How severe a viral infection is depends on how much the virus is replicating, damaging cells as it does so, and on the response of the immune system. Or so one would think. “Some of the most severe cases of COVID-19 are happening in the absence of replicating virus,” Joseph Guarnieri told BioWorld. In work published in Science Translational Medicine on Aug. 9, 2023, Guarnieri and his colleagues have described how those severe cases unfold, even as there is no replicating virus to be found.