Plasma Sphingomyelin Disturbances: Unveiling Its Dual Role as a Crucial Imunopathological Factor and a Severity Prognostic Biomarker in COVID-19 (preprint)

SARS-CoV-2 infection triggers distinct patterns of disease development, characterized by significant alterations in host regulatory responses. Severe cases exhibit profound lung inflammation and systemic repercussions. Remarkably, critically ill patients display a "lipid storm", influencing the inflammatory process and tissue damage. Sphingolipids (SL) play pivotal roles in various cellular and tissue processes, including inflammation, metabolic disorders, and cancer. In this study, we employed high-resolution mass spectrometry to investigate SL metabolism in plasma samples obtained from control subjects (n=55), COVID-19 patients (n=204), and convalescent individuals (n=77). These data were correlated with inflammatory parameters associated with the clinical severity of COVID-19. Additionally, we utilized RNAseq analysis to examine the gene expression of enzymes involved in the SL pathway. Our analysis revealed the presence of thirty-eight SL species from seven families in the plasma of study participants. The most profound alterations in the SL species profile were observed in patients with severe disease. Notably, the predominant sphingomyelin (SM d18:1) species emerged as a potential biomarker for COVID-19 severity, showing decreased levels in the plasma of convalescent individuals. Elevated SM levels were positively correlated with age, hospitalization duration, clinical score, neutrophil count, as well as the production of IL-6 and IL-8. Intriguingly, we identified a putative protective effect against disease severity mediated by SM (d18:1/24:0), while ceramide (Cer) d18:1/24:1 and d18:1/24:0 was associated with increased risk. Moreover, we observed enhanced expression of key enzymes involved in SL pathway, in blood cells from severe COVID-19 patients, suggesting a primary flow towards Cer generation in tandem with SM synthesis. These findings underscore the potential of SM as a prognostic biomarker for COVID-19 and highlight promising pharmacological targets. By targeting sphingolipid pathways, novel therapeutic strategies may emerge to mitigate the severity of COVID-19 and improve patient outcomes.

Effects of moderate-intensity intermittent hypoxic training on health outcomes of patients recovered from covid-19: the AEROBICOVID study protocol for a randomised controlled trial (preprint)

Background: Recent studies point to a lower number and a reduction in the severity of cases in higher altitude cities, with decreased oxygen concentration. Specific literature has shown several benefits of physical training, so, in this sense, physical training with hypoxic stimulus appears as an alternative that supports the conventional treatments of the COVID-19 patient's recovery. Thus, this study's primary aim is to analyse the effects of moderate-intensity intermittent hypoxic training on health outcomes in COVID-19 recovered patients. Methods: A clinical trial controlled double-blind study was designed. Participants (30-69 years old) will be recruited among those with moderate to severe COVID-19 symptoms, approximately 30 days after recovery. They will be included in groups according to the training (T) and recovery (R) association with hypoxia (H) or normoxia (N): a) TH:RH, b) TN:RH, c) TN:RN, and, last, d) the control group. The 8-week exercise bike intervention will be carried out with a gradual load increase according to the established periods, three times a week in sets of 5 minutes, 90 to 100% of the anaerobic threshold (AT), and a 2,5-minute break. Blood will be collected for genotyping. First, after four weeks (partial), after eight weeks, and later, four weeks after the end of the physical training intervention, participants will perform assessments. The primary outcome is the maximum oxygen consumption (VO2max). The secondary outcomes include lung function, inflammatory mediators, haematological, autonomic parameters, AT, body composition analysis, quality of life, mental health, anthropometric measurements, and physical fitness. The statistical analysis will be executed using the linear regression model with mixed effects at a 5% significance level. Discussion: This study is designed to provide evidence to support the clinical benefits of moderate-intensity intermittent hypoxic training as a part of the treatment of patients recovered from COVID-19. It may also provide evidence on the efficacy and safety of intermittent hypoxic training in different health conditions. Lastly, this study presents an innovative strategy enabling up to 16 participants in the same training session.Trial registration: Brazilian Clinical Trials Registry, RBR-5d7hkv. Registered after the start of inclusion; 3 November 2020; https://ensaiosclinicos.gov.br/rg/RBR-5d7hkv