Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease 2019 Cytokine Storm

Abstract

Background: Cytokine storm is a marker of coronavirus disease 2019 (COVID-19) illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes.

Research question: Do immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm (CCS)?

Study design and 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 24, 2020, were included. CCS was defined by inflammatory markers: ferritin, > 700 ng/mL; C-reactive protein (CRP), > 30 mg/dL; or lactate dehydrogenase (LDH), > 300 U/L. Patients were subdivided into six groups: no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-IL-6 antibody (tocilizumab), or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality.

Results: Five thousand seven hundred seventy-six patients met the inclusion criteria. The most common comorbidities were hypertension (44%-59%), diabetes (32%-46%), and cardiovascular disease (5%-14%). Patients most frequently met criteria with high LDH (76.2%) alone or in combination, followed by ferritin (63.2%) and CRP (8.4%). More than 80% of patients showed an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination showed lower mortality compared with patients receiving standard-of-care (SoC) treatment (hazard ratio [HR], 0.44; 95% CI, 0.35-0.55; P < .0001) and with patients treated with corticosteroids alone (HR, 0.66; 95% CI, 0.53-0.83; P = .004) or in combination with anakinra (HR, 0.64; 95% CI, 0.50-0.81; P = .003). Corticosteroids when administered alone (HR, 0.66; 95% CI, 0.57-0.76; P < .0001) or in combination with tocilizumab (HR, 0.43; 95% CI, 0.35-0.55; P < .0001) or anakinra (HR, 0.68; 95% CI, 0.57-0.81; P < .0001) improved hospital survival compared with SoC treatment.

Interpretation: The combination of corticosteroids with tocilizumab showed superior survival outcome when compared with SoC treatment as well as treatment with corticosteroids alone or in combination with anakinra. Furthermore, corticosteroid use either alone or in combination with tocilizumab or anakinra was associated with reduced hospital mortality for patients with CCS compared with patients receiving SoC treatment.

Keywords: SARS-CoV-2; anakinra; coronavirus; corticosteroids; infection; tocilizumab.

Figure 1

Consort diagram showing selection of patients, inclusion criteria, and exclusion criteria applied to form the final cohort of 3,098 patients. Exclusion criteria included receiving any of the immunomodulatory drugs before the diagnosis of cytokine storm, age younger than 18 years, having received all three study drugs, having received the combination of anakinra and tocilizumab, or missing clinically relevant covariates. Three thousand ninety-eight patients remained in the final analysis. CCS = coronavirus disease 2019 cytokine storm; COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; LDH = lactate dehydrogenase; PCR = polymerase chain reaction.

Figure 2

Model-based Kaplan-Meier plots showing treatment groups (adjusted for covariates). This figure represents the unadjusted Kaplan-Meier plots for treatment groups with number of patients at risk (ie, patients who remained admitted at the hospital at that time point). The treatment groups are as follows: A = anakinra only; S = steroid only; SA = steroids plus anakinra; SoC = standard of care; ST = steroids plus tocilizumab; T = tocilizumab only.

Figure 3

Graph showing hazard ratios for treatment differences using Tukey’s adjustment for multiple comparisons. The figure represents pairwise comparisons for all treatment groups with Tukey’s adjustment for multiple comparison. Groups in red are statistically significant. The groups are as follows: A = anakinra only; S = steroid only; SA = steroids plus anakinra; SoC = standard of care; ST = steroids plus tocilizumab; T = tocilizumab only.