A wide variety of infections can trigger cytokine storm syndromes including those caused by bacteria, viruses, fungi and parasites. The most frequent viral trigger is Epstein-.Barr virus which is covered in Chapter 16. CSS associated with COVID-19 is also discussed separately (Chapter 22). This chapter will focus on other viruses including the hemorrhagic fever viruses, influenza, parainfluenza, adenovirus, parvovirus, hepatitis viruses, measles, mumps, rubella, enterovirus, parechovirus, rotavirus, human metapneumovirus and human T-lymphotropic virus. The published literature consists of many single case reports and moderate-sized case series reporting CSS, in most circumstances meeting the 2004 diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH). There is no published clinical trial evidence specifically for management of HLH associated with these viruses. In some situations, patients received supportive therapy and blood product transfusions only but in most cases, they were treated with one or more of intravenous corticosteroids, intravenous immunoglobulin and/or etoposide. These were successful in many patients although in significant numbers progression of infection to CSS was associated with mortality.

BACKGROUND: Human parechovirus (HPeV) infection can result in severe disease in infants, including sepsis, seizures, brain injury, and death. In 2022, a resurgence of HPeV was noted in young infants. Spectrum of illness and outcomes remain to be fully described.
METHODS: A multi-state retrospective cohort study was conducted to evaluate hospitalizations and outcomes of infants aged ≤6 months admitted in 2022 with laboratory-confirmed HPeV infection. Infants with severe disease were defined as having clinical seizures, or abnormalities on MRI or EEG during admission. Infants with severe vs non-severe disease were compared using descriptive statistics.
RESULTS: 124 U.S. infants were identified with HPeV in 11 states. Cases of HPeV peaked in May and presented at a median of 25.8 days of life (0-194 d) with fever, fussiness, and poor feeding. Bacterial and other viral co-infections were rare. 33 (27%) of infants had severe neurologic disease, were more likely to present at an earlier age (13.9 vs 30 days of life, p<0.01), have preterm gestation (12% vs. 1%, p = 0.02), and present with respiratory symptoms (26% vs. 8%, p = 0.01) or apnea (41% vs. 1%, p <0.001). Subcortical white matter cytoxic cerebral edema was common in severe cases. Two infants with HPeV died during admission with severe neurologic HPeV disease; no infant with mild HPeV disease died.
CONCLUSIONS: This is the largest, geographically-diverse U.S. study to describe the 2022 HPeV outbreak among infants. Longitudinal follow up of infants is needed to define predictors and outcomes of severe HPeV disease.

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OBJECTIVE: This study aims to analyse the clinical presentation caused by enterovirus (EV) and/or human parechovirus (HPeV) infection in children, as well as the management of such cases admitted to a regional hospital in Australia.
METHODS: Retrospective study reviewing medical records.
METHODS: Single hospital in regional Australia.
METHODS: All children under 18 years admitted over the 5-year period beginning from 1 January 2017 with confirmed EV and/or HPeV infection. Cases with clinically insignificant EV/HPeV isolation were excluded.
METHODS: Data collected included demographic data, signs and symptoms present, specimens of EV/HPeV isolation, co-occurring pathogens, peak C-reactive protein (CRP), antibiotic therapy, discharge diagnosis and follow-up after discharge.
RESULTS: Overall, 27 patients fulfilled the inclusion criteria; 81.5% of the patients were ≤3 months of age with a median of 2 months (interquartile range 1-3); 74.1% were males. The most common clinical features were a fever ≥38°C and irritability/lethargy/high-pitched cry. 29.6% of the patients had co-occurring pathogens detected, and a CRP ≤10 mg/L was observed in 77.8% of cases. All but two children were treated with antibiotics while awaiting polymerase chain reaction results. The most common discharge diagnosis was meningitis. In all, 74.1% of the children attended follow-up appointments.
CONCLUSIONS: EV and HPeV should be considered as a possible aetiology of fever and irritability/lethargy/high-pitched cry in children under 3 months.

