First parechovirus reported case in Saudi Arabia in hospitalized immunocompromised adult patient.

Human parechovirus, a member of the Picornaviridae family (PeVs), can lead to severe infections, including severe meningitis, meningoencephalitis, and sepsis-like syndrome. We report a case of human parechovirus-related encephalitis in a 52-year-old woman diagnosed with glioblastoma multiforme. She underwent surgical resection in June 2022. Unfortunately, her disease recurred, and she underwent a second resection in August 2022, followed by radiation therapy and Temozolomide therapy. She presented to the hospital with acute confusion followed by seizures, necessitating intubation for airway support. A cerebrospinal fluid (CSF) sample was obtained and processed using the Biofire FilmArray, which reported the detection of HSV-1. Despite being on Acyclovir, the patient did not show signs of improvement. Consequently, a second CSF sample was obtained and sent for next-generation sequencing (NGS), which returned a positive result for Parechovirus. In this presented case, the patient exhibited symptoms of an unknown infectious cause. The utilization of NGS and metagenomic analysis helped identify Parechovirus as the primary pathogen present, in addition to previously identified HSV. This comprehensive approach facilitated a thorough assessment of the underlying infection and guided targeted treatment. In conclusion, the application of NGS techniques and metagenomic analysis proved instrumental in identifying the root cause of the infection.

Early Neonatal Presentation and Neuroimaging of Parechovirus Meningoencephalitis in a Preterm Baby: A Case Report.

Neonatal meningoencephalitis caused by human parechovirus infection is being increasingly recognized in recent literature. While most cases are postnatally acquired, intrauterine infection is rare, presents early and has a more severe impact on brain health and development. We discuss here an infant born preterm at 34 weeks gestational age, with neonatal course remarkable for severe encephalopathy presenting on day 2 of life due to human parechovirus meningoencephalitis transmitted in utero. Early magnetic resonance brain imaging detected extensive white matter injury and subsequently evolved into multicystic leukoencephalopathy. Posthospital discharge, infant was noted to have early neurodevelopmental impairment at 4 months corrected age.

MYADM binds human parechovirus 1 and is essential for viral entry.

Human parechoviruses (PeV-A) are increasingly being recognized as a cause of infection in neonates and young infants, leading to a spectrum of clinical manifestations ranging from mild gastrointestinal and respiratory illnesses to severe sepsis and meningitis. However, the host factors required for parechovirus entry and infection remain poorly characterized. Here, using genome-wide CRISPR/Cas9 loss-of-function screens, we identify myeloid-associated differentiation marker (MYADM) as a host factor essential for the entry of several human parechovirus genotypes including PeV-A1, PeV-A2 and PeV-A3. Genetic knockout of MYADM confers resistance to PeV-A infection in cell lines and in human gastrointestinal epithelial organoids. Using immunoprecipitation, we show that MYADM binds to PeV-A1 particles via its fourth extracellular loop, and we identify critical amino acid residues within the loop that mediate binding and infection. The demonstrated interaction between MYADM and PeV-A1, and its importance specifically for viral entry, suggest that MYADM is a virus receptor. Knockout of MYADM does not reduce PeV-A1 attachment to cells pointing to a role at the post-attachment stage. Our study suggests that MYADM is a multi-genotype receptor for human parechoviruses with potential as an antiviral target to combat disease associated with emerging parechoviruses.

Parechovirus infection in human brain organoids: host innate inflammatory response and not neuro-infectivity correlates to neurologic disease.

Picornaviruses are a leading cause of central nervous system (CNS) infections. While genotypes such as parechovirus A3 (PeV-A3) and echovirus 11 (E11) can elicit severe neurological disease, the highly prevalent PeV-A1 is not associated with CNS disease. Here, we expand our current understanding of these differences in PeV-A CNS disease using human brain organoids and clinical isolates of the two PeV-A genotypes. Our data indicate that PeV-A1 and A3 specific differences in neurological disease are not due to infectivity of CNS cells as both viruses productively infect brain organoids with a similar cell tropism. Proteomic analysis shows that PeV-A infection significantly alters the host cell metabolism. The inflammatory response following PeV-A3 (and E11 infection) is significantly more potent than that upon PeV-A1 infection. Collectively, our findings align with clinical observations and suggest a role for neuroinflammation, rather than viral replication, in PeV-A3 (and E11) infection.

