Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019

Price, Christina; Altice, Frederick L.; Shyr, Yu; Koff, Alan; Pischel, Lauren; Goshua, George; Azar, Marwan M.; McManus, Dayna; Chen, Sheau-Chiann; Gleeson, Shana; Britto, Clemente J.; Azmy, Veronica; Kaman, Kelsey; Gaston, David C; Davis, Matthew W.; Burrello, Trisha; Harris, Zachary M.; Villanueva, Merceditas; Aoun-Barakat, Lydia; Kang, Insoo; Seropian, Stuart; Chupp, Geoffrey; Bucala, Richard; Kaminski, Naftali; Lee, Alfred Ian; LoRusso, Patricia; Topal, Jeffrey; Cruz, Charles S. Dela; Malinis, Maricar

doi:10.1016/j.chest.2020.06.006

Cited by 199 publications

(225 citation statements)

References 27 publications

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“…Thus, 28 articles included 991 COVID-19 patients underwent tocilizumab administration were included in this study 10,11, . Of the 28 included studies, 7 of which included 377 patients were case-control studies with a control group not using tocilizumab 28,29,32,36,39,40,42 .…”

Section: Resultsmentioning

confidence: 99%

“…Data were unavailable for mortality in 3 studies, and a pooled all-cause death rate of 16% (95% CI, 11-22%; I 2 = 67%, P< 0.0001) was reported in 870 patients when treated with tocilizumab. 17 studies 10,11,19,[21][22][23][25][26][27][28][29]31,33,[35][36][37]40 comprising 562 patients were de ned as severe COVID-19 infection, and the pooled ORR of treatment with tocilizumab was 78% (95% CI, 70-85%; I 2 = 65%, P< 0.0001), while pooled ORR in 64 nonsevere infection was 93% (95% CI, 85-98%; I 2 = 0%, P=0.66) ( Figure S2).…”

Section: Impact Of Tocilizumab Treatment On Orr and Mortality Of Covimentioning

confidence: 99%

“…At the point of study completion, median LOH and LOI was 14 days (range 11-34) and 8 days (range [5][6][7][8][9][10][11] in patients receiving tocilizumab, which was speci ed in 15 studies 10,[20][21][22][23]28,29,31,32,35,36,[38][39][40][41] and 8 studies 10,23,27,29,32,33,36,42 , separately. Moreover, the median duration of mechanical ventilation was 7 days (range 5-10) after treatment of tocilizumab which was documented in 9 articles 10,11,[21][22][23]27,28,40,41 ( Table 2).…”

Section: Impact Of Tocilizumab Treatment On Duration Of Hospitalizatimentioning

confidence: 99%

“…The timing of tocilizumab administration was clari ed in 8 studies. 10,[22][23][24][25]27,36,40 With this data, the second-order polynomial equation was given as following: y = p1*x2 + p2*x + p3. (p1 = 0.004099 (-0.006127, 0.01433), p2 = -0.05933 (-0.257, 0.1384), p3 = 0.3474 (-0.5564, 1.251).…”

Section: Optimal Timing and Safety In Use Of Tocilizumabmentioning

confidence: 99%

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Efficacy and safety of tocilizumab in COVID-19 patients: A Meta-Analysis

Liu

Zong

et al. 2020

Preprint

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The therapeutic effect of tocilizumab remains controversial. We aimed to evaluate whether tocilizumab might be beneficial in COVID-19 patients. We searched PubMed, Embase and Cochrane library from inception to June 23, 2020. Summary estimates of overall response rate (ORR) and all-cause death rate in all patients were analyzed. This study was registered with PROSPERO (CRD42020191313). We included data from 28 articles including 991 COVID-19 patients who underwent tocilizumab administration. The pooled ORR was 72% (95% CI, 66-79%) and pooled all-cause death rate was 16% (95% CI, 11-22%). The optimal timing of administration was the 7.15 day from the symptom onset and with the lowest death rate of 13.11%. 562 patients were defined as with severe infection, and the pooled ORR was 78% (95% CI, 70-85%). The pooled ORR of 56 organ transplantation recipients was 53% (95% CI, 26-78%), which was lower than non-transplant patients [75% (95% CI, 69-81%)]. Nearly all studies confirmed the safety of tocilizumab administration. Tocilizumab improves the clinical outcome of COVID-19 patients, especially in severe cases, and the optimal timing of administration may provide the guidance for management. However, tocilizumab may be used with caution in solid transplant recipients for the suboptimal efficacy.

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Section: Resultsmentioning

confidence: 99%

Section: Impact Of Tocilizumab Treatment On Orr and Mortality Of Covimentioning

confidence: 99%

Section: Impact Of Tocilizumab Treatment On Duration Of Hospitalizatimentioning

confidence: 99%

Section: Optimal Timing and Safety In Use Of Tocilizumabmentioning

confidence: 99%

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Efficacy and safety of tocilizumab in COVID-19 patients: A Meta-Analysis

Liu

Zong

et al. 2020

Preprint

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“…1,3 A recent study in Chest followed IL-6 levels after tocilizumab administration and found an immediate increase followed by a steady decrease but did not differentiate IL-6 levels between survivors and non-survivors. 4 Data from China found patients with rising IL-6 levels greater than 4000 pg/mL perished despite receiving tocilizumab. 5 These IL-6 levels begin to reach those seen in cytokine release syndrome (CRS) following CAR T cell infusion where levels reach a median value of 8,309 pg/mL for grade 4 or 5 CRS.…”

Section: Methodsmentioning

confidence: 99%

Lack of Tocilizumab effect on mortality in COVID19 patients

Holt

Batra

Murthi

et al. 2020

Preprint

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Abstract Off-label tocilizumab use in COVID-19 patients reflects concern for cytokine release syndrome. Comparison of matched COVID-19 pneumonia patients found elevated IL-6 levels correlated with mortality that did not change with tocilizumab administration. Correlating mortality with increased IL-6 doesn’t imply causality however lack of improvement by tocilizumab requires clinical trial alterations.

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

et al. 2021

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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.

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Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019

Cited by 199 publications

References 27 publications

Efficacy and safety of tocilizumab in COVID-19 patients: A Meta-Analysis

Efficacy and safety of tocilizumab in COVID-19 patients: A Meta-Analysis

Lack of Tocilizumab effect on mortality in COVID19 patients

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

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