SARS-CoV-2 infection is often associated with a hyperinflammation that is thought to drive disease severity and death. However, it is unclear whether tissue inflammation is induced by a direct response to the virus or by an independent immunopathological process. By analysing SARS-CoV-2 organotropism and organ inflammation in post-mortem tissues from 11 patients who died of COVID-19, Dorward et al. report that, despite a wide distribution of viral products in pulmonary and extra-pulmonary tissues, severe inflammation was limited to the lung and reticuloendothelial system and was not consistently associated with presence of virus. Overall, this preprint suggests that immune mechanisms of SARS-CoV-2 tissue-specific tolerance function independently of viral clearance and that fatal COVID-19 is a consequence of immunopathology that may be dissociated from virus presence.