ABSTRACT
Background: The mechanisms driving SARS-CoV-2 susceptibility remain poorly understood, especially the factors determining why unvaccinated individuals remain uninfected despite high-risk exposures. Objective: to understand lipid and metabolite profiles related with COVID-19 susceptibility and disease progression. Methods: we collected samples from an exceptional group of unvaccinated healthcare workers heavily exposed to SARS-CoV-2 but not infected (‘non-susceptible’) and subjects who became infected during the follow-up (‘susceptible’), including non-hospitalized and hospitalized patients with different disease severity providing samples at early disease stages. Then, we analyzed their plasma metabolomic profiles using mass spectrometry coupled with liquid and gas chromatography. Results:we show specific lipids profiles and metabolites that could explain SARS-CoV-2 susceptibility and COVID-19 severity. More importantly, non-susceptible individuals show a unique lipidomic pattern characterized by the upregulation of most lipids, especially ceramides and sphingomyelin, which could be interpreted as markers of low susceptibility to SARS-CoV-2 infection. Conclusion: this study strengthens the findings of other researchers about the importance of studying lipid profiles as relevant markers of SARS-CoV-2 pathogenesis.
Subject(s)
COVID-19 , Severe Acute Respiratory SyndromeABSTRACT
Despite of the scientific and human efforts to understand COVID-19, there are questions still unanswered. Variations in the metabolic reaction to SARS-CoV-2 infection could explain the striking differences in the susceptibility to infection and the risk of severe disease. Here, we used untargeted metabolomics to examine novel metabolic pathways related to SARS-CoV-2 susceptibility and COVID-19 clinical severity using capillary electrophoresis coupled to a time-of-flight mass spectrometer (CE-TOF-MS) in plasma samples. We included 27 patients with confirmed COVID-19 early after symptom onset who were prospectively followed and 29 healthcare workers heavily exposed to SARS-CoV-2 but with low susceptibility to infection ( nonsusceptible). We found that the metabolite profile was predictive of the study group. We identified a total of 55 metabolites as biomarkers of SARS-CoV-2 susceptibility or COVID-19 clinical severity. We report the discovery of new plasma biomarkers for COVID-19 that provide mechanistic explanations for the clinical consequences of SARS-CoV-2, including mitochondrial and liver dysfunction as a consequence of hypoxemia (citrulline, citrate, and BAIBA), energy production and amino acid catabolism (L-glycine, L-alanine, L-serine, L-proline, L-aspartic acid and L-histidine), endothelial dysfunction and thrombosis (citrulline, L-ADMA, 2-AB, and Neu5Ac), and we found interconnections between these pathways. In summary, in this first report of the metabolomic profile of individuals with severe COVID-19 and SARS-CoV-2 susceptibility by CE-MS, we define several metabolic pathways implicated in SARS-CoV-2 susceptibility and COVID-19 clinical progression that could be developed as biomarkers of COVID-19.
Subject(s)
COVID-19 , Hypoxia , Thrombosis , Liver DiseasesABSTRACT
BackgroundWhile there are no treatments with proven efficacy for patients with severe coronavirus disease 2019 (COVID-19), tocilizumab has been proposed as a candidate therapy, especially among patients with higher systemic inflammation. MethodsWe conducted a cohort study of patients hospitalized with COVID-19 in Spain. The primary outcome was time to death and the secondary outcome time to intensive care unit admission (ICU) or death. We used inverse-probability weighting to fit marginal structural models adjusted for time-varying covariates to determine the causal relationship between tocilizumab use and the outcomes. ResultsA total of 1,229 and 10,673 person/days were analyzed. In the adjusted marginal structural models, a significant interaction between tocilizumab use and high C- reactive protein (CRP) levels was detected. Tocilizumab was associated with decreased risk of death (aHR 0.34, 95% CI 0.16-0.72, p=0.005) and ICU admission or death (aHR 0.38, 95% CI 0.19-0.81, p=0.011) among patients with baseline CRP >150 mg/L, but not among those with CRP [≤]150 mg/L. Exploratory subgroup analyses yielded point estimates that were consistent with these findings. ConclusionsIn this large observational study, tocilizumab was associated with a lower risk of death or ICU or death in patients with higher CRP levels. While the results of ongoing clinical trials of tocilizumab in patients with COVID-19 will be important to establish its safety and efficacy, our findings have implications for the design of future clinical trials and support the use of tocilizumab among subjects with higher CRP levels.