key: cord-0810362-fu51dk76 authors: Stoffel, Larissa; Agyeman, Philipp K A; Keitel, Kristina; Barbani, Maria Teresa; Duppenthaler, Andrea; Kopp, Matthias V; Aebi, Christoph title: Striking Decrease of Enteroviral Meningitis in Children During the COVID-19 Pandemic date: 2021-04-08 journal: Open Forum Infect Dis DOI: 10.1093/ofid/ofab115 sha: 326a31992a325fbf65688a1df3c8984e75bbce9f doc_id: 810362 cord_uid: fu51dk76 We report the unprecedented complete absence of pediatric enteroviral meningitis in 2020 in the area of Bern, Switzerland. Presumably an unintended effect of COVID-19 public health measures, this finding highlights the potential of community-wide non-pharmaceutical interventions (NPI) for controlling the circulation of a major pediatric pathogen, which is mainly transmitted by the fecal-oral route. M a n u s c r i p t 3 In temperate climates, infections caused by non-poliovirus enteroviruses (EV) in children peak between June and October [1 -3] . Outbreaks recur each year despite cycling changes of the predominant EV types [1, 4] . Human-to-human transmission occurs primarily via the fecal-oral route, and less commonly by respiratory secretions [5] . EV cause various non-specific febrile syndromes. They are also the most commonly identified etiology of acute CNS infection in children [6] , with the greatest age-specific incidence in infants [4, 6] . At our institution, EV meningitis case counts peak each summer and testing CSF for EV by PCR is part of the standard diagnostic algorithm for all infants less than 90 days of age undergoing lumbar puncture for sepsis work-up and for children of any age evaluated for possible meningitis. Unexpectedly, we observed no case in 2020. Here we describe the occurrence of EV meningitis over 11 consecutive years and correlate the epidemic curve with the timing of various NPI introduced to halt the COVID-19 pandemic in 2020. Since the NPI were primarily designed to interrupt respiratory transmissions and EV may also, albeit less commonly, be transmitted by the respiratory route, we also calculated the epidemic curve for respiratory rhinovirus/enterovirus detections. This is a retrospective single-center time series analysis of the occurrence of EV meningitis at an institution, which is the only provider of advanced pediatric emergency services (20'000 consultations per year) and in-patients services (100 beds; 6'000 admissions per year) for a catchment area population of 1.5 million. We defined EV meningitis as the detection of enteroviral RNA by CSF PCR, which was A c c e p t e d M a n u s c r i p t 4 introduced in 2010/2011 into the in-house diagnostic algorithm for infants less than 90 days of age undergoing sepsis work-up and pediatric patients of any age evaluated for meningitis. Using the electronic hospital database, we analyzed three separate datasets from January 1, 2010 to December 31, 2020: (1) CSF real-time EV PCR test results were used to capture the number of patients tested and the number of EV meningitis cases; (2) hospital admissions coded for EV meningitis (ICD-10 code A87.0) were obtained for validation of PCR results; (3) nasopharyngeal aspirate (NPA) immunofluorescence (IF) tests for rhinovirus/enterovirus [7] were obtained to monitor overall respiratory rhinovirus/enterovirus activity (IF assay does not distinguish between rhinoviruses and enteroviruses). For each case, the date and patient age were recorded. We plotted counts by month, quarter or year and (table 1) . NPI to prevent the spread of COVID-19 have been associated with markedly decreased community activity of major respiratory viruses other than SARS-CoV-2 [8] [9] [10] [11] . Here we report the complete absence in 2020 of the summer outbreak of enteroviral meningitis, which previously peaked in the third quarter of each year since at least 2010. This finding strongly suggests that community-wide COVID-19 control measures intended to prevent respiratory transmissions also dramatically impacted on enteroviral transmission, which most commonly occurs by direct human-to-human contact [5] . This striking disruption of enteroviral epidemic cycles was first reported for the second quarter of 2020 from Korea [9] and Taiwan [12] [13] [14] by analysis of a national health insurance database [12] , ICD codes for hand, foot and mouth disease and herpangina [13] and national disease notification systems [9, 14] . More recently, two clinical microbiology reports from south-east France [15] and the US [16] describe the near absence in EV CSF PCR detections during the third quarter of 2020. The starting point of our study was the clinical observation of absent EV meningitis cases in children in 2020. Infants appear to be a suitable sentinel population for enteroviral circulation in the community, because their febrile presentation is usually brought to medical attention and the work-up for fever without source or meningitis commonly includes EV PCR in CSF and/or blood [17] . M a n u s c r i p t 7 Conversely, for older children such data may be less reliable, because EV disease is mostly mild, non-specific and rarely confirmed virologically. Also, health care avoidance during lockdown periods [18, 19] to be the most likely drivers of reduced enteroviral circulation. Day care centers were never closed [11] . While horizontal spread of EV in this setting is well established [20] , our findings suggest that effective control of community transmission is possible without day care closure. Similarly, schools were reopened well before the expected onset of the EV season [11] . Thus, school closure between March and May 2020 was either irrelevant for subsequent EV suppression in the third quarter or exerted a critical delay by reducing early reproduction in spring. Finally, the use of face masks in public was not enforced until later in the year and, consistent primarily fecal-oral transmission, is unlikely to have contributed substantially. The reduction of combined rhinovirus/enterovirus detection in NPA in 2020 was significant, but substantially less pronounced (supplementary material, table 3) than EV detection in CSF. This suggests that there was ongoing circulation of respiratory types of the genus enterovirus, i.e., mainly rhinoviruses [21] , while non-respiratory enterovirus genotypes, which cause the majority of CNS infections, were largely suppressed. This further supports the notion that fecal-oral transmission was disrupted in 2020. The strengths of this study include the long observation period and the A c c e p t e d M a n u s c r i p t 8 hospital setting, which affords greater precision in associating EV detection with specific clinical disease than public health or clinical microbiology data. Limitations include the following: First, our single site approach may not be representative for other geographic areas. Second, we did not routinely search for parechoviral infections in CSF, which in Europe occur with biannual peaks in even numbered years [3] . However, EV and parechoviruses co-circulate with no apparent mutual interference [2] . Third, we may have underestimated the true number of EV meningitis cases since CSF PCR is less sensitive for detection of EV than PCR of stool or respiratory specimens [22] . Fourth, as with all retrospective studies, factors unaccounted for may have contributed to the effects observed. persons banned, 13/03/2020 -06/06/2020; ④ Public venues closed, 06/03/2020 -11/05/2020; ⑤ Tertiary schools and Universities closed (age > 16 years), 16/03/2020 -06/06/2020; ⑥ Primary and secondary schools closed (age 6 -12 Centers for Disease C, Prevention. 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