Human parechovirus (HPeV) is a small nonenveloped RNA virus within the genus Parechovirus, in the virus family Picornaviridae that also include a number of other animal and human picornaviruses such as human enteroviruses. To date, 19 genotypes of HPeV have been identified.1 HPeV typically infects young children younger than 2 years and infection is often asymptomatic,2,3 although the rate at which disease versus asymptomatic infection occurs is uncertain. By 2 years of age, greater than 90% of children have antibodies to at least one of the HPeV types.4,5
HPeV type 3 (HPeV3) is associated with more severe clinical manifestations than other HPeV types, including central nervous system infection, and a sepsis-like syndrome, particularly affecting young infants.6–11 Surveillance and testing from several countries suggests there is a 2- or 3-year cycle between outbreaks of HPeV3.7,9,12 The first documented Australian outbreak of HPeV3 occurred in the spring and summer of 2013–2014, initially reported in young infants in and around Sydney in New South Wales (NSW)8,13 and subsequently from other states.14,15 A second epidemic occurred in 2015–2016,16,17 following which it was determined that these 2 epidemics had been predominantly caused by a novel recombinant HPeV3 that had emerged sometime between 2012 and 2013.16,18 A third large-scale national epidemic, the largest recorded HPeV epidemic reported globally to date,19 occurred in 2017–2018, again caused predominantly by the recombinant Australian HPeV3 strain.19,20
This study was undertaken to define the scope and burden of disease associated with the 2017–2018 HPeV outbreak in NSW using laboratory testing data.
Laboratory diagnosis of HPeV infection is usually made by nucleic acid testing of cerebrospinal fluid, gastrointestinal and/or respiratory tract samples using HPeV-specific real-time polymerase chain reaction (PCR). At the time of the 2017/2018 outbreak, HPeV-specific PCR testing using various commercially available kits targeting the 5′ untranslated region (Parechovirus R-GENE, bioMérieux, Marcy l’Etoile, France21 and Paediatric Respiratory Pathogens [16 well], AusDiagnostics, Mascot, Australia) was available at the public laboratories based at, or linked to, the 3 tertiary level pediatric hospitals in NSW—the Children’s Hospital at Westmead (CHW), Sydney Children’s Hospital (SCH; NSW Health Pathology, SEALS, Randwick) and John Hunter Hospitals (JHH). Approximately, 19% of all emergency department presentations, and 33% of inpatient admissions for children 0–16 years of age in NSW occur at these pediatric hospitals.22 HPeV testing using an in-house assay targeting the 5′ untranslated region, modified from a previously published method,23 was also available at the Institute for Clinical Pathology and Medical Research, Westmead Hospital during the study period, which together with the 3 laboratories above, provided HPeV PCR testing upon referral for residents in NSW (population approximately 1.47 million less than 15 years of age, with around 497,000 less than 5 years of age).20 These 4 laboratories provided data regarding HPeV PCR tests performed from July 1, 2017 to June 30, 2018 (Fig. 1).
Partially deidentified samples that were obtained within a week of each other and had matching date of birth, sex and postcode were imputed as being from the same case. Test results from samples that met the above criteria and were taken from the same anatomic site, at the same time were assumed to be duplicate tests of the same sample. All duplicate samples were removed from analysis (Fig. 1). “Cases” where matching date of birth, sex and postcode occurred on samples taken between 8 and 28 days apart were assumed to be “representations” of the same illness in the same individual. These presumed “representations” were included as separate cases for all analyses, with the exception of determining gender ratios and estimates of population incidence where each individual was only counted once. Pediatric cases were defined as those in children less than 15 years of age. Limited demographic and clinical data were obtained from the laboratory and respective hospital electronic medical records for all laboratory test-positive cases that presented to each of the pediatric hospitals (CHW, SCH and JHH). The study was approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee as an amendment of an ongoing larger study on the molecular epidemiology of picornaviruses (reference LNR/14/SCHN/528).
