Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS

Abstract

Background Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions. Methods and findings In this study, we compared COVID-19 ARDS (n = 43) and bacterial sepsis-induced (non-COVID-19) ARDS (n = 24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within- ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation. Conclusion We present a first comprehensive molecular characterization of differences between two ARDS etiologies–COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions. Author summary Acute respiratory distress syndrome (ARDS) is a critical condition of the lung that can arise after severe infections, traumatic injury, or inhalation of toxins. Patients with ARDS are in a complex disease state and at risk of multiple clinical complications, such as thrombosis, lung fibrosis, acute kidney injury, and increased mortality. Currently, there are substantial challenges in the treatment of ARDS due to the high heterogeneity of this condition across patients. Our study compared metabolomic and proteomic changes induced by two different causes of ARDS—COVID-19 infection and bacterial sepsis. We used blood samples of patients from each ARDS group for molecular profiling and identified several hundred molecules from various biological processes differing between the two groups. Based on these results, we made several new propositions: (1) A role of arginine metabolism in long-term sequelae of ARDS. (2) The potential use of JAK-STAT pathway inhibitors for bacterial sepsis-induced ARDS. (3) ARDS-associated mitochondrial dysfunction as a reason for poor prognosis of acute kidney injury that occurred during ARDS. (4) A synergy between prothrombotic processes as a potential reason for hypercoagulation in ARDS. We hypothesize that combination therapy targeting two or more of these prothrombotic processes may ameliorate hypercoagulation.