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

Abstract

Background Cytokine storm is a marker of COVID-19 illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. Research Question To identify if immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm. 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. 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 antibody (tocilizumab) or anti-interleukin-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. Results 5,776 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 lactate dehydrogenase (76.2%) alone or in combination, followed by ferritin (63.2%) and C-reactive protein (8.4%). More than 80% of patients had an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination had lower mortality compared to standard of care (Hazard Ratio (HR):0.44, 95% confidence interval (CI): 0.35-0.55; p <0.0001) and when compared to corticosteroids alone (HR:0.66, 95%CI: 0.53-0.83; p-value=0.004), or in combination with anakinra (HR:0.64, 95%CI:0.50-0.81; p-value=0.003) . Corticosteroids when administered alone (HR:0.66, 95%CI:0.57-0.76; p<0.0001) or in combination with tocilizumab (HR:0.43, 95%CI:0.35-0.55; p<0.0001) or anakinra (HR:0.68, 95%CI:0.57-0.81; p<0.0001) improved hospital survival compared to standard of care. Interpretation The combination of corticosteroids with tocilizumab had superior survival outcome when compared to standard of care and 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 COVID-19 cytokine storm compared to standard of care.

Combination of Tocilizumab and Steroids to Improve Mortality in Patients with Severe COVID-19 Infection: A Spanish, Multicenter, Cohort Study

“…A singlecentre Italian study jointly analysed data regarding the administration of both tocilizumab and steroids, together or separately, and suggested the need for evaluating combined use of these therapies [22]. More recently, Narain et al published the results of a retrospective cohort study and concluded that the combination of corticosteroids with tocilizumab showed superior survival outcome compared with SoC treatment and treatment with corticosteroids alone or in combination with anakinra [23]. These results are consistent with our findings.…”

Risk of Hepatitis B Virus Reactivation in Rheumatoid Arthritis Patients Undergoing Tocilizumab-Containing Treatment

“…Without a suitable comparison population, the relationship of steroid and bDMARD treatment with HBV reactivation risk could not be observed in this study. Recently, tocilizumab with steroids has been applied in severe COVID-19 patients to reduce the cytokine storm [ 10 , 40 ], and the risk of HBV reactivation needs to be considered. Our reports indeed strengthen the evidence of the high HBV reactivation risk of TCZ in this population.…”

“…Tocilizumab (TCZ), a humanized monoclonal antibody that selectively neutralizes both the soluble and membrane-bound forms of interleukin (IL)-6 receptor, is a developed biological agent that effectively alleviates RA disease symptoms. Recently, tocilizumab has been applied in patients with severe COVID-19 to reduce the cytokine storm and has the potential to reduce the mortality rate [ 9 , 10 ]. However, the risk of HBV reactivation needs to be considered.…”

Treatment With Tocilizumab for Patients With COVID‐19 Infections: A Case‐Series Study

“…In particular, the safety of TCZ in this setting including increased risk of superinfections should be investigated thoroughly in long‐term trials, given its very long and dose‐dependent half‐life. In addition, the question of whether combination therapy with TCZ plus corticosteroids would improve outcomes in COVID‐19 patients is worth exploring further, given that a recent study suggested that the combination of corticosteroids with TCZ was associated with the lowest mortality compared with other treatment groups (no immunomodulatory treatment, corticosteroids alone, or corticosteroids plus anakinra) 22 . Second, the optimal dosing regimen and timing of TCZ for the treatment of COVID‐19 infections have not been well established in the literature.…”

“…In addition, the question of whether combination therapy with TCZ plus corticosteroids would improve outcomes in COVID-19 patients is worth exploring further, given that a recent study suggested that the combination of corticosteroids with TCZ was associated with the lowest mortality compared with other treatment groups (no immunomodulatory treatment, corticosteroids alone, or corticosteroids plus anakinra). 22 Second, the optimal dosing regimen and timing of TCZ for the treatment of COVID-19 infections have not been well established in the literature. Last, future research is needed to determine which patients with COVID-19 are likely to benefit most from TCZ.…”