Data were collected and analyzed using Microsoft Excel 2019, with mapping performed in Microsoft Excel 365. Proportions between groups were compared using the Chi-squared test and continuous, and nonparametric data were compared using the Mann-Whitney U test. Estimates of population incidence of laboratory confirmed HPeV infection in children were calculated and annualized using census data from the Australian Bureau of Statistics for persons residing in NSW (2018 mid-year estimate).24 The average cost of admission per case of laboratory confirmed HPeV infection requiring hospitalization was calculated based on the average length of stay (LOS) in hospital, and the average LOS in intensive care unit (ICU) for the children in this cohort where information was available, and the current cost of admission to hospital per day for a nonsurgical patient in either CHW or SCH to a general ward (AUD$1275) or to the ICU (AUD$3640).25
In total 16,405 HPeV PCR tests were performed during the 12-month study period, of which 581 (3.5%) were positive. Testing at CHW, SCH and the Institute for Clinical Pathology and Medical Research was performed ad hoc, at the discretion of treating clinicians, throughout the study period. However, in August 2017, a multiplex PCR assay was introduced in JHH for tests on all respiratory samples, which included HPeV as a target together with multiple other respiratory pathogens [Paediatric Respiratory Pathogens (16 well), AusDiagnostics]. Excluding JHH tests, 2553 HPeV PCR tests were performed at the 3 other testing centers, of which 399 were positive (15.6%), and this includes 352 of 1419 (24.8%) tests performed during main HPeV epidemic of September 2017–January 2018 (further details below). In comparison, the rate of HPeV test-positivity during the whole study period at JHH was 1.3% (182/13,853), and outside of the main HPeV epidemic, once the multiplex respiratory assay had been introduced, was 57/7727 (0.7%).
Five hundred eighty-one HPeV-positive samples obtained from 395 cases during the study period were included in the analysis (Fig. 1). “Cases” included 5 children with presumed representations (one representation for each child) and 7 individuals ≥15 years of age. Cases were widely distributed in NSW, broadly reflecting the population density throughout the region, including throughout metropolitan Sydney (Fig. 2). The majority of pediatric cases were male (221/383; 58%).
The peak of the outbreak occurred in late November 2017 (approximately 35 new cases each week), with the main HPeV epidemic occurring between the spring and summer months of September 2017 to January 2018 (Fig. 3). However, the spring-early summer seasonality seen throughout NSW was observed primarily in infants younger than 12 months. Among the 53 cases that occurred in children older than 12 months, a steady low number of cases were seen throughout the year with a small peak during the main HPeV epidemic (Fig. 3).
Among the 388 pediatric cases, the great majority were infants younger than 12 months (335; 86%), with almost half younger than 2 months (188; 47%). Only 10 were children older than 2 years (7 of whom were 2–3 years of age). Of these 10 children, 7 cases were identified at JHH through multiplexed PCR testing of respiratory samples. Of 328, 192 (58.5%) pediatric cases where clinical data were available from medical records were admitted to hospital. The median LOS was 3 days [interquartile range (IQR) 2–4 days; mean 3.9 days]. Of 186, 34 (18.3%) admissions were admitted to ICU, with a median LOS in ICU of 3 days (IQR 1.75–5 days; mean 4.1 days). The age distribution of pediatric cases according to hospitalization and seasonality is provided in Table 1. Among hospitalized children, those admitted to ICU were significantly younger than those not admitted to an ICU. In addition, children with HPeV infection occurring during the epidemic were significantly younger than cases occurring outside of the main HPeV epidemic.
The annualized estimate of the incidence of laboratory confirmed HPeV infection in children was 142.4 cases per 100,000 population <5 years of age during the 2017–2018 epidemic spanning 5 months; a 5.1-fold increase compared with the incidence during interepidemic periods (27.7 cases per 100,000 population <5 years of age). The respective incidence rates for hospitalized cases of HPeV infection were 71.5 cases per 100,000 population <5 years of age during the epidemic and 13.5 cases per 100,000 population <5 years of age during interepidemic periods (5.3-fold increase).
The average cost of admission per case of laboratory confirmed HPeV infection requiring hospitalization was AUD$4976, with an additional cost of $14,788 for each case admitted to ICU. The crude estimate of the total direct hospitalization costs for all of the reported cases in this outbreak is AUD$898,109.
The largest recorded outbreak of HPeV occurred in Australia in late 2017-early 2018. This was the third national epidemic to occur in Australia since 2013, where HPeV outbreaks tend to be larger than those observed in other countries and associated with worse clinical outcomes.19 This may in part be related to greater virulence associated with the recombinant Australian HPeV3 virus that appears to be the predominant strain responsible for these 2-yearly outbreaks, and probably first appeared sometime between 2012 and 2013.16,20 In NSW, the most populous state in Australia, 395 cases of HPeV infection were detected in a 12-month period from July 2017 to June 2018 from the laboratories that provide almost all of the HPeV testing services for the state. Spring and early summer seasonality was observed, predominantly among infants younger than 12 months, although there appeared to be a 4-week later start to the outbreak in areas outside of metropolitan Sydney (northern NSW).
