age and maternal education. The developmental and behavioral (CBCL) assessments were completed by different observers for each cohort and were not blinded; we cannot completely exclude an observer bias in the assessment of the HPeV cohort. We emphasize that both the observers are experienced assessors of childhood development. We acknowledge that HPeV infection occurs frequently in children and may be mild or asymptomatic. As such, and in the absence of serological testing, we cannot exclude the possibility that the control group may have had HPeV infection in early life although none were hospitalized with HPeV infection. Although children with early, predominantly nonencephalitic HPeV infection showed age-appropriate cognitive, language, and motor development at 3 years of age, they demonstrated increased behavioral problems relative to their healthy peers. The impact of these early behavioral problems, such as attention, may potentially compound and contribute to difficulties in learning and with later socialization. This finding warrants further investigation and we suggest that further long-term follow-up studies are warranted with a focus on learning, academic achievement, behavior, and cognitive function. Children with early childhood hospitalized HPeV infection should be monitored clinically across the preschool period to identify problems early, allowing for intervention to optimize outcomes. n We thank Dr Ameneh Khatami, who provided access to the original hospitalization data on the HPeV cases. We gratefully acknowledge
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the research staff and students who assisted with collection of the data, study investigators not included as authors, the hospitals and antenatal clinics for their assistance with recruitment, and the study participants and their families. Submitted for publication Aug 15, 2019; last revision received Oct 30, 2019; accepted Dec 12, 2019. Reprint requests: Philip N. Britton, PhD, C/o Discipline of Pediatrics and Child Heath, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia 2145. E-mail: [email protected]
References 1. Britton PN, Jones CA, Macartney K, Cheng AC. Parechovirus: an important emerging infection in young infants. Med J Aust 2018;208:365-9. 2. Benschop KS, Schinkel J, Minnaar RP, Pajkrt D, Spanjerberg L, Kraakman HC, et al. Human parechovirus infections in Dutch children and the association between serotype and disease severity. Clin Infect Dis 2006;42:204-10. 3. Skram MK, Skanke LH, Krokstad S, Nordbo SA, Nietsch L, Dollner H. Severe parechovirus infection in Norwegian infants. Pediatr Infect Dis J 2014;33:1222-5. 4. Kadambari S, Braccio S, Ribeiro S, Allen DJ, Pebody R, Brown D, et al. Enterovirus and parechovirus meningitis in infants younger than 90 days old in the UK and Republic of Ireland: a British Paediatric Surveillance Unit study. Arch Dis Child 2019;104:552-7. 5. Britton PN, Dale RC, Nissen MD, Crawford N, Elliot E, Macartney K, et al. Parechovirus encephalitis and neurodevelopmental outcomes. Pediatrics 2016;137:e20152848. 6. Khatami A, McMullan BJ, Webber M, Stewart P, Francis S, Timmers KJ, et al. Sepsis-like disease in infants due to human parechovirus type 3 during an outbreak in Australia. Clin Infect Dis 2015;60:228-36. 7. Walters B, Penaranda S, Nix WA, Oberste MS, Todd KM, Katz BZ, et al. Detection of human parechovirus (HPeV)-3 in spinal fluid specimens from pediatric patients in the Chicago area. J Clin Virol 2011;52:187-91. 8. Verboon-Maciolek MA, Groenendaal F, Hahn CD, Hellmann J, van Loon AM, Boivin G, et al. Human parechovirus causes encephalitis with white matter injury in neonates. Ann Neurol 2008;64:266-73. 9. Gupta S, Fernandez D, Siddiqui A, Tong WC, Pohl K, Jungbluth H. Extensive white matter abnormalities associated with neonatal Parechovirus (HPeV) infection. Eur J Paediatr Neurol 2010;14:531-4. 