Tocilizumab in Coronavirus Disease 2019-Related Critical Illness: A Propensity Matched Analysis

Abstract

Objectives: The primary objective was to evaluate ICU mortality at 28 days in patients with severe hypoxemic respiratory failure due to coronavirus disease 2019 infection who received tocilizumab. The secondary objectives were to evaluate ICU-, hospital-, mechanical ventilation-, and vasopressor-free days at day 28 and development of secondary infections. Design: Retrospective, observational, multicenter, cohort study between March 15, 2020, and May 31, 2020. Using propensity score matching based on ICU admission source, C-reactive protein, Sequential Organ Failure Assessment score, vasopressor use, age, race, weight, and mechanical ventilation, patients who received tocilizumab were matched to patients who did not receive tocilizumab. Setting: Ten hospitals within the Cleveland Clinic Enterprise. PATIENTS: Adult patients admitted to a medical, surgical, neurosciences, or mixed ICU with severe acute respiratory syndrome coronavirus 2 infection. Interventions: None. Measurements and Main Results: Four-hundred forty-four patients were included: 342 patients (77%) did not receive tocilizumab and 102 patients (23%) received tocilizumab. Of those, 82 patients in each arm were matched. Before matching, patients who received tocilizumab had higher Sequential Organ Failure Assessment scores (6.1 ± 3.4 vs 4.7 ± 3.6), higher C-reactive protein (21.0 ± 10.2 vs 13.7 ± 9.6 mg/dL), higher frequency of intubation, vasopressor requirement, and paralytics. After matching, characteristics were more balanced and over 85% of patients required mechanical ventilation. ICU mortality was lower in tocilizumab group (23.2% vs 37.8%; risk difference, –15%; 95% CI, –29% to –1%), with more ICU-, hospital-, and vasoactive-free days at day 28 compared with those who did not receive tocilizumab. There was no difference in mechanical ventilation-free days at day 28 or development of secondary infections. Conclusions: Tocilizumab use was associated with a significant decrease in ICU mortality in critically ill coronavirus disease 2019 patients with severe hypoxemic respiratory failure. Future randomized controlled trials limited to tocilizumab administration in critically ill coronavirus disease 2019 patients, with severe hypoxemic respiratory failure, are needed to support these findings.

Association between tocilizumab and emerging multidrug-resistant organisms in critically ill patients with COVID-19: A multicenter, retrospective cohort study

“…Our primary outcome of no difference in microbial isolation rate was observed after adjusting for possible co-founders. This finding is similar to the results of previous studies that conducted adjusted matched analyses for tocilizumab and controls and showed no difference between the groups [ 24 , 25 ]. This was also demonstrated in another multicenter cohort study of 4485 adults with COVID-19 admitted to ICUs and a recent meta-analysis that found no differences in secondary infection rate between tocilizumab and the control group [ 5 , 26 , 27 ].…”

Tocilizumab Association with Emerging Multi-drug Resistance Organisms and Mortality in critically ill patients with Coronavirus disease 2019 (COVID-19): A Multicenter, Retrospective Cohort Study

“…Our primary outcomes ndings were observed after adjusting for the patient's comorbidities, history of hospitalization or invasive procedure within one year, history of antibiotics exposure in the last three months, systemic corticosteroids during ICU, and ICU LOS. The nding of no difference in secondary infections rate is similar to previous studies that conducted adjusted matched analyses for tocilizumab and controls and showed no difference between the arms only (26 in the treatment arm, 25 in the control arm; 95% CI for difference, − 0.15 to 0.13; P = 1.00) (20,21). This was also demonstrated in another multicenter cohort study of 4485 adults with COVID-19 admitted to (ICUs) has found no differences in secondary infection rate (140 [32.3%] vs 1085 [31.1%]) (22,23 ).…”

Tocilizumab reduces COVID-19 mortality and pathology in a dose and timing-dependent fashion: a multi-centric study

“…But Tcz’s effects over critically-ill patients could not be correctly assessed as we found few clinical files of patients with such condition. However, the administration of Tcz at the LIS and/or in doses of > 800 mg seemed to prolong hospitalization, which may be in line with data describing an enhanced propensity for Tcz-treated patients to develop the aforementioned nosocomial superinfections 23 , and thus to present a prolonged stay at intensive care units 25 . We lack bacterial culture data from our patients as a means to confirm this hypothesis, but it seems plausible and we think that further investigation on the prophylactic use of antibiotics to avoid prolonged hospitalization in Tcz-treated COVID-19 patients would help to clarify such point.…”

“…Due to the fact that IL-6 is highly expressed in the severe to critical presentations of COVID-19 5 , many research teams have used Tocilizumab (Tcz), a humanized monoclonal antibody that targets the IL-6 receptor (IL-6R) in its membrane-bound and soluble forms 12 , to down-modulate inflammation, and thus to avoid respiratory and multi-organ dysfunction. These studies have shown varied results that range from a lack of effect on mortality, time to clinical improvement, laboratory parameters and/or prevention of progression to a more severe disease 13 – 16 , to success in the modulation of some or all of these parameters in moderately 17 , severely 18 – 22 , and/or critically-ill patients 23 – 25 .…”