Clinical course and peculiarities of Parechovirus and Enterovirus central nervous system infections in newborns: a single-center experience.

Parechovirus (HpEV) and Enterovirus (EV) infections in children mostly have a mild course but are particularly fearsome in newborns in whom they may cause aseptic meningitis, encephalitis, and myocarditis. Our study aimed to describe the clinical presentations and peculiarities of CNS infection by HpEV and EV in neonates. This is a single-center retrospective study at Istituto Gaslini, Genoa, Italy. Infants aged ≤ 30 days with a CSF RTq-PCR positive for EV or HpEV from January 1, 2022, to December 1, 2023, were enrolled. Each patient's record included demographic data, blood and CSF tests, brain MRI, therapies, length of stay, ICU admission, complications, and mortality. The two groups were compared to identify any differences and similarities. Twenty-five patients (15 EV and 10 HpEV) with a median age of 15 days were included. EV patients had a more frequent history of prematurity/neonatal respiratory distress syndrome (p = 0.021), more respiratory symptoms on admission (p = 0.012), and higher C-reactive protein (CRP) levels (p = 0.027), whereas ferritin values were significantly increased in HpEV patients (p = 0.001). Eight patients had a pathological brain MRI, equally distributed between the two groups. Three EV patients developed myocarditis and one HpEV necrotizing enterocolitis with HLH-like. No deaths occurred.  Conclusion: EV and HpEV CNS infections are not easily distinguishable by clinical features. In both cases, brain MRI abnormalities are not uncommon, and a severe course of the disease is possible. Hyper-ferritinemia may represent an additional diagnostic clue for HpEV infection, and its monitoring is recommended to intercept HLH early and initiate immunomodulatory treatment. Larger studies are needed to confirm our findings. What is Known: • Parechovirus and Enteroviruses are the most common viral pathogens responsible for sepsis and meningoencephalitis in neonates and young infants. • The clinical course and distinguishing features of Parechovirus and Enterovirus central nervous system infections are not well described. What is New: • Severe disease course, brain MRI abnormalities, and complications are not uncommon in newborns with Parechovirus and Enteroviruses central nervous system infections. • Hyper-ferritinemia may represent an additional diagnostic clue for Parechovirus infection and its monitoring is recommended.

The evolutionary phylodynamics of human parechovirus A type 3 reveal multiple recombination events in South Korea.

Human parechovirus A (HPeV-A) is a causative agent of respiratory and gastrointestinal illnesses, acute flaccid paralysis encephalitis, meningitis, and neonatal sepsis. To clarify the characteristics of HPeV-A infection in children, 391 fecal specimens were collected from January 2014 to October 2015 from patients with acute gastroenteritis in Seoul, South Korea. Of these, 221/391 (56.5%) HPeV-A positive samples were found in children less than 2 years old. Three HPeV-A genotypes HPeV-A1 (117/221; 52.94%), HPeV-A3 (100/221; 45.25%), and HPeV-A6 (4/221; 1.81%) were detected, among which HPeV-A3 was predominant with the highest recorded value of 58.6% in 2015. Moreover, recombination events in the Korean HPeV-A3 strains were detected. Phylogenetic analysis revealed that the capsid-encoding regions and noncapsid gene 2A of the four Korean HPeV-A3 strains are closely related to the HPeV-A3 strains isolated in Canada in 2007 (Can82853-01), Japan in 2008 (A308/99), and Taiwan in 2011 (TW-03067-2011) while noncapsid genes P2 (2B-2C) and P3 (3A-3D) are closely related to those of HPeV-A1 strains BNI-788St (Germany in 2008) and TW-71594-2010 (Taiwan in 2010). This first report on the whole-genome analysis of HPeV-A3 in Korea provides insight into the evolving status and pathogenesis of HPeVs in children.

