The clinical features of COVID-19 range from a mild illness to patients with a very severe illness with acute hypoxemic respiratory failure requiring ventilation and Intensive Care Unit admission. Risk factors for a fatal disease include older age, respiratory disease, diabetes mellitus, obesity and hypertension. Little is known about the mechanisms behind observed episodes of sudden deterioration or the infrequent idiosyncratic clinical demise in otherwise healthy and young subjects. As in other diseases, the answer to some of these questions may in time be provided by genotyping as well careful clinical, serological, radiological and histopathological phenotyping, which enable mechanistic insights into the differences in pathogenesis and underlying immunological and tissue regenerative response patterns. We will aim to provide a brief overview of the existing evidence for such differences in host response and outcome, and generate hypotheses for divergent patterns and avenues for future research, by highlighting similarities and differences in histopathological appearance between COVID19 and influenza as well as previous coronavirus outbreaks, and by discussing predisposition through genetics and underlying disease.This article is protected by copyright. All rights reserved.