47 Hepatitis outbreak in children 3 Introduction In March 2022, a series of cases of severe hepatitis in young children was recognised in central Scotland1. As of August 26th, 2022, 1115 probable cases were reported - acute hepatitis (not caused by hepatitis A-E virus) with serum transaminase >500 U/L (aspartate transaminase (AST) or alanine transaminase (ALT)) in children aged 16 or under2. In this period, 22 children died in 35 countries1–3 and 47 (4%) have undergone emergency liver transplant3. The majority of children meeting the case definition were younger than 5 years (range 1 month - 16 years)1. No new cases were reported since late summer 20224. We have recently reported evidence that the outbreak was caused by adeno-associated virus 2 (AAV2), in some cases in combination with adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B)5–7. AAV2 relies on coinfection with a helper virus for replication, such as HAdV or herpes viruses6. In the majority of outbreaks of infectious diseases, the number of mild cases is much higher than the number of severe cases8. In this hepatitis outbreak, milder, selflimiting cases (e.g., without severe symptoms or jaundice) have not been reported. However, it is possible that this outbreak has been more widespread than recorded data suggest. Assessing the magnitude of the outbreak is crucial for understanding pathophysiological mechanisms and considering whether there is a future need to identify mild cases in early stages to prevent clinical deterioration. Hepatitis refers to inflammation of the liver and is characterised by an increase in transaminase levels, for which quantitative recordings are available in clinical laboratory databases10. These routinely collected laboratory data are rarely exploited for public health surveillance, but could be used as an opportunistic measure for disease surveillance in new or periodic outbreaks. In order to be effective, the biomarkers should have a clear relationship with the disease of interest and this relationship should be specific. For example, C-reactive protein can be increased as a consequence of many different disease processes, and is therefore less suitable for disease surveillance11. Routinely collected laboratory data could also be used in widespread poisoning incidents (e.g., acute kidney injury linked to the consumption of cough syrup medication in Indonesia and Gambia in 2022)12, 13. To our knowledge, this is the first study using routinely collected laboratory data to detect and follow-up on the hepatitis outbreak in children. In order to assess any potential rise in the number of mild hepatitis cases, as measured by elevated serum transaminases, we conducted a pragmatic survey to analyse changes in the proportion of hospitalised children with elevated AST or ALT over time. Even though there are many different causes for an increase in ALT and/or AST, the proportion of elevated measurements relative to all measurements is expected to be stable over extended periods, especially in young children, where the threshold to take blood samples is relatively high. In addition, we studied the feasibility of using routinely collected clinical laboratory results to detect or follow up an outbreak of an infectious disease. Locally aggregating patient-level data to
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