Post hoc, ergo propter hoc? Evaluating a Potential Increase in Childhood Severe Hepatitis in a Post-COVID World

The SARS-CoV-2 pandemic has altered the world in many ways, with impacts unequally distributed between and within individual countries. The biology of SARS-CoV-2, its variants, the individual host immune responses, and the timing of COVID outbreaks interact with multiple other variables. These include different COVID mitigation policy implementation or withdrawal, vaccination availability and administration, and background presence of other viral pathogens. This results in a very challenging milieu for medical investigators to isolate factors and develop firm conclusions about the causality of new clinical observations. A very rich environment exists, however, to generate reasonable hypotheses about the potential of SARS-CoV-2 to induce immune activation triggering new “post-COVID” clinical events. In this issue of the Journal of Pediatric Infectious Diseases Society, Paraskevis and co-authors suggest that the recently reported “severe hepatitis cases” in children could be the result of post-COVID primed immune responses to a subsequent enteric adenovirus infection [1]. A similar hypothesis recently published online suggested that a SARS-CoV-2 reservoir in the gastrointestinal (GI) tract could give rise to repeated immune activation by a superantigen motif in the spike protein of the virus, resulting in gamma-interferon T-cell activation. This superantigen motif might be a trigger to the multisystem inflammatory syndrome in children [2, 3].