ABSTRACT: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused more than 7 million deaths out of more than 777 million confirmed cases since the pandemic began (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Disease severity is multi-factorial, contributing to over 5,100 new hospitalizations in the 28-day period leading up to April 2025 (https://data.who.int/dashboards/covid19/hospitalizations?n=c). In intensive care units (ICUs), the mortality rates exhibited significant variation across countries and regions, reaching 22.4% in Europe, 26.9% in Asia, 24% in Africa, 25% in North America, and 16.2% in Central and South America, according to the largest cohort of hospitalized COVID-19 patients during 2020-2021 (ISARIC clinical group; n=708,158).1 Most severe cases were associated with old age, male gender, and chronic conditions, where type 2 diabetes mellitus (T2D) and hypertension (HTN) were the most frequent pre-existing diseases in hospitalized patients.2, 3 Due to the nature of these comorbidities, the immune system is heavily challenged by the burden of a SARS-CoV-2 infection. Patients with diabetes and hypertension are prone to higher disease severity, higher mortality rates, long COVID, secondary infections, and accelerated cardiac and renal failure due to impaired immune system functions.4, 5 The response to SARS-CoV-2 infection has been inspected among asymptomatic, mild, and severe cases at different OMICs layers. In mass spectrometry (MS)-based studies, the protein profiles of infected patients revealed significant markers to the disease severity from circulation,6 cerebrospinal fluid (CSF),7 nasopharyngeal swabs,8 and from multi-organ tissues.9 Nevertheless, limited studies have reported the proteomics profile of subgroups within severe cases with respect to comorbidities10 and outcome during ICU stay. Consequently, proteomic signatures specific to T2D and HTN may be masked in general cohort studies, obscuring the distinct molecular mechanisms that drive mortality in this high-risk population. This study investigates the protein signatures from a critical COVID-19 cohort with and without comorbidities (T2D and HTN), recruited on the first day of ICU (FDI) and on the last day of ICU (LDI). We hypothesized that severe COVID-19 patients with dual comorbidities possess a unique protein profile on the FDI compared to non-comorbid patients. We hypothesized that the proteomic profile of comorbid COVID-19 patients can distinguish survivors from deceased patients on the LDI. Therefore, we collected plasma samples from critical COVID-19 patients on the FDI and LDI and from healthy donors. The plasma proteomics were measured and analyzed based on these grouping strategies.
Sunkyu Choi