Identification and Analysis of Shared Risk Factors in Sepsis and High Mortality Risk COVID-19 Patients

Abstract

BACKGROUNDCoronavirus disease 2019 (COVID-19) is a novel coronavirus strain disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease is highly transmissible and severe disease including viral sepsis has been reported in up to 16% of hospitalized cases. The admission characteristics associated with increased odds of hospital mortality among confirmed cases of COVID-19 include severe hypoxia, low platelet count, elevated bilirubin, hypoalbuminemia and reduced glomerular filtration rate. These symptoms correlate highly with severe sepsis cases. The diseases also share similar comorbidity risks including dementia, type 2 diabetes mellitus, coronary heart disease, hypertension and chronic renal failure. Sepsis has been observed in up to 59% of hospitalized COVID-19 patients.It is highly desirable to identify risk factors and novel therapy/drug repurposing avenues for late-stage severe COVID-19 patients. This would enable better protection of at-risk populations and clinical stratification of COVID-19 patients according to their risk for developing life threatening disease. METHODSAs there is currently insufficient data available for confirmed COVID-19 patients correlating their genomic profile, disease severity and outcome, co-morbidities and treatments as well as epidemiological risk factors (such as ethnicity, blood group, smoking, BMI etc.), a direct study of the impact of host genomics on disease severity and outcomes is not yet possible. We therefore ran a study on the UK Biobank sepsis cohort as a surrogate to identify sepsis associated signatures and genes, and correlated these with COVID-19 patients.Sepsis is itself a life-threatening inflammatory health condition with a mortality rate of approximately 20%. Like the initial studies for COVID-19 patients, standard genome wide association studies (GWAS) have previously failed to identify more than a handful of genetic variants that predispose individuals to developing sepsis. RESULTSWe used a combinatorial association approach to analyze a sepsis population derived from UK Biobank. We identified 70 sepsis risk-associated genes, which provide insights into the disease mechanisms underlying sepsis pathogenesis. Many of these targets can be grouped by common mechanisms of action such as endothelial cell dysfunction, PI3K/mTOR pathway signaling, immune response regulation, aberrant GABA and neurogenic signaling. CONCLUSIONThis study has identified 70 sepsis related genes, many of them for the first time, that can reasonably be considered to be potentially relevant to severe COVID-19 patients. We have further identified 59 drug repurposing candidates for 13 of these targets that can be used for the development of novel therapeutic strategies to increase the survival rate of patients who develop sepsis and potentially severe COVID-19.

Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

“…Due to the limited number of patients with confirmed mild disease we were unfortunately not able to use this cohort directly as our control set due to its small size and lack of statistical power. We therefore adopted similar control cohort criteria to our previous sepsis study 4 , based on evidence of shared risk factors and that severe COVID-19 patients often present with a similar pattern of co-morbid chronic conditions to those with sepsis. We selected patients who had not developed sepsis in spite of having been exposed to the most common sepsis-causing pathogens as well as having at least one of the most common chronic comorbidities known to increase a patient's risk of developing sepsis and COVID-19 ( Figure 2).…”

“…In our previous paper, we explored the shared risk factors between sepsis (a major clinical feature in hospitalized COVID-19 patients) and severe COVID-19 disease 4 . We observed that 59% of hospitalized COVID-19 cases also have sepsis 5 , and that the two diseases share similar co-morbidity risks 6 .…”

Exploration of prognostic factors for critical COVID-19 patients：a nomogram analysis

“…of patients in intensive care died from the disease 9 . According to the survey, COVID-19 is signi cantly associated with age, gender and potential comorbidity, with the highest mortality rate among elderly men 10 . According to the general data and relevant clinical indicators of critically ill coronavirus pneumonia patients , it is very important to explore relevant risk factors.…”

COVID-19: A Challenge to Physiology of Aging

“…It does seem reasonable to associate inflammaging with proneness to exaggerated humoral immune responses manifested in the elderly as increases in the incidences of autoimmune disorders ( Vadasz et al, 2013 ) and systemic septic responses ( Mayr et al, 2014 ; Starr and Saito, 2014 ), sepsis being especially similar to the cytokine storm observed in severe COVID-19 cases ( Colantuoni et al, 2020 ; Das et al, 2020 ; Li et al, 2020 ). According to the hyperfunction theory of aging in general, inflammaging is a particular manifestation of the primary aging-associated hyperactivity of almost everything in the body, including the immune system, predominantly its inborn and humoral branches, rather than a results of a reduced ability of its T-cellular branch to control B-cells, monocytes/macrophages and neutrophils.…”