Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19

JAMA Intern Med. 2021 Jan 1;181(1):41-51. doi: 10.1001/jamainternmed.2020.6252.

Abstract

Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness.

Objective: To test whether tocilizumab decreases mortality in this population.

Design, setting, and participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding.

Exposures: Treatment with tocilizumab in the first 2 days of ICU admission.

Main outcomes and measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences.

Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%).

Conclusions and relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adrenal Cortex Hormones / therapeutic use
  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Anticoagulants / therapeutic use
  • COVID-19 / drug therapy*
  • COVID-19 / physiopathology
  • Cohort Studies
  • Critical Illness
  • Early Medical Intervention
  • Female
  • Hospital Mortality*
  • Hospitalization
  • Humans
  • Intensive Care Units
  • Male
  • Middle Aged
  • Mortality
  • Organ Dysfunction Scores
  • Patient Positioning
  • Prone Position
  • Proportional Hazards Models
  • Receptors, Interleukin-6 / antagonists & inhibitors
  • Respiration, Artificial
  • Respiratory Insufficiency / physiopathology
  • Respiratory Insufficiency / therapy*
  • SARS-CoV-2
  • Young Adult

Substances

  • Adrenal Cortex Hormones
  • Antibodies, Monoclonal, Humanized
  • Anticoagulants
  • Receptors, Interleukin-6
  • tocilizumab

Supplementary concepts

  • COVID-19 drug treatment