Severe Human Parechovirus Infections in Infants and the Role of Older Siblings.

Human parechovirus (HPeV) infections can cause sepsis and meningoencephalitis in infants. To improve our knowledge of the consequences of HPeV infections in young children, the incidence, clinical spectrum, and short-term outcome among infants infected with HPeV were investigated retrospectively. The presence of HPeV RNA was investigated by polymerase chain reaction in cerebrospinal fluid from 327 children aged 0 to 12 months sampled between 2014 and 2017. Eighty-one were infected with HPeV and included in the study. These infants were divided into 3 groups based on clinical assessment: HPeV was the presumed cause of disease (n = 35); HPeV could have contributed to or been considered the cause of disease (n = 24); and HPeV was not considered the cause of disease (n = 22). Infection with HPeV type 3 was common in all groups (n = 54), and most children were younger than 3 months (n = 63). The children in the first group (HPeV as presumed cause) had meningoencephalitis (n = 20), viral sepsis (n = 9), or non-severe viral infection (n = 6). The youngest were more prone to develop meningoencephalitis, while the slightly older children had symptoms of viral sepsis or nonsevere viral infection (P < .05). Eleven had symptom onset within 2 days after birth. Two infants diagnosed with sudden infant death syndrome were HPeV infected when tested postmortem. HPeV infections were identified in 25% of children with suspected central nervous system infection. The clinical presentation of those infected with HPeV varied with age. HPeV infections may be associated with sudden infant death syndrome, although this is not well studied. The results suggest that HPeV infections may be underdiagnosed in young infants.

Infections with human parechoviruses (HPeVs) are highly prevalent, particularly in neonates, where they may cause substantial morbidity and mortality. The clinical presentation of HPeV infection in neonates is indistinguishable from that of enterovirus (EV) infection and may vary from mild disease involving gastrointestinal and/or respiratory symptoms to more severe illness with sepsis‐like symptoms such as fever, seizures, irritability, rash and/or feeding problems. HPeV is among the most common single causes of aseptic meningitis/meningoencephalitis in infants &lt;90 days old worldwide. The mainstay of diagnosis for HPeV infections involves the use of molecular diagnostic techniques for detection of virus RNA (ribonucleic acid) in various materials (e.g. faeces, cerebrospinal fluid (CSF), nasopharyngeal, bronchial and autopsy materials). Despite the relatedness of HPeV and EV both at the genomic and clinical presentation levels, routine nucleic acid detection methods for EV will not detect HPeV. Laboratory diagnosis of these viral infections is important not only for differential diagnostic purposes and determining a patient's prognosis but also for guidance of clinical management. Clinical disease varies somewhat among genotypes; while HPeV1 mostly causes gastrointestinal illness, HPeV3 prominence is due to sepsis syndromes and central nervous system (CNS) infections in preterm and term infants. Of diagnostic importance, HPeV3 CNS infections usually lack CSF pleocytosis, and despite ‘unremarkable’ CSF, HPeV3 RNA can be amplified from CSF, nasopharyngeal and rectal swabs in an infected individual. Taking the global incidence of reported laboratory‐confirmed HPeV cases into consideration, mortality and sequelae are overall uncommon and usually accompanying initially severe or neurologically complicated acute illnesses. However, underreporting due to lack of testing and/or appropriate diagnostic methodology likely means gross underestimation of the true incidence of HPeV disease. Currently, neither effective treatment nor vaccines are available in the control of these common viruses with the potential to cause severe harm in neonates and young children worldwide. Key Concepts HPeV infections are common among infants and children worldwide. HPeV infections are underdiagnosed, and HPeV disease burden underestimated. Nineteen HPeV types identified so far – their role/significance in human infections unclear except for HPeV3. HPeV3 is a major cause of neonatal infections including severe meningoencephalitis. Genomic differences between EV and HPeV. Diagnostics: HPeV required specific PCR for detection, not that easy to culture. Majority of children with HPeV3 infection lack pleocytosis in CSF/have normal CSF. Having older siblings are associated with higher risk for an infant to be hospitalised with severe HPeV infection. HPeV infection should always be ruled out when caring for infants with sepsis‐like illness and/or CNS infection.