BACKGROUND: In the conjugate vaccine era, viruses are the most common cause of meningitis. Here, we evaluated epidemiological trends in laboratory-confirmed viral meningitis across all age-groups over an 11-year period in England.
METHODS: In England, hospital laboratories routinely report laboratory-confirmed infections electronically to the UK Health Security Agency. Records of positive viral detections in cerebrospinal fluid during 2013-2023 were extracted. Incidence rates with confidence intervals were calculated using mid-year resident population estimates.
RESULTS: There were 22,114 laboratory-confirmed viral meningitis cases, including 15,299 cases during 2013-19 (pre COVID-19), with a gradual increase in incidence from 3.5/100,00 (95%CI: 3.3-3.6) to 3.9/100,000 (95%CI: 3.6-4.1). During 2020-21 when pandemic restrictions were in place, there were 2061 cases (1.8/100,000; 1.7-1.9), which increased to 4754 (4.2/100,000; 4.0-4.3) during 2022-23 (post pandemic restrictions). Infants aged <3 months accounted for 39.4% (8702/22,048) of all cases, with a stable incidence 2013-19 (504/100,000, 95%CI: 491-517), followed by a significant decline during 2020-21 (204/100,000; 188-221) and then an increase during 2022-23 (780/100,000; 749-812), with enteroviruses being the commonest cause (84.9%, 7387/8702; 424.74/100,000; 95%CI: 415.12-434.51), followed by parechoviruses (9.1%, 792/8702; 45.54/100,000; 95%CI: 42.42-48.82) and herpes simplex virus (4.4%, 380/8702; 21.85/100,000; 95%CI: 19.71-24.16). Pandemic restrictions were associated with significant declines in the incidence of enterovirus (77.7%) and parechoviruses (64% lower), with rebounds after societal restrictions were lifted.
CONCLUSIONS: Rates of viral meningitis have returned to pre-pandemic levels since societal restrictions were lifted. The highest incidence of viral meningitis remains in infants aged <3 months and most commonly due to enteroviral infection.

Human Parechoviruses (HPeVs) have rarely been considered in the virological investigation of Acute Flacid Paralysis (AFP) cases in Africa, where enteric infections are very common. This study investigated the prevalence and genetic diversity of HPeV in 200 children aged ≤ 15 years with AFP in Cameroon from 2018 to 2019. HPeVs were detected in their faecal RNA using 5\'-untranslated real-time RT-PCR. Detected HPeVs were typed by phylogenetic comparison with homologous sequences from homotypic reference strains. Overall, HPeV RNA was detected in 11.0% (22/200) of the 200 stool samples tested. Twelve HPeVs were successfully sequenced and reliably assigned to HPeV-A1, A4, A5, A10, A14, A15, A17 and A18 genotypes. Phylogenetic analyses revealed a high genetic variability among the studied HPeVs, as well as between the studied HPeVs and their previously reported counterparts from Cameroon in 2014. These findings suggest that different HPeV genotypes co-circulate in Cameroon without documented epidemics.

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.

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 A (PeV-A) infections have been detected with increasing frequency in US infants under 6 months of age, leading to a Centers for Disease Control and Prevention (CDC) health advisory in July 2022. Clinicians are advised to consider PeV-A laboratory testing of blood and cerebrospinal fluid when infants present with unexplained fever, sepsis-like illness, or neurological issues. Clinical laboratories are encouraged to offer in-house molecular testing for PeV-A to avoid diagnostic delays, unnecessary use of antibiotics, and prolonged hospitalization of infants presenting with sepsis-like illness. While data are evolving on potential neurodevelopmental sequelae after PeV-A infant central nervous system infections, most infected infants return to baseline health for age. This review examines the PeV-A literature with a focus on PeV-A3, including aspects of epidemiology, clinical presentations/management, laboratory diagnostics, genotyping, and post-infectious sequelae related to PeV-A infections in infants.

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.