MEDIATION OF BIOMARKERS OF INFLAMMATION IN SLEEP-RELATED HYPOXIA AND COVID-19 CLINICAL OUTCOMES

ABSTRACT

Introduction: Central to the pathophysiology of SARS-CoV-2 is immune dysregulation and systemic inflammation, however, it is yet unknown whether sleep-related hypoxemia-which we have recently noted to be associated with worse COVID-19 clinical outcomes-is mediated by these biomarkers and pathways. Methods: Data from patients who tested positive for SARS-CoV-2 and part of the integrated Cleveland Clinic COVID-19 and sleep laboratory registries from March-November 2020 were included. To assess the mediation effect of biomarkers, the relationship between sleep-related hypoxia measures (% sleep time<90%SaO2,T90) and moderate/severe WHO-7 COVID-19 score (use of supplemental oxygen, non-invasive ventilation, mechanical ventilation/ ECMO or death) was first tested. The mediation effect, or natural indirect effect, of biomarkers of inflammation (C-Reactive Protein (CRP), white blood cell (WBC) count (with a focus on lymphocyte count) and lactate) was then estimated by logistic regression models adjusted for demographics, comorbidities, smoking pack year and site location using PROC CAUSALMED statement in SAS software (version 9.4, Cary, NC). Results: The analytic sample included 446 patients hospitalized due to COVID-19 age63.3.±13.8 years,51.3% female,39% African American with body mass index(BMI)=36.1±9.3kg/ m2. Thirty-six percent used supplemental oxygen, 4% used highflow or non-invasive ventilation,5% required ECMO or mechanical ventilation and 2% died. Hypoxic measures were associated with moderate/severe WHO-7 COVID-19 outcome: T90 median (>1.8%vs.≤1.8%) (OR=2.04, 95%CI1.28-3.23,p=0.003), 5% increases in both mean SaO2 (OR=0.43, 95%CI 0.26-0.70,p=<0.001) and minimum SaO2 (OR=0.84, 95%CI 0.72-0.99,p=0.03). CRP was associated with mean SaO2 (p=0.040) and minimum SaO2 (p=0.029), likewise mediation analysis showed that there was a significant natural indirect effect of CRP in both hypoxia measures (OR=0.86,95%CI 0.73-0.99,p=0.036;OR=0.95,95%CI 0.90- 1.00,p=0.034 respectively). WBC count, but not lymphocyte count subset, was associated with mean SaO2 (p=0.044), but the natural indirect effect was not significant (p=0.23. Lactate was associated with minimum SaO2 (p=0.044), but the natural indirect effect was not significant (p=0.23). T90 median was not associated with CRP(p=0.13), WBC count(p=0.87) or lactate(p=0.28). Conclusion: CRP appears to represent a relevant mediator of sleep-related hypoxia and WHO-7 clinical outcomes. Further investigation is needed to elucidate if treatment of sleep-related hypoxia downregulates biomarkers of systemic inflammation to modify disease course.