Tocilizumab for treatment of mechanically ventilated patients with COVID-19

Abstract

Background: Severe COVID-19 can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers. This presentation is consistent with cytokine release syndrome in chimeric antigen receptor T cell therapy, for which IL-6 blockade is approved treatment.

Methods: We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability post-intubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared to tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability weighting (IPTW).

Findings: 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean 55 vs. 60 years), less likely to have chronic pulmonary disease (10% vs. 28%), and had lower D-dimer values at time of intubation (median 2.4 vs. 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death [hazard ratio 0.55 (95% CI 0.33, 0.90)] and improved status on the ordinal outcome scale [odds ratio per 1-level increase: 0.59 (0.36, 0.95)]. Though tocilizumab was associated with an increased proportion of patients with superinfections (54% vs. 26%; p<0.001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection [22% vs. 15%; p=0.42].

Interpretation: In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with a decreased likelihood of death despite higher superinfection occurrence. Randomized controlled trials are urgently needed to confirm these findings.

Keywords: COVID-19; SARS-CoV-2; interleukin-6; tocilizumab.

Figure 1.. Study cohort flow chart.

IPTW=inverse probability of treatment weighted MI=multiple imputation

Figure 2.

Kaplan-Meier estimates for probability of survival as a function of time since mechanical ventilation onset, stratified by tocilizumab treatment (n=154; n=46 deaths).

Figure 3.. Patient status post-ventilator onset on a six-level ordinal scale integrating superinfection occurrence, stratified by tocilizumab treatment.

A. The distribution of patient status, by number of days after onset of mechanical ventilation through day 28 of follow-up. B. Individual patient trajectories on the six-level ordinal scale over the study period. Each row represents changes in individual patient status from time of onset of mechanical ventilation until event (death) or end of the study period (May 19, 2020). Horizontal lines correspond to elapsed time, with colors corresponding to clinical status of the patient. Solid circles represent death, and hollow circles represent discharge from hospital (alive). The middle panel indicates the most recent patient status. Grey vertical lines mark 28-day follow-up.

Figure 3.. Patient status post-ventilator onset on a six-level ordinal scale integrating superinfection occurrence, stratified by tocilizumab treatment.

A. The distribution of patient status, by number of days after onset of mechanical ventilation through day 28 of follow-up. B. Individual patient trajectories on the six-level ordinal scale over the study period. Each row represents changes in individual patient status from time of onset of mechanical ventilation until event (death) or end of the study period (May 19, 2020). Horizontal lines correspond to elapsed time, with colors corresponding to clinical status of the patient. Solid circles represent death, and hollow circles represent discharge from hospital (alive). The middle panel indicates the most recent patient status. Grey vertical lines mark 28-day follow-up.