49 Hepatitis outbreak in children 3 Cases of non A-E hepatitis Monthly incidence of children meeting the case definition for non A-E hepatitis was also collected. If there was a larger outbreak of mild cases of hepatitis, this most likely occurred in the same time period in which the cases of children presenting with non A-E hepatitis were reported. For the Netherlands, these data were provided by the National Institute for Public Health and the Environment (RIVM) and the Dutch Society of Pediatrics (NVK). For other countries these data were retrieved from several published studies4, 15. Primary care population data In parallel, with the approval of NHS England, we used the OpenSAFELY secure health analytics platform to conduct a retrospective cohort study of liver function tests across the full pseudonymised patient primary care records held by the electronic health record provider TPP, covering 40% of general practices in England. Using data for the period between 1st April 2017 and March 31st 2022 we identified individuals aged <=30 years registered at a general practitioner (GP) at the beginning of each month. In these patients, we then identified anyone with any of the following liver function tests: ALT, AST and bilirubin. For AST and ALT tests, we identified the number of tests in the clearly pathological range (>500 U/L), as set out in the WHO working case definition2. For bilirubin tests, the number of tests out of range was calculated using the upper reference range attached to the lab result. Statistical analysis Summary data from each centre were combined to calculate pooled counts, means and variances. We tabulated the number of individuals with AST and ALT measurements by location, and plotted the number of tests per month. We plotted rates for elevated AST and ALT measurements by month in each age group as the proportion of the total number of tests. For example, a rate of 0.05 means that 5% of all tests were elevated. We also plotted the mean of AST and ALT amongst all those who had elevated measurements by month in each age group. This analysis was carried out for each centre individually, and for various pooled datasets (e.g., all locations in England, Scotland and Wales were pooled for the UK analysis). We calculated a Z-score, which measures the extent to which the rate for elevated ALT and/or AST was higher or lower in the period of interest compared to a baseline period, for the 3-week to 5-year-olds. Since health seeking behaviour might have changed during the COVID-19 pandemic, a pre-COVID-19 period was used as a baseline period (01-01-2012 to 31-12-2019). The period of interest included months in which children meeting the case definition were recorded (01-12-2021 to 31-082022). For example, if the Z-score was 0.4 for a certain location for ALT, the rate for elevated ALT was 0.4 standard deviations higher in the period of interest compared to the baseline period.
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