From December 1987 through August 2004, lung tissue, nasopharyngeal swabs, and colon swab specimens obtained during 1263 autopsies of infants and young children were examined to assess the role of viruses in deaths of children aged <2 years. Multiple cell cultures were used to isolate viruses. With 4 exceptions, virus isolates were identified by neutralization, immunofluorescence assay, or enzyme immunoassay. RNA extracted from these 4 isolates and associated autopsy specimens was tested using parechovirus-specific real-time polymerase chain reaction (RT-PCR) and sequencing assays. Specimens from 426 (34%) autopsies were positive for at least 1 virus; enteroviruses and adenoviruses were the most commonly identified. Human parechoviruses (HPeVs) were identified antigenically in isolates from 18 decedents (all HPeV type 1) and by RT-PCR in isolates and multiple autopsy specimens from 4 decedents with untypeable virus isolates. Sequencing of the VP1 region identified these 4 HPeVs as HPeV type 3 (n = 3) and HPeV type 6 (n = 1). Despite the detection of HPeV, the deaths of decedents 3 and 4 were determined to have been from noninfectious causes. These are the first confirmed HPeV type 3 and HPeV type 6 detections in the United States. This is also the initial report of fatal cases with associated HPeV type 3 infection. These results support prior findings associating HPeVs with serious disease in young children. Clinical testing for HPeVs and routine HPeV surveillance by public health laboratories will help determine the burden of disease caused by HPeVs.

Early Life Parechovirus Infection Neurodevelopmental Outcomes at 3 Years: A Cohort Study

Parechoviruses are small, non-enveloped, icosahedral-shaped capsid viruses belonging to the Picornaviridae family. They are characterized by a single-positive-strand genomic RNA and as others RNA viruses have a great potential for genetic variation, the rapid evolution and adaptation. Genus Parechovirus has been established in the 90s and currently, 19 types of human parechoviruses (HPeV) are discovered. They usually cause mild respiratory or gastrointestinal illness, mainly in young children, but also can cause severe diseases such as encephalitis, meningitis, myocarditis, acute flaccid paralysis and sepsis. Severe HPeV infections in infants are also associated with a risk of long-term complications. Although it is known that HPeV plays a significant role in severe pediatric diseases, routine diagnostics are not performed in clinical practice. No antiviral drugs have been approved for the treatment of HPeV infections, and only symptomatic treatment is available. Increased detection of human parechovirus infection in infants and connection of serious clinical complication with parechovirus infection was the reason why surveillance was established in some countries, while the worldwide extensive surveillance needs to be performed in order to monitor prevalence, genetic diversity, and clinical significance of HPeV. Although the first HPeV strains were discovered 6 decades ago, recognition of HPeV biology, epidemiology, evolution and pathogenicity still requires more research to appreciate the risk for public health that these small viruses can be. 1. Introduction. 2. Classification, structure and replication. 3. Cellular receptors and HPeV variability. 4. Course of infection 5. HPeV types in the world 6. Diagnosis 7. Pathogenesis 8. Summary

Sepsis-like illness is a main cause for hospital admission in young infants. Our aim was to investigate incidence, epidemiology and clinical characteristics of enterovirus (EV) and human parechovirus (HPeV) infections in young infants with sepsis-like illness. This is a prospective observational cohort study in which infants younger than 90 days of age, presenting with sepsis-like symptoms in a secondary care children's hospital, underwent a full sepsis work-up. Clinical signs and infectious indices were recorded. EV or HPeV RNA was detected by polymerase chain reaction in plasma and/or cerebrospinal fluid (CSF). Infants were diagnosed with EV, HPeV, fever of unknown origin or severe infection. EV and HPeV were detected in 132 of 353 (37%) and 52 of 353 (15%) of cases, respectively. EV and HPeV have distinct seasonability. Some differences in clinical signs and symptoms occurred between children with EV and HPeV infection but were of limited clinical value. CSF pleocytosis occurred in 44% of EV positive infants, and only in 13% of those with HPeV infection. EV and HPeV infections are major causes of sepsis-like illness in infants < 90 days of age. Neither clinical characteristics nor laboratory indices were predictive for EV/HPeV infection. CSF pleocytosis occurs, but not in all patients. Testing for EV and HPeV in all young infants with sepsis-like illness is strongly advised.