Parechovirus A Circulation and Testing Capacities in Europe, 2015-2021.

Parechovirus infections usually affect neonates and young children; manifestations vary from asymptomatic to life-threatening. We describe laboratory capacity in Europe for assessing parechovirus circulation, seasonality, and epidemiology. We used retrospective anonymized data collected from parechovirus infection case-patients identified in Europe during January 2015-December 2021. Of 21 laboratories from 18 countries that participated in the study, 16 (76%) laboratories with parechovirus detection capacity reported 1,845 positive samples; 12/16 (75%) with typing capability successfully identified 517 samples. Parechovirus A3 was the most common type (n = 278), followed by A1 (153), A6 (50), A4 (13), A5 (22), and A14 (1). Clinical data from 1,269 participants highlighted correlation of types A3, A4, and A5 with severe disease in neonates. We observed a wide capacity in Europe to detect, type, and analyze parechovirus data. To enhance surveillance and response for PeV outbreaks, sharing typing protocols and data on parechovirus-positive cases should be encouraged.

A Case Series of Infants 60 Days of Age or Younger With Human Parechovirus (PeV) Meningitis From a New York City Pediatric Emergency Department.

Human parechovirus is a relatively lesser known virus that has recently spread across the United States, primarily affecting newborns and young infants. A particular strain of parechovirus, PeV-A3, has been found in the cerebrospinal fluid studies of many young patients in the spring and summer of 2022; however, short- and long-term neurologic effects of this virus are often not well known. We present a case series of 4 infants, 60 days of age or younger, found to have human parechovirus meningitis. Our retrospective study found that none of the 4 infants presented with any significant neurological findings, nor did they develop any specific neurologic signs or symptoms during their hospitalizations. Patients should continue to be monitored for long-term neurological and neurodevelopmental sequelae.

A Summer of Fevers and Fussiness: Eighteen Infants Admitted With Parechovirus Meningitis.

OBJECTIVE: To define the presentation, spectrum of illness, and outcomes in infants with parechovirus (PeV) meningitis admitted to our inpatient general pediatrics service during a spike in incidence of admissions in summer 2022. PATIENTS AND METHODS: This study is a retrospective case series of all patients aged 3 months and younger discharged from our institution with a CSF BioFire (BioFire Diagnostics, Salt Lake City, UT) FilmArray Polymerase Chain Reaction Meningitis/Encephalitis Panel result positive for PeV between January 1 and September 19, 2022. We collected and analyzed clinical and demographic data. RESULTS: Eighteen infants with PeV meningitis were admitted within our time frame, with 8 (44%) of the admissions occurring in July. Patients' mean age was 28.7 days and mean length of stay was 50.5 hours. Although all had a history of fever, only 72% were febrile on presentation. Laboratory findings showed a procalcitonin of less than 0.5 ng/mL in 86% of the 14 patients who had it drawn and no cerebrospinal fluid (CSF) pleocytosis in 83% of the patients who had CSF cell counts sent. Neutropenia was present in 17%. Although 89% of infants were given initial antibiotics, antibiotics were discontinued in 63% once their CSF panel returned positive for PeV, and in all by 48 hours. CONCLUSIONS: Infants hospitalized with PeV meningitis were febrile and fussy, but experienced uncomplicated hospital stays without neurological deficits. Parechovirus meningitis must be considered as a common cause of acute viral meningitis in young infants even without CSF pleocytosis. This study, although limited in scope and follow-up, can potentially assist in the diagnosis and treatment of PeV meningitis at other institutions.

An outbreak investigation of parechovirus-A3 in a newborn nursery.

