An unorthodox pathophysiology of severe cases of COVID-19 the weak heme hypothesis.

Important amount of severe cases is the main concern in COVID-19 pandemic. It could be the running cause of the burn out of the health system in many countries. The aim of this paper is to suggest a pathophysiologic hypothesis to explain the main characteristics of severe cases of COVID-19 and its underlying conditions. In fact, the clinical and biological picture of severe cases of COVID-19 can easily be explained by free heme toxicity exceeding the endogenous antioxidant systems. Severe cases of COVID-19 are comparable to acute porphyria. On the other hand, the geographical distribution of severe cases of COVID-19 is directly associated to how fresh or polluted the air is. Finally, the relatively low rate of severe cases of COVID-19 could be explained by the presence of an unstable hemoglobin variant highly sensitive to the intrinsic conditions resulting from the acute pneumonia secondary to SARS-CoV2 infection. The combination of air pollution and free heme toxicity, resulting from the interaction between an unstable hemoglobin variant and SARS-CoV2 infection, seems to be the best scheme to explain clinical and biological manifestations in severe COVID-19. The arguments to support this hypothesis are detailed. We also propose some strategies to verify the concordance of our hypothesis with the reality and the implications it could have, if verified, either for scientists and decision makers.