BackgroundSevere manifestations of human parechovirus (HPeV) infection, including meningoencephalitis and sepsis, can occur in neonates and young infants. Death has rarely been reported. Rates of HPeV infection fluctuate from year to year in the community. After the home isolation during the initial COVID-19 era in 2020, waves of respiratory viral outbreaks at unusual times of the year were identified in the pediatric community in 2021 and 2022, including increased number of cases of severe HPeV infection in young infants. This study characterizes the U.S. outbreak of HPeV infections that occurred in newborns and young infants in 2022.MethodsA multi-site, retrospective and prospective observational study identified hospitalized infants < =6 months, with a body fluid specimen positive for HPeV. IRB approval of a single protocol was obtained at each site. Data obtained included hospital summary, maternal and birth history, medications, bacterial and viral testing, and radiology results. Analysis included infants with hospitalizations from January 1 through December 31, 2022.Results13 academic sites were enrolled, which included 8 sites achieving full IRB approval/activation and completed data collection, and 5 sites pending activation [Fig 1A]. Interim analysis shows 112 infants across eleven states hospitalized with HPeV infection with a median hospital duration of 3 days (range 0-178 d), peaking in May 2022 [Fig 1B], with a spectrum of biochemical markers [Table 1]. The median age at hospitalization was 21.5 days of life (IQR 10, 32 d). All but five infants received antibiotics during the admission, and more than half (54%) received acyclovir. Other pathogens were rarely reported [Table 2]. 45 (38%) infants received MRI brain imaging during hospitalization of which 29 were abnormal; 10 reports directly mentioning HPeV in the interpretation. A total of 51 EEGs were completed in 31 infants; 20 infants (18%) had seizures reported. 17 infants required anticonvulsants. Two infants died.ConclusionWe report the first multi-site, clinical description of the 2022 U.S. outbreak of HPeV among neonates and young infants. This is the first large series of infants with HPeV to report mortality. Further development of a multi-site U.S. collaboration to improve surveillance for HPeV is needed.DisclosuresLaura Filkins, PhD, Avsana Labs: Board Member|Avsana Labs: Stocks/Bonds|Biofire Diagnostics: Grant/Research Support Claudia M. Espinosa, MD, MSc, AstraZeneca: Grant/Research Support|Enanta: Grant/Research Support|Jansen and Jansen: Advisor/Consultant|Kentucky Rural Health Association: Honoraria|Merck: Grant/Research Support|Sanofi: Advisor/Consultant|Sanofi: Grant/Research Support|Sanofi: Honoraria|Sobi: Dinner Joseph A. Bocchini, Jr., MD, Avalere: Advisor/Consultant|Enanta: Site PI on multicenter clinical trials, contract with employer|Moderna: Advisor/Consultant|Novavax: Sub-I on multicenter clinical trials, contract with employer|Pfizer: Advisor/Consultant|Pfizer: Site PI on multicenter clinical trials, contract with employer|Regeneron: Site PI on multicenter clinical trials, contract with employer|Sobi: Advisor/Consultant|Valneva: Advisor/Consultant Roberto P. Santos, MD, MSCS, Eli Lilly (SARS-CoV-2, baricitinid) - Site Open for Enrollment on March 8, 2023: Industry-sponsored clinical trials with research contract awarded to the University of Mississippi Medical Center with RPS as site PI|Eli Lilly (SARS-CoV-2, LY3819253, LY3832479) - study discontinuation on January 3, 2022: Industry-sponsored clinical trials with research contract awarded to the University of Mississippi Medical Center with RPS as site PI|JNJ (RSV, rilematovir) - study discontinuation on March 1, 2022: Industry-sponsored clinical trials with research contract awarded to the University of Mississippi Medical Center with RPS as site PI|MSD (HIV, islatravir, doravirine) - study discontinuation on December 6, 2022: Industry-sponsored clinical trials with research contract awarded to the University of Mississippi Medical Center with RPS as site PI Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, FAAM, Abbott: Honoraria|Altona Diagnostics: Grant/Research Support|Baebies Inc: Advisor/Consultant|BioMerieux: Advisor/Consultant|BioMerieux: Grant/Research Support|Bio-Rad: Grant/Research Support|Cepheid: Grant/Research Support|GSK: Advisor/Consultant|Hologic: Grant/Research Support|Lab Simply: Advisor/Consultant|Luminex: Grant/Research Support David W. Kimberlin, MD, Gilead: Grant/Research Support|Gilead: I served as site PI on Gilead's study of remdesivir in pediatric patients. All monies went directly to my university and not to me.

