In our multicenter observational study, COVID-19-related MODS and secondary infections were determined to be the two main causes of death in severe COVID-19 patients admitted to the ICU.
Our investigation into the timing and causes of death in severe COVID-19 patients stands out, irrespective of previous studies in the same topic currently in the literature [4, 5], due to the following distinct points. First, this is the first multi-center study, albeit in the same country. Second, in contrast to Ketcham et al., who studied organ dysfunction as the main cause of death, we reported causes of disease processes. Finally, regarding the classification of diseases, our study is the first to assess the burden of secondary infection-related death, which is an emerging threat during the massive utilization of corticosteroids and immunomodulatory drugs among COVID-19 patients . Prior studies report high proportions of septic shock as a cause of death in patients with severe COVID-19, ranging from 15 to 27%. According to the SEPSIS-3 definition of septic shock , the lactate level must be higher than 2 mmol/L. However, it is noteworthy that lactate values in septic shock patients mostly do not exceed this threshold, as reported in a large cohort of 4,244 severe COVID-19 patients . Considering this, we reported the existence of MODS rather than septic shock to avoid the gathering of several different etiologies under the identity of septic shock. Moreover, studies reporting causes of death in patients with SARS-CoV-2 infection admitted to the ICU report either a striking 48% mortality rate  or no data regarding the in-ICU mortality rate , therefore limiting the external validity of these results.
Although understanding the causes of mortality is of major interest, identifying the precise pathway to death faces several constraints. First, assigning a single cause of death is complex and their definitions may vary among practitioners. Therefore, in our study, all medical reports were blindly reviewed by two independent senior intensivists. Whether causal mediation analysis could have permitted precise causes of death, the retrospective design of the study without systematic biological sampling does not allow for such analysis. However, we assessed the variation in the proportion of each cause of death over time. We hypothesize that if there is a selection bias in our study, there is no reason that it would not have varied over time. Thus, since the proportion of each cause of death remains constant over time, the possibility of such a bias remains minimal. Second, several diseases may be deeply intertwined and lead to death, especially after a protracted period of ICU stay, which is associated with the occurrence of ICU-acquired complications. Thus, the attributable mortality of each potential cause of death remains highly debated, especially in severe COVID-19 patients . Autopsy findings and histopathological postmortem evidence are therefore crucial for improving our understanding of severe COVID-19, especially in distinguishing the exact cause of death from other contributing factors. A recent review focusing on postmortem examinations in COVID-19 patients reported pulmonary embolism as a major cause of death in COVID-19, with a high prevalence of peripheral deep venous thromboembolism . These observations are in line with several studies reporting both venous and arterial thrombotic events as common in severe COVID-19 patients [16,17,18]. Consequently, one can hypothesize that the high incidence of COVID-19-related MODS might rely on diffuse thromboembolic complications.
Unlike what is observed in severe COVID-19 patients in this study, early mortality is high in severe bacterial or viral pneumonia. In septic shock, approximately one-third of patients die during the first 72 h, with a vast majority being primary infection-related MODS . Early mortality is also high in severe viral pneumonia, with the identification of bacterial co-infection as a major cause of death . This early mortality has been ascribed to the existence of an overwhelming inflammation at the initial stages of septic shock, including the overexpression of pro-inflammatory cytokines such as IL-6, IL-12, and TNFα . In line with our results, a recent study reported IL-6 serum levels to be 27-times lower in COVID-19 patients than in septic shock patients, therefore questioning the existence of a cytokine storm in COVID-19 . Once again, the in-hospital course of COVID-19 patients admitted to the ICU is different, with a low reported rate of bacterial co-infection at admission as compared to other causes of viral pneumonitis . However, recent studies have reported that patients with SARS-CoV-2 infection are at higher risk for ICU-acquired pneumonia [24, 25] as compared with other causes of pneumonitis, with some data suggesting a significant association between increased mortality and ICU-acquired pneumonia in severe COVID-19 patients . However, precise evaluation of the attributable mortality, defined as the percentage of deaths that would not have occurred without infection, is complex for ICU-acquired pneumonia and requires the use of competing risk statistical models. Hence, recent studies have found little impact of ICU-acquired infections on ICU mortality [26, 27]. Therefore, our results urge the reappraisal of effects of ICU-acquired pneumonia on mortality in patients with severe COVID-19.
The EOL decision accounted for 45% of patients among deceased COVID-19 patients. Ethical issues in the ICU have been a challenging point in the COVID-19 pandemic context for two main reasons: 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 therapy discontinuation could reflect the existence of unusual external constraints . However, two points argue against this assertion: First, such a proportion has been previously reported, with EOL decision as the main cause of death in septic shock patients . Second, the median time from admission to death in patients with life-sustaining therapy discontinuation is 16 days, which is higher than the time usually reported in the literature . Finally, we report no difference in time to death between patients with and without EOL decisions, which suggests that withdrawal of care has been decided in a non-emergency context.
This study had several limitations. First, as stated by a recent publication, causal inferences from observational data are one of the main problems . Whether our assessment of inter-observer reliability served to solely decrease the risks of interpretation bias, it could only be verified by further studies considering to perform causal mediation analysis using biomarkers. This approach was not possible in our current study due to the lack of longitudinal systematic blood sampling in our cohort. Another possibility could be to perform a competitive survival analysis. However, given the several intertwined competing factors and the sample size of our cohort, this approach was not possible. Second, the multicenter 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. Third, the standard of care has evolved since the outbreak of the COVID-19 pandemic and might therefore limit the external validity of our results. Of note, published data on the topic are conflicting, some suggesting similar mortality between the different periods  or an increase over time of the risk-adjusted survival to hospital discharge . Notably, the recent emergence of SARS-CoV-2 variants is reported to be associated with higher mortality rates . However, data concerning the causes of mortality related to these emerging variants are missing and require further investigation. Finally, we focused our analysis on in-ICU death, therefore setting aside other causes of death that may rely on long-term effects of SARS-Cov-2 infection.