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.

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories

“…We further quantified the correlation of each protein or metabolite with disease severity. Consistent with previous reports (Somers et al, 2020), several cytokines associated with immune defense and inflammation, including IFN-γ, IL6, and IL8 showed positive correlations with disease severity and exhibited the highest levels in ICU samples (Table S4, Figures 1C and S1E). Similarly, the inflammation and hypoxia associated metabolite lactate (Ivashkiv, 2020) exhibited a positive correlation with disease severity (Table S5).…”

Effects of Tocilizumab in COVID-19 patients: a cohort study

“…Our discharge rate was higher than the 18% reported by Rimland et al but lower than the 63% reported by Campochiaro et al [29,30]. We observed a 30-day mortality rate of 15%, which is comparable to prior studies ranging between 13% and 27% [11,13,[15][16][17][29][30]. So far, only a few studies have compared mortality associated with tocilizumab versus standard of care in COVID-19 patients.…”

“…So far, only a few studies have compared mortality associated with tocilizumab versus standard of care in COVID-19 patients. Campochiaro et al found no signi cant difference in 28-day mortality (15% vs. 22%, p=0.15) whereas Somers et al identi ed a 45% reduction in the risk of death (HR 0.55, 95% CI 0.33-0.90) in mechanically ventilated patients [15,30]. Guaraldi et al also found tocilizumab to be associated with a reduced risk of all-cause mortality after adjusting for age, sex, recruiting center, duration of symptoms, and SOFA score (HR 0.38, 95% CI 0.17-0.83) [17].…”

“…Kimmig et al found an even higher incidence of infection of 64.2% but they had a longer follow-up time at 8 weeks and a broader de nition for infection to also capture highly suspected infections rather than just con rmed [31]. Another study by Somers et al found a two-fold higher incidence of infections in patients who received tocilizumab at 28 days (54% vs. 26%, p<0.001) but more patients in the tocilizumab arm received steroids [15]. To date, the only study who excluded steroid use reported a 13% infection incidence at 28 days [34].…”

“…Previously approved for the treatment of severe or life-threatening chimeric antigen receptor (CAR) T cell-induced CRS, its ability to down regulate the immune system may have positive implications for COVID-19 [8,9]. Studies have demonstrated tocilizumab to be associated with improvements in in ammatory markers, clinical response, and survival [10][11][12][13][14][15][16][17][18]. During an unprecedented time when proven effective therapies are lacking, we aimed to describe our real-life experience using tocilizumab for COVID-19.…”