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Tocilizumab Trims Mortality 45% in Intubated COVID-19 Patients
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Mark Mascolini
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A 154-person nonrandomized comparison linked the antiinflammatory tocilizumab to a 45% lower death risk after intubation in people with COVID-19 [1]. Although people taking tocilizumab, a monoclonal antibody, had a doubled rate of superinfection, 28-day mortality did not differ significantly between tocilizumab-treated people with versus without superinfection.
Advanced COVID-19 can culminate in runaway inflammation threatening multiorgan failure and marked by high levels of interleukin 6 (IL-6), which can be lowered via IL-6 blockade with tocilizumab. The US FDA has licensed tocilizumab for treatment of chimeric antigen receptor T-cell-associated severe or life-threatening cytokine-release syndrome, similar to the cytokine storm seen in people with advanced COVID-19.
University of Michigan researchers designed this observational study to compare outcomes in COVID-19 patients requiring mechanical ventilation who did or did not receive tocilizumab. At university clinics, clinicians consider tocilizumab for COVID-19 patients with hyperinflammation signaled by rapidly worsening respiratory status and lofty inflammatory markers.
To be eligible for the analysis, patients had to be admitted from March 9 to April 20, 2020 with severe COVID-19 pneumonia and a positive PCR for SARS-CoV-2, the virus that causes COVID-19. Participants required invasive mechanical ventilation. The investigators excluded people younger than 16, those intubated for conditions unrelated to COVID-19, and those enrolled in a randomized controlled trial of sarilumab, another antiinflammatory monoclonal antibody. The researchers chose a high single tocilizumab dose of 8 mg/kg to saturate IL-6 receptors quickly and thus stymie IL-6 signaling.
Survival probability after intubation was the primary outcome. To address the nonrandomized nature of the study, the researchers compared outcomes in people who received tocilizumab and the control group by multivariable Cox regression with propensity score inverse probability weighting. To further compare tocilizumab with untreated controls, the investigators created an ordinal scale of illness severity that had 6 levels: (1) discharged alive, (2) hospitalized/off ventilator without superinfection, (3) hospitalized/off ventilator with superinfection, (4) hospitalized/mechanically ventilated without superinfection, (5) hospitalized/mechanically ventilated with superinfection, and (6) dead.
The analysis included 154 people who required mechanical ventilation: 78 received tocilizumab and 76 did not. Similar proportions of people receiving tocilizumab and untreated controls were women (34% overall), black (53%), or white (27%). The groups did not differ significantly in body mass index (average 34.1 kg/m2 overall, putting participants high in the overweight range). People receiving tocilizumab were significantly younger than the control group (average 55 versus 60, P = 0.05) and significantly less likely to have chronic pulmonary disease (10% versus 28%, P = 0.006). D-dimer, a coagulation marker, was significantly lower (better) at intubation in the tocilizumab group (median 2.4 versus 6.5 mg/dL, P = 0.005).
Follow-up continued through May 19, 2020, and median follow-up stood at 47 days (range 28 to 67). The case fatality rate proved significantly lower in participants receiving tocilizumab than in untreated people at 14 days after intubation (9% versus 26%, P = 0.005), at 21 days (14% versus 33%, P = 0.006), and at 28 days (18% versus 36%, P = 0.01). A significantly higher proportion in the tocilizumab group got discharged alive by the end of follow-up (56% versus 40%, P = 0.04).
Cox proportional hazards models linked tocilizumab to a significantly lower death risk whether adjusting for (1) demographics alone (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.29 to 1.00), (2) propensity score inverse probability weighting in the subset with complete lab data (HR 0.55, 95% CI 0.33 to 0.90), or (3) propensity score inverse probability weighting including people with imputed lab data in the full cohort (HR 0.54, 95% CI 0.35 to 0.84). Thus participants receiving tocilizumab had about a 45% lower risk of death.
The tocilizumab group also had improved status on the ordinal outcome scale of illness severity (odds ratio per 1-level increase 0.58, 95% CI 0.36 to 0.94).
A significantly higher proportion of people in the tocilizumab group than the control group had superinfection (54% versus 26%, P < 0.001). Ventilator-associated pneumonia largely accounted for the higher superinfection rate with tocilizumab (45% versus 20%, P < 0.001). But 28-day case fatality did not differ significantly in tocilizumab patients with versus without superinfection (22% versus 15%, P = 0.42).
The researchers noted that, despite the independent association of tocilizumab with improved survival, the high superinfection rate with tocilizumab underscores the need for well-powered randomized controlled trials to weigh the efficacy and safety of this monoclonal antibody in COVID-19 patients requiring mechanical ventilation.
An Italian retrospective observational study of 544 adults with severe COVID-19 pneumonia, but not necessarily candidates for intubation, charted death rates of 7% in people treated with tocilizumab and 20% in those not treated with tocilizumab (P < 0.0001) [2]. An analysis adjusted for demographic and clinical variables indicated a 40% lower risk of intubation with tocilizumab (HR 0.61, 95% CI 0.40 to 0.92, P = 0.02). Superinfection rates were 13% with tocilizumab versus 4% in the comparison group (P < 0.0001).
References
1. Somers EC, Eschenauer GA, Troost JP, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis. 2020 Jul 11. https://doi.org/10.1093/cid/ciaa954
2. Guaraldi G, Meschiari M, Cozzi-Lepri Al, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatology. June 24, 2020. doi: https://doi.org/10.1016/S2665-9913(20)30173-9
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