10. Brownell AD, Reynolds TQ, Livingston B, McCarthy CA. Human parechovirus-3 encephalitis in two neonates: acute and follow-up magnetic resonance imaging and evaluation of central nervous system markers of inflammation. Pediatr Neurol 2015;52:245-9. 11. Vergnano S, Kadambari S, Whalley K, Menson EN, Martinez-Alier N, Cooper M, et al. Characteristics and outcomes of human parechovirus infection in infants (2008-2012). Eur J Pediatr 2015;174:919-24. 12. Britton PN, Khandaker G, Khatami A, Teutsch S, Francis S, McMullan BJ, et al. High prevalence of developmental concern amongst infants at 12 months following hospitalised parechovirus infection. J Paediatr Child Health 2018;54:289-95. 13. Joseph L, May M, Thomas M, Smerdon C, Tozer S, Bialasiewicz S, et al. Human Parechovirus 3 in Infants: expanding our knowledge of adverse outcomes. Pediatr Infect Dis J 2019;38:1-5. 14. Felsenstein S, Yang S, Eubanks N, Sobrera E, Grimm JP, Aldrovandi G. Human parechovirus central nervous system infections in southern California children. Pediatr Infect Dis J 2014;33:e87-91. 15. Cumming G, Khatami A, McMullan BJ, Musto J, Leung K, Nguyen O, et al. Parechovirus genotype 3 outbreak among infants, New South Wales, Australia, 2013–2014. Emerg Infect Dis 2015;21:1144-52. 16. Britton PN, Dale RC, Elliott E, Festa M, Macartney K, Booy R, et al. Pilot surveillance for childhood encephalitis in Australia using the Paediatric Active Enhanced Disease Surveillance (PAEDS) network. Epidemiol Infect 2016;144:1-11.
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- 2019 17. Hutchinson D, Wilson J, Allsop S, Elliott E, Najman J, Burns L, et al. Cohort profile: the Triple B Pregnancy Cohort Study: a longitudinal study of the relationship between alcohol, tobacco and other substance use during pregnancy and the health and well-being of Australian children and families. Int J Epidemiol 2018;47:26-7. 18. Bayley N. Bayley scales of infant and Toddler development. London (UK): PsychCorp, Pearson; 2006. 19. Walker K, Loughran-Fowlds A, Halliday R, Holland AJ, Stewart J, Sholler GF, et al. Developmental outcomes at 3 years of age following major non-cardiac and cardiac surgery in term infants: a populationbased study. J Paediatr Child Health 2015;51:1221-5. 20. Walker K, Badawi N, Halliday R, Stewart J, Sholler GF, Winlaw DS, et al. Early developmental outcomes following major noncardiac and cardiac surgery in term infants: a population-based study. J Pediatr 2012;161: 748-52. 21. Albers CA, Grieve AJ. Test review: Bayley, N.(2006). Bayley Scales of Infant and Toddler Development–third edition. San Antonio (TX): Harcourt assessment. J Psychoeduc Assess 2007;25:180-90. 22. Achenbach TM, Rescorla LA. Manual for the ASEBA preschool forms and profiles. Burlington: University of Vermont, Research Center for Children, Youth; 2000. 23. Achenbach TM, Rescorla LA. Child Behavior Checklist for ages 1 1/2-5: ASEBA. Burlington: University of Vermont; 2000. 24. van Hinsbergh TMT, Elbers RG, van Furth MAM, Obihara CCC. Longitudinal association between human parechovirus central nervous system infection and gross-motor neurodevelopment in young children. Pediatr Infect Dis J 2019;38:110-4. 25. Martin Del Valle F, Menasalvas Ruiz A, Cilla A, Gonzalez AV, de Ceano Vivas M, Cabrerizo Sanz M, et al. Neurodevelopment mediumterm outcome after parechovirus infection. Early Human Dev 2019;132:1-5. 26. de Jong EP, Holscher HC, Steggerda SJ, Van Klink JMM, van Elzakker EPM, Lopriore E, et al. Cerebral imaging and neurodevelopmental outcome after entero- and human parechovirus sepsis in young infants. Eur J Pediatr 2017;176:1595-602. 27. Berk MC, Bruning AHL, van Wassenaer-Leemhuis AG, Wolthers KC, Pajkrt D. Human Parechovirus meningitis with adverse neurodevelopmental outcome: a case report. Pediatr Infect Dis J 2018;37:e256-7. 28. Belcastro V, Bini P, Barachetti R, Barbarini M. Teaching neuroimages: neonatal parechovirus encephalitis: typical MRI findings. Neurology 2014;82:e23.