Enteroviruses (EVs) and human parechoviruses (HPeVs) are small, non-enveloped RNA viruses in the Picornaviridae family, which are known or suspected to cause a spectrum of clinical manifestations in humans. Although most infected persons are asymptomatic, mild presentations can include respiratory infections, herpangina, and hand, foot, and mouth disease. Among the more severe syndromes associated with EV and HPeV infection are acute flaccid paralysis, meningitis, encephalitis, myocarditis, and sepsis. Neonates and infants are at higher risk for infection and for severe clinical outcomes than older children or adults (1–3). As of August 2015, a total of 16 HPeV types and 118 EV types (within four EV species known to infect humans: A, B, C, and D) had been identified, and the spectrum of illness caused differed among virus types (4). To describe trends in EV and HPeV circulating in the United States during 2009–2013, CDC summarized detections reported through two surveillance systems. The most commonly reported types of EV and HPeV during this period were coxsackievirus (CV) A6 and HPeV3. The large number of CVA6 detections likely reflected an increase in testing in response to an outbreak of severe hand, foot, and mouth disease in late 2011 and 2012 (5). Most HPeV3 detections originated from a single hospital that routinely tested for HPeV (6). Clinicians and public health practitioners should consider the EV and HPeV types recently circulating in the United States to inform diagnostic and surveillance activities. When EV and HPeV typing is performed, clinical and public health laboratories should routinely report their results to improve the reliability and generalizability of surveillance data.

Severity of parechovirus infections in infants under 3 months of age and comparison with enterovirus infections: A French retrospective study

IntroductionEnterovirus (EV) or Human Parechovirus (HPeV) infections are common causes of sepsis-like illness in young children. We investigated differences in incidence, clinical characteristics and management of EV and HPeV infections...

Human parechoviruses (HPeVs) within the large and growing family of Picornaviridaeare common human pathogens associated with a wide spectrum of disease presentations. Although 10 different HPeV types have been published to date, there is increasing evidence for a specific role of HPeV type 3 (HPeV3) in severe neonatal disease. In this review, we will describe both the disease associations and underlying epidemiological and/or biological basis for the often marked differences in disease outcomes between HPeV types. Application of molecular-based diagnostic techniques has revealed an association between neonatal sepsis, encephalitis and hepatitis with HPeV3 but not with other parechovirus types. HPeV3 shows evidence for very recent emergence in human populations as well as inferred differences in cellular receptor usage. The recently discovered HPeV3 has been shown to play an important role in severe neonatal infections, observations possibly linked to its very recent emergence or possibly different cellular tropism that underlie its targeting of the most susceptible individuals. HPeV infections are currently under-diagnosed and should be considered in the clinical and diagnostic evaluation of severe neonatal disease presentations.

Human parechovirus infections, Lyon, France, 2008–10: Evidence for severe cases

Severe human parechovirus type 3 myocarditis and encephalitis in an adolescent with hypogammaglobulinemia

Human parechovirus (HPeV) is a leading cause of Central Nervous System (CNS) infection in infancy. Despite this, little is known regarding the long-term neuropsychological impacts from HPeV infection. The aim of the present study was to explore the long-term neuropsychological impacts eight-year post-HPeV infection contracted during infancy. This study also aimed to investigate the differential impacts of HPeV itself compared to the effects of secondary meningitis (n = 23) or encephalitis (n = 3) associated with HPeV infection. Thirty-nine HPeV children participated in the study. Children completed performance-based measures of neuropsychological and language functioning (the Wechsler Abbreviated Scale of Intelligence, the Clinical Evaluation of Language Fundamentals – Fourth Edition, and the Test of Everyday Attention for Children). Parents completed questionnaire-based measures of emotional, behavioral, and pragmatic language functioning (the Behaviour Rating Inventory of Executive Functioning, the Child Behavior Checklist, and the Social Communication Questionnaire). Results revealed that, overall, children with HPeV were significantly more impaired on measures of selective, sustained, and divided attention compared to normative test populations. The current study incidentally found at least double the prevalence of Attention-Deficit/Hyperactivity Disorder (ADHD) in the HPeV sample than what is typical in the normal population, suggesting that HPeV infection during infancy may be a risk factor for the later development of ADHD. Additionally, the presence of secondary meningitis or encephalitis did not relate to poorer neuropsychological outcomes in the current sample. The findings of this study have important implications regarding clinical management for children following HPeV infection in infancy.

PCR detection rates for serum and cerebrospinal fluid from neonates and young infants infected with human parechovirus 3 and enteroviruses.