OBJECTIVE: To investigate parechovirus-A3 (PeV-A3) transmission in a newborn nursery, after encountering 3 neonates with fever and rash. DESIGN: An observational study. SETTING: At a newborn nursery at the general hospital in Hyogo, Japan. PARTICIPANTS: Symptomatic neonates and their family members, and asymptomatic neonates born during the same period. METHODS: PCR assays for PeV-A and genotyping were used for the investigation of PeV-A3. Preserved umbilical cords were used to identify the route of transmission. RESULTS: PeV-A3 infection was confirmed in the three symptomatic neonates. The index case had fever and rash, and the 2 neonates treated later became symptomatic and had serum, cerebrospinal fluid, and stool specimens that were positive for PeV-A3 on PCR. The umbilical cord of the index case was positive for PeV-A3 on PCR. The family members of the index case, including the mother, were asymptomatic before delivery. The older sister and cousin of the PeV-A3-infected neonate had positive PCR results. The sequence analysis suggested 2 possible transmission routes: vertical and horizontal transmission in a newborn nursery and/or a family outside the hospital. The incubation period of PeV-A3 infection was estimated to be 1-3 days (maximum, 7 days). CONCLUSION: Horizontal transmission of PeV-A3 was confirmed in a newborn nursery. Vertical transmission was suggested by the detection of RNA in an umbilical cord sample from the index case. These observations indicate that PeV-A3 can be horizontally transmitted in a newborn nursery and that special caution is required to prevent healthcare-associated transmission of PeV-A3.

The Burden of Human Parechoviruses Among Children in Oman: A retrospective study.

Objectives: This study aimed to evaluate the burden, clinical and laboratory features and outcomes of human parechoviruses (HPeVs) infection among children in Oman. Methods: This retrospective study included children (aged <18 years) with molecularly proven HPeV infection who were managed at Sultan Qaboos University Hospital, Muscat, Oman, between January 2017 and December 2019. Data were obtained from the patients' medical records and analysed to describe their demographics, clinical and laboratory features, management and outcomes. Results: HPeV was detected in 61 patients, 44 (72%) of whom were males. The median age of these patients was nine months (interquartile range [IQR]: 6-15 months). HPeV was detected throughout the year without any significant peaks. Majority of the patients (n = 51, 84%) had co-infection with other viruses. Forty-eight (79%) children with HPeV infection required hospitalisation, and their median length of hospital stay was five days (IQR: 3-8 days). Ex-prematurity (n = 10, 16%) was the commonest comorbidity among this group. Fever (n = 41, 67%) and cough (n = 41, 67%) were the commonest presenting symptoms among the children. Two-thirds of the HPeV-infected children in this cohort were managed for lower respiratory tract infection; none was managed for meningitis. Gastroenteritis was not common in this cohort; only eight children had diarrhoea. All children made a full recovery. Conclusion: HPeVs infection does not show a clear seasonality in Oman. Most of the children were aged <2 years and had a viral co-infection. The outcomes of HPeV infection were favourable, with no mortalities, but a thorough follow-up for neurological outcomes was lacking.

Detection of parechovirus A in respiratory, gastrointestinal, and neurological clinical samples of pediatric patients from Panama (2014-2015).

Parechovirus A (PeV-A, Parechovirus, Picornaviridae) are human pathogens associated with mild to severe gastrointestinal and respiratory diseases in young children. While several studies have investigated the association of PeV-A with human disease, little is known about its epidemiology or detection in Latin America. Between the years 2014 and 2015, a total of 200 samples were collected from Panamanian pediatric patients aged < 16 years old exhibiting symptoms associated with respiratory (n = 64), gastrointestinal (n = 68), or neurological (n = 68) diseases. These samples were gathered from patients who had previously received negative diagnoses for the main respiratory viruses, rotavirus, and neurological viruses like herpes virus, enterovirus, and cytomegalovirus. The presence of PeV-A was analyzed by real time RT-PCR.Eight positive PeV-A infections (4.0%, 95% CI: 1.7 to 7.7) were detected: two in respiratory samples (3.0%, 95% CI: 0.3 to 10.8), five in gastrointestinal samples (7.3%, 95% CI: 2.4 to 16.3), and one in cerebrospinal fluid (1.5%, 95% CI: 1.4 to 7.9). The study provides evidence of PeV-A circulation in Panama and the data collectively, remarked on the importance of considering PeV-A in the Panamanian pediatric diagnostic landscape, especially when conventional testing for more common viruses yields negative results.