ORIGINAL ARTICLES 29. Verboon-Maciolek MA, Krediet TG, Gerards LJ, de Vries LS, Groenendaal F, van Loon AM. Severe neonatal parechovirus infection and similarity with enterovirus infection. Pediatr Infect Dis J 2008;27: 241-5. 30. van Hinsbergh TMT, de Crom SCM, Lindeboom R, van Furth MAM, Obihara CC. Human parechovirus meningitis and gross-motor neurodevelopment in young children. Eur J Pediatr 2019;178:473-81. 31. Granerod J, Davies NW, Ramanuj PP, Easton A, Brown DW, Thomas SL. Increased rates of sequelae post-encephalitis in individuals attending primary care practices in the United Kingdom: a population-based retrospective cohort study. J Neurol 2017;264:407-15. 32. Bissel SJ, Auer RN, Chiang CH, Kofler J, Murdoch GH, Nix WA, et al. Human parechovirus 3 meningitis and fatal leukoencephalopathy. J Neuropathol Exp Neurol 2015;74:767-77. 33. de Vries LS, Jongmans MJ. Long-term outcome after neonatal hypoxicischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2010;95: F220-4. 34. Gonzalez FF, Miller SP. Does perinatal asphyxia impair cognitive function without cerebral palsy? Arch Dis Child Fetal Neonatal Ed 2006;91: F454-9. 35. McClelland MM, Cameron CE. Developing together: the role of executive function and motor skills in children’s early academic lives. Early Childhood Res Q 2019;46:142-51. 36. Brennan LM, Shaw DS, Dishion TJ, Wilson MN. The predictive utility of early childhood disruptive behaviors for school-age social functioning. J Abnormal Child Psychol 2015;43:1187-99. 37. ten Braak D, Kleemans T, Størksen I, Verhoeven L, Segers E. Domain-specific effects of attentional and behavioral control in early literacy and numeracy development. Learning Individ Differ 2018;68:61-71. 38. Vandenbroucke L, Verschueren K, Baeyens D. The development of executive functioning across the transition to first grade and its predictive value for academic achievement. Learn Instr 2017;49:103-12. 39. Chinta S, Walker K, Halliday R, Loughran-Fowlds A, Badawi N. A comparison of the performance of healthy Australian 3-year-olds with the standardised norms of the Bayley Scales of Infant and Toddler Development (version-III). Arch Dis Child 2014;99:621-4. 40. Anderson PJ, De Luca CR, Hutchinson E, Roberts G, Doyle LW. Victorian Infant Collaborative Group. Underestimation of developmental delay by the new Bayley-III Scale. Arch Pediatr Adolesc Med 2010;164: 352-6.
