Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study

Abstract

ObjectivesTo prospectively investigate in patients with severe COVID-19-associated cytokine storm syndrome (CSS) whether an intensive course of glucocorticoids with or without tocilizumab accelerates clinical improvement, reduces mortality and prevents invasive mechanical ventilation, in comparison with a historic control group of patients who received supportive care only.MethodsFrom 1 April 2020, patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two out of three biomarkers with important elevations (C-reactive protein >100 mg/L; ferritin >900 µg/L; D-dimer >1500 µg/L), received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2–5). If the respiratory condition had not improved sufficiently (in 43%), the interleukin-6 receptor blocker tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Control patients with COVID-19-associated CSS (same definition) were retrospectively sampled from the pool of patients (n=350) admitted between 7 March and 31 March, and matched one to one to treated patients on sex and age. The primary outcome was ≥2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital. Secondary outcomes were hospital mortality and mechanical ventilation.ResultsAt baseline all patients with COVID-19 in the treatment group (n=86) and control group (n=86) had symptoms of CSS and faced acute respiratory failure. Treated patients had 79% higher likelihood on reaching the primary outcome (HR: 1.8; 95% CI 1.2 to 2.7) (7 days earlier), 65% less mortality (HR: 0.35; 95% CI 0.19 to 0.65) and 71% less invasive mechanical ventilation (HR: 0.29; 95% CI 0.14 to 0.65). Treatment effects remained constant in confounding and sensitivity analyses.ConclusionsA strategy involving a course of high-dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated CSS.

Ferritin in the coronavirus disease 2019 (COVID‐19): A systematic review and meta‐analysis

“…Similarly, Toniati et al also showed that tocilizumab can improve the prognosis of COVID‐19 patients with ARDS, ferritin, CRP, and fibrinogen levels that steadily decrease after 10 days of tocilizumab treatment 82 . Ramiro et al observed that patients with COVID‐19‐associated cytokine storm syndrome treated by tocilizumab and glucocorticoids have better treatment benefit, especially those with serum ferritin levels above the median value of 1419 µg/L 83 . However, Pérez‐Sáez et al found that the level of CRP rather than the one of ferritin decreases after tocilizumab treatment in patients who need kidney transplant, and the decrease is positively related to survival 84 …”

Tocilizumab in the treatment of rapidly evolving COVID-19 pneumonia and multifaceted critical illness: A retrospective case series

“…The aforementioned concerns remain to be further clarified in upcoming TCZ randomized control trials [ 48 , 49 ]. Recently, a therapeutic regime involving a course of high-dose methylprednisolone, followed by TCZ if needed, showed that it may accelerate respiratory recovery, reduce hospital mortality and the rate of invasive mechanical ventilation in COVID-19-associated cytokine storm syndrome [ 50 ]. Of note, the preliminary findings of a phase III global TCZ versus placebo study (EMPACTA) showed that the administration of TCZ in patients with COVID-19 associated pneumonia plus standard of care were 44% less likely to progress to mechanical ventilation or death compared to patients who received placebo plus standard of care [(log-rank p-value = 0.0348; hazard ratio (95% CI) = 0.56 (0.32, 0.97)] [ 51 ].…”

“…This retrospective case-series has several limitations, which prevent its generalizability. First, our patients might have improve to concomitant empiric antiviral and steroid therapy [ 4 , [7] , [8] , [9] , [10] , 30 , 47 , 50 ]. However, given the severity of their clinical status, the administration of TCZ might have helped by mitigating a full blown picture of hyperinfammation.…”

“…We are uncertain of the putative effect of TCZ on viral clearance although the RT-PCR results were negative in survivors post therapy. Surely, future studies should explore the indications and the optimal TCZ regime in COVID-19 critically ill patients [ [48] , [49] , [50] , [51] , [52] ]. In this study, the lack of a comparative control arm, the small number of enrolled patients, and the absence of a detailed laboratory documentation and follow-up rendered its power.…”

Intensive immunosuppression reduces deaths in covid-19-associated cytokine storm syndrome, study finds

“…Intensive immunosuppressive treatment with high dose glucocorticoids, followed by an interleukin-6 (IL-6) receptor antagonist where needed, accelerates respiratory recovery and reduces deaths in patients with covid-19-associated cytokine storm syndrome (CSS), an observational study1 has shown.…”