Human Parechovirus Central Nervous System Infection in a Young Infant Cohort.

In 2022, a surge in cases of pediatric human parechovirus (HPeV) central nervous system infections in young infants was seen at our institution. Despite the dramatic increase in the number of cases seen that year, the clinical features of the illness were similar to prior years. The recent pediatric HPeV surge highlights the need to evaluate treatment options and standardize follow-up to better understand the long-term prognosis of infants with HPeV infection.

Human parechovirus meningitis in children: state of the art.

Human Parechovirus is a common cause of infection occurring especially during the first years of life. It may present with a broad spectrum of manifestations, ranging from a pauci-symptomatic infection to a sepsis-like or central nervous system disease. Aim of this study is to explore the knowledge on Parechovirus meningitis. According to the purpose of the study, a systematic review of the literature focusing on reports on central nervous system. Parechovirus infection of children was performed following PRISMA criteria. Out of the search, 304 papers were identified and 81 records were included in the revision dealing with epidemiology, clinical manifestations, laboratory findings, imaging, therapy and outcome. Parechovirus meningitis incidence may vary all over the world and outbreaks may occur. Fever is the most common symptom, followed by other non-specific signs and symptoms including irritability, poor feeding, skin rash or seizures. Although several reports describe favourable short-term neurodevelopmental outcomes at discharge after Parechovirus central nervous system infection, a specific follow up and the awareness on the risk of sequelae should be underlined in relation to the reported negative outcome. Evidence seems to suggest a correlation between magnetic imaging resonance alteration and a poor outcome.

First description and phylogenetic analysis of coxsackie virus A non-polio enteroviruses and parechoviruses A in South Sudanese children.

Enteroviruses (EV) and parechoviruses A (PeV-A) are commonly circulating viruses able to cause severe disease. Surveillance studies from sub-Saharan Africa are limited and show high but variable infection rates and a high variation in genotypes. This is the first study to describe EV and PeV-A circulation in children in South Sudan. Of the fecal samples collected, 35% and 10% were positive for EV and PeV-A, respectively. A wide range of genotypes were found, including several rarely described EV and PeV-A types. Coxsackie virus A (CVA) EV-C types, particularly CVA13, were the most dominant EV types. The CVA13 types had a high diversity with the majority belonging to four different previously described clusters. PeV-A1 and -A14 were the most common PeV-A genotypes. A lack of representative data from our and other studies from sub-Saharan Africa demonstrates the need for more systematic surveillance of non-polio EV and PeV-A types in this region.

Detection of parechovirus-A in hospitalized children with acute lower respiratory infection in Myanmar, 2017-2018.

Parechovirus-A (PeV-A) causes emerging infection in children, and clinical presentation depends on genotype. The virus has been investigated mainly in developed countries; however, data from developing countries, especially in Asia, are sparse. This study investigated whether PeV-A circulated in children in Myanmar. This retrospective study evaluated PeV-A in nasopharyngeal samples from children aged 1 month to 12 years who were hospitalized with acute lower respiratory infection at Yankin Children Hospital, Yangon, Myanmar, during the period from May 2017 to April 2019. Real-time polymerase chain reaction (PCR) was used to detect PeV-A, and PCR-positive samples were used for genotyping and phylogenetic analysis. In total, 11/570 (1.9%) of samples were positive for PeV-A; 7 were successfully genotyped by sequencing the VP3/VP1 region, as follows: PeV-A1 (n = 4), PeV-A5 (n = 1), PeV-A6 (n = 1), and PeV-A14 (n = 1). Median age was 10.0 months (interquartile range 4.0-12.0 months), and other respiratory viruses were detected in all cases. Phylogenetic analysis showed that all detected PeV-A1 strains were in clade 1 A, which was a minor clade worldwide. Four PeV-A genotypes were detected in Myanmar. The clinical impact of PeV-A in children should be evaluated in future studies.