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Funding and Conflicts of Interest Disclosure Funded in part by the Cerebral Palsy Alliance Grant (PG5616 [to C.J., P.B., K.W., H.S-S.]), Australian National Health and Medical Research Council (NHMRC) Centre for Research Excellence in Emerging Infectious Diseases (1079575 [to C.J. and P.B.]), NHMRC Early Career Fellowship (ECF) (1145817 [to P.B.]), NHMRC ECF (1144566 [to H.S-S.]), funding from the NHMRC Australasian Cerebral Palsy Clinical Trials Network (to H.S-S.), and Sydney Children’s Hospital Foundation Research Starter Grant (to B.M.). The Triple B Pregnancy Cohort Study was funded by NHMRC Project Grant (630517), and was financially supported by the National Drug and Alcohol Research Centre (NDARC), University of New South Wales (UNSW). The cohort is led by the National Drug and Alcohol Research Centre (NDARC) at UNSW Australia, the National Drug Research
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Institute (NDRI) at Curtin University, and the School of Psychology at Deakin University, in collaboration with the University of Sydney, the University of Queensland, the University of Canterbury, Christchurch, and the Murdoch Children’s Research Institute. NDARC and the National Drug Research Institute (NDRI), Curtin University of Technology are funded by the Australian Government under the Substance Misuse Prevention and Service Improvements Grants Fund. The study has also been supported by Australian Rotary Health (ARH; 2012-2013; 2018-2020), the Foundation for Alcohol Research and Education (FARE; 20102011), and the Financial Markets Foundation for Children (Australia) (2015-2016). Additionally, PhD candidates on the project have been funded through ARH; the NDARC Education Trust (NET) and the Australian Centre for Perinatal Science and NDARC, UNSW. The authors declare no conflicts of interest.
Table V. Developmental and behavioral outcomes in the HPeV cohort stratified by clinical syndrome at presentation and the presence of Central Nervous System (CNS) infection (HPeV detected in Cerebrospinal Fluid) Variables
Fever (n = 11)
Sepsis-like illness (n = 36)
Encephalitis (n = 3)
BSID-III Cognition Receptive language Expressive language Fine motor Gross motor CBCL Emotionally reactive Anxious/depressed Somatic complaints Withdrawn Sleep problems Attention problems Aggressive behavior Internalizing problems Externalizing problems Total problems Depressive disorders Anxiety disorders Autism spectrum disorder ADHD Oppositional defiant disorder
n = 10† 10.7 1.42 11.3 1.25 10.8 1.87 11.7 2.06 9.9 1.36 n=9 58.3 10.27 54.3 7.05 55.4 6.80 57.9 7.90 56.3 8.15 57.6 8.38 56.9 9.93 52.1 15.36 49 17.58 51.1 17.09 56.7 10.25 54.9 6.31 59.6 10.04 56.4 8.00 56.9 8.24
n = 36‡ 10.1 2.44 10.9 2.44 10.9 2.86 11.6 2.48 9.9 1.85 n = 27 52.1 4.02 51.7 3.72 53.0 5.60 53.3 6.19 51.9 2.98 53.5 7.26 52.2 4.58 43.8 10.72 45.3 10.04 44.0 9.75 53.3 4.58 51.4 3.25 53.4 5.88 52.8 5.54 52.5 4.64
n=3 9.3 0.58 11.0 1.00 10.7 2.08 10.3 1.53 9.0 2.00 n=3 56.3 10.97 50.7 1.15 55.0 8.66 57.7 13.28 57.7 8.62 59.7 8.74 53.3 5.77 43.3 21.46 49.3 13.58 49.3 17.90 57.3 11.02 57.7 13.28 59.7 16.74 53.0 3.61 52.3 2.52
P value Welch ANOVA*–fever/SLI 0.318 0.537 0.912 0.854 0.991 0.113 0.305 0.350 0.139 0.145 0.220 0.206 0.162 0.562 0.266 0.369 0.146 0.111 0.229 0.159
Confirmed CNS infection (n = 35) n = 33§ 10.4 2.00 11.3 1.71 10.9 2.44 11.7 1.98 9.7 1.98 n = 27 54.3 7.62 52.3 4.84 54 6.37 54.3 7.06 53.9 5.98 55.9 8.65 54.1 7.10 45.9 13.36 47.1 13.46 46.6 13.17 55.1 7.74 52.9 5.99 55.5 8.91 54.3 6.87 54.1 6.44
Values are mean SD unless otherwise noted. *Between-group differences were calculated for children with HPeV who had a clinical classification of fever and SLI, a Welch ANOVA was used owing to unequal sample sizes and violation of homogeneity of variances. †n = 9 in gross motor domain. ‡n = 35 in both receptive and expressive language domains, n = 34 in gross motor domain. §n = 32 in receptive and expressive language domains, and gross motor domain.
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