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

Abstract

BackgroundAcute 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 FindingsIn 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.ConclusionWe 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.

Urine-based multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS

“…Among 60 proteins that were significantly different between survivors and non-survivors, 22 were higher in survivors, 38 higher in non-survivors ( Figure 3a, left) . Remarkably, in our recent plasma-based study 15 , we did not find any proteins that were associated with mortality in the same COVID-19 patients ( Figure 3a, right) .…”

“…Proteomic profiling was performed by the Proteomics Core of Weill Cornell Medicine-Qatar using the Olink platform (Uppsala, Sweden) 15 . Briefly, manufacturer’s instructions were followed to profile the samples using four panels including Inflammation, Cardiovascular II, and Cardiovascular III panels.…”

“…Metabolic profiling was performed by Metabolon, Inc (Morrisville, NC) using ultrahigh performance liquid chromatograph-tandem mass spectroscopy (UPLC-MS/MS) 15 . Briefly, samples were subjected to methanol extraction and then divided into four aliquots for each of the mass spectroscopic methods.…”

“…To address these critical knowledge gaps, we recently elucidated molecular differences between and within two ARDS etiologies - COVID-19 and bacterial sepsis 15 . Extending this blood-based ARDS comparison, we here performed a similar analysis on urine samples.…”

How sepsis parallels and differs from COVID-19

“…Conversely, COVID-19 ARDS features a robust alveolar thrombosis accompanied by an excessive fibro-proliferative lung tissue remodeling. 3 Another phenomenon for COVID-19 respiratory failure, not observed in other etiologies, is the so-called “silent hypoxemia” (a critically low pO 2 accompanied by mild dyspnea). 4 Silent hypoxemia is especially detrimental, as it delays timely therapeutic management and facilitates multi-organ failure.…”