Comparative Survival Analysis of Immunomodulatory Therapy for COVID-19 'Cytokine Storm': A Retrospective Observational Cohort Study

Abstract

Background: Cytokine storm is a marker of COVID-19 illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. Methods: We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020 and April 15, 2020, were included. Cytokine storm was defined by inflammatory markers: ferritin >700ng/mL, C-reactive protein >30mg/dL, or lactate dehydrogenase >300U/L. Patients were subdivided into six groups -no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-interleukin 6 (IL-6) antibody (tocilizumab) or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. Results: There were 3,098 patients who met inclusion criteria. The most common comorbidities were hypertension (40-56%), diabetes (32-43%) and cardiovascular disease (2-15%). Patients most frequently met criteria with high lactate dehydrogenase (74·8%) alone, or in combination, followed by ferritin (71·4%) and C-reactive protein (9·4%). More than 80% of patients had an elevated D-dimer. Patients treated with a combination of tocilizumab and corticosteroids (Hazard Ratio [HR]: 0·459, 95% Confidence Interval [CI]: 0·295-0·714; p<0·0001) or corticosteroids alone (HR: 0·696, 95% CI: 0·512-0·946; p=0·01) had improved hospital survival compared to standard of care. Corticosteroids and tocilizumab was associated with increased survival when compared to corticosteroids and anakinra (HR: 0·612, 95% CI: 0·391-0·958; p-value=0·02). Conclusions: When compared to standard of care, corticosteroid and tocilizumab used in combination, or corticosteroids alone, was associated with reduced hospital mortality for patients with COVID-19 cytokine storm. Funding Statement: A.S.C. was supported by The Primary Immune Deficiency Treatment Consortium (U54 AI 082973), funded jointly by the National Center for Advancing Translational Sciences (NCATS) and the National Institute of Allergy and Infectious Diseases (NIAID). O.B. was supported by grants from the US DOD (#W81XWH-15-1-0614) and the New York State Spinal Cord Injury Research Board (DOH01-ISSCI6- 2016-00018). N.H. was supported by a grant from the Patient Centered Outcomes Research Institute (PCORI # AD-1511-33066). Declaration of Interests: There are no competing interests. Ethics Approval Statement: The Institutional Review Board for the Feinstein Institutes of Medical Research at Northwell Health approved this study as minimal-risk research and waived the requirement for informed consent.