Article Text

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
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  1. Sofia Ramiro1,2,
  2. Rémy L M Mostard3,
  3. César Magro-Checa1,
  4. Christel M P van Dongen1,
  5. Tom Dormans4,
  6. Jacqueline Buijs5,
  7. Michiel Gronenschild3,
  8. Martijn D de Kruif3,
  9. Eric H J van Haren3,
  10. Tom van Kraaij3,
  11. Mathie P G Leers6,
  12. Ralph Peeters1,
  13. Dennis R Wong7,
  14. Robert B M Landewé1,8
  1. 1 Rheumatology, Zuyderland Medical Center, Heerlen, Limburg, The Netherlands
  2. 2 Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
  3. 3 Department of Pulmonology, Zuyderland Medical Center, Heerlen, Limburg, The Netherlands
  4. 4 Department of Intensive Care, Zuyderland Medical Center, Heerlen, Limburg, The Netherlands
  5. 5 Department of Internal Medicine, Zuyderland Medical Center, Heerlen, Limburg, The Netherlands
  6. 6 Department of Clinical Chemistry and Hematology, Zuyderland Medical Center, Heerlen, Limburg, The Netherlands
  7. 7 Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Heerlen, Limburg, The Netherlands
  8. 8 Amsterdam Rheumatology Center, AMC, Amsterdam, The Netherlands
  1. Correspondence to Dr Sofia Ramiro, Rheumatology, Zuyderland Medical Center, Heerlen, Limburg 6419, The Netherlands; sofiaramiro{at}gmail.com

Abstract

Objectives To 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.

Methods From 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.

Results At 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.

Conclusions A 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.

  • cytokines
  • glucocorticoids
  • biological therapy
  • epidemiology

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors SR, RLMM, CMC and RBML designed the study. All authors contributed to data collection. SR and RBML analysed the data. SR, RLMM and RBML critically interpreted the results and drafted the first version of the manuscript. All coauthors discussed the findings together, critically reviewed the manuscript and approved its final version.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests SR reports personal fees from AbbVie, personal fees from Eli Lilly, grants and personal fees from MSD, personal fees from Novartis, personal fees from UCB, personal fees from Sanofi, outside the submitted work. RLMM reports personal fees from Boehringer Ingelheim, personal fees from Roche, personal fees from Galapagos, outside the submitted work. CMC is a clinical trial investigator for a study sponsored by Lilly and was a subinvestigator for a study sponsored by GSK. CvD reports personal fees from Novartis, personal fees from Roche, outside the submitted work. TD reports grants from Adrenomed, grants from Inotrem, grants from Roche, grants from Shionogi and Co, other from CASTOR, outside the submitted work. MG reports personal fees from Roche, personal fees from MSD, outside the submitted work. MdK reports personal fees from ALK, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Sanofi Genzyme, outside the submitted work. ML reports grants from AstraZeneca, grants from Pfizer, personal fees from Roche, outside the submitted work. RP reports grants and personal fees from Pfizer, grants and personal fees from AbbVie, outside the submitted work. RL reports personal fees from AbbVie, personal fees from BMS, personal fees from Galapagos, personal fees from Gilead, personal fees from Jansen, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from UCB, outside the submitted work; and owner and director of Rheumatology Consultancy, a company that provides consultancy and read services for clinical trials.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Obtained.

  • Ethics approval The Medical Ethics Committee and the Board of ZMC approved the study protocol and the study started enrolling patients on 1 April 2020.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data may be obtained from a third party and are not publicly available.

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