To the best of our knowledge, this is the first study reporting causes and timing of death in severe COVID-19 patients. COVID-19-related MODS and end-of-life decision were the two main causes of death in severe COVID-19 patients admitted in ICU. Regarding the timing of death, only one patient died within three days.
Although understanding causes of mortality is of major interest, identifying the precise pathway to death faces several constraints. First, determining the precise cause of death is highly dependent on the implemented strategies of diagnosis that may vary among centres and countries. Second, several diseases may be deeply intertwined and lead to death, especially after a protracted period of ICU stay that is associated with the occurrence of ICU-acquired complications. Thus, the attributable mortality of each potential causes of death remains highly debated, especially in severe COVID-19 patients11. Autopsy findings and histopathological post-mortem evidences are therefore crucial to improve our understanding of severe COVID-19, especially in distinguishing the exact cause of death from other contributing factors. A recent review focusing on post-mortem examinations in COVID-19 patients reported pulmonary embolism as a major cause of death among COVID-19 patients, with a high prevalence of peripheral deep venous thrombo-embolism 12. These observations are in line with several studies reporting a high proportion of both venous and arterial thrombotic events in severe COVID-19 patients13–15. Consequently, one can hypothesize that the high incidence of COVID-19 related MODS we observed might rely on diffuse thromboembolic complications. In this perspective, the 13% rate of fatal ischemic events we report might be underestimated.
Unlike what is observed in severe COVID-19 patients in this study, the early mortality is high in severe bacterial or viral pneumonia. In septic shock, approximately one third of patients die during the first 72 hours, with a vast majority of primary infection related MODS16. Early mortality is also high in severe viral pneumonia, with the identification of bacterial co-infection as a major cause of death17. This early mortality has been ascribed to the existence of an overwhelming inflammation at initial stages of septic shock, including the overexpression of pro-inflammatory cytokines such as IL-6, IL-12 and TNFα18. In line with our results, a recent study reported IL-6 serum levels to be 27-times lower in COVID-19 patients when compared to septic shock patients, therefore questioning the existence of a cytokine storm in COVID-1919. Once again, the in-hospital course of COVID-19 patients admitted in ICU is different, with a low reported rate of bacterial co-infection20.
Apart from COVID-19 related MODS, end of life decision accounted for 25% of death among severe COVID-19 patients. Ethical issues in the ICU have been a challenging discussion in the COVID-19 pandemic context for two main reasons that are 1/ the higher mortality rate in the elderly and frail patients and 2/ the shortage of medical resources. Therefore, the high rate of life-sustaining therapies discontinuation could reflect the existence of unusual external constraints. However, two points argues against this assertion. First, such a proportion has been previously reported, with end-of-life decision as the main cause of death in septic shock patients16. Second, the median time from admission to death in patients with life sustaining therapies discontinuation is 16 days, suggesting withdrawal of care has been decided in a non-emergency context.
This study acknowledges two main limitations. First, such a retrospective study limits the establishment of a definite causality inference. Second, the multicentre design is associated with differences in diagnosis procedures and the determination of causes of death was left at the discretion of the physician in charge.