Our data suggest a very large burden of disease caused by HPeV infections in children, particularly during epidemics, and provide for the first time to our knowledge, an estimate of the incidence of laboratory confirmed HPeV infection in children. The annualized incidence in NSW during the epidemic of 2017–2018 was approximately 142.4 cases per 100,000 children younger than 5 years, with a hospitalization rate of 71.5 cases per 100,000 children younger than 5 years. In comparison, in 2018, in Australia, the incidence for children younger than 5 years of various nationally notifiable diseases was 4.6 per 100,000 for invasive meningococcal disease, 19.5 per 100,000 for invasive pneumococcal disease, 97.2 per 100,000 for pertussis and 433.2 per 100,000 for laboratory confirmed influenza.26 Although our data are largely limited to cases presenting to hospital, among these, more than half (58.5%) required hospital admission, and almost one-fifth (18.3%) of hospitalized children required an ICU admission resulting in a significant direct cost to the healthcare system during the HPeV epidemic. In addition, the rapid and dramatic increase (over 5-fold) in the incidence of infection, including those requiring admission to hospital, from the interepidemic to epidemic periods posed a considerable burden on pediatric ICU services in the state during the main HPeV epidemic.
Although typing of viruses was not undertaken in the current study, a small number of strains from this NSW outbreak were sequenced as part of another study20 and most viruses from the epidemic period were confirmed to be the recombinant Australian HPeV3 virus with one additional HPeV3 lineage detected in 2 cases.20 Interestingly, in that study, a small number of HPeV1 strains were detected between March and May 2017 and from late January to May 2018, periods before and following the HPeV3 epidemic. The majority of HPeV3 cases occurred in infants less than 3 months of age, while HPeV1 cases were seen in infants older than 3 months.20 Surveillance in other countries also suggests that nontype 3 HPeV circulate continuously among children in the community, while HPeV3 tends to occur as 2–3 yearly epidemics,7,9,12 often associated with more severe clinical signs in young infants.6–11 These observations align with much of the data drawn from the current study in which interepidemic cases of HPeV infection tended to occur in older children (median age older than 7 months) compared with epidemic cases that occurred in much younger children (median age younger than 2 months). The increased susceptibility of neonates and young infants to epidemic HPeV may be related to lower rates of HPeV3-specific antibodies in adults, particularly in women of childbearing age, although a recent serosurvey demonstrated a high prevalence of HPeV3-specific neutralizing antibody in the Australian population.27 It should be noted though that no protective threshold of antibody has been determined for HPeV infection or disease.
In the current study, the small number of cases that occurred in children older than 12 months (53 of 388 pediatric cases) occurred at a steadier rate throughout the year with only a small peak during the epidemic, and may represent background circulation of HPeV1 virus. HPeV1 infections are on average less severe than HPeV3 infections,2,6,10–12 and the relatively small number of cases presenting to hospital and tested outside of the HPeV epidemic in this study may not reflect the frequency of infection or the range of clinical presentations seen at a community level.
The introduction in August 2017 of a multiplexed PCR assay which includes a PeV target among a large panel targets for routine testing of respiratory samples at JHH, reflects a different testing paradigm compared with the situation at the other laboratories and hospitals where “specific” HPeV tests were requested by clinicians. Although our data did not include detailed clinical information for each case, the test-positive rate for HPeV testing requested during the epidemic months at the 3 study sites that performed “specific” HPeV testing was almost 25%, which suggests clinicians had a high suspicion of HPeV infection based on the presentation of cases. In contrast the low overall positivity rate of HPeV PCR tests performed at JHH (1.3%), as well as the very low test-positivity outside of the main HPeV epidemic (0.7%) suggests that a small number of additional cases may be picked up using a “general” testing paradigm, and these may represent milder, nonspecific illness which may be caused by non-HPeV3 types.
The retrospective nature of this study is an important limitation that does not allow assessment of children presenting with a clinically compatible illness where testing was not requested. This may have occurred due to a lack of awareness about the need and/or the lack of availability of HPeV PCR tests for general pediatricians in smaller centers or general practitioners in the community. In addition, we are not able to exclude HPeV testing being performed in private or community laboratories using commercially available kits; thus, our population incidence rates are likely a minimum estimate. Furthermore, only limited clinical data were available for the majority of cases because the data were primarily drawn from laboratory databases. As such, it was difficult to compare clinical syndromes and presentations occurring during epidemic and interepidemic periods, and in different age-groups, and we were unable to fully assess for other coinfections and their role in disease presentations. Overall, hospitalization frequency and health system burden may also have been underestimated as we did not have access to information regarding admissions to hospitals other than the pediatric hospitals included in this study.
More research on the burden and spectrum of HPeV disease in the community and its epidemiology in Australia is warranted, including assessment of risk factors for transmission such as family structure and daycare attendance. Parechovirus is not a nationally notifiable in disease in Australia; however, this and other reports on the outbreaks since 2013 highlight the need for more comprehensive national surveillance of HPeV infections to better define the infection and disease burden and to evaluate strategies and interventions to prevent transmission and improve case management.
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