Immunomodulatory therapy for the management of critically ill patients with COVID-19: A narrative review

Table 2 Summary of studies addressing interleukin-6 blockers on coronavirus disease 2019 (randomized clinical trials and observational studies including critically ill patients)

Ref.	Patients	Intervention	Comparison	Outcomes	Overinfection rate
Salama et al[110], RCT	377	TCZ (8 mg/kg, 1-2 doses)	Placebo	MV/ECMO/mortality 28 d; 19.3% TCZ vs 12% placebo, P = 0.004	TCZ 10% vs placebo 12.6%
Rosas et al[113], RCT	438	TCZ (8 mg/kg, 1-2 doses)	Placebo	Mortality: NS. Hospital LOS: TCZ: 20, placebo: 28 d (P = 0.037). ICU admission: TCZ: 23.6%, SC: 40.6% (P = 0.01). ICU, LOS: TCZ: 9.8, SC: 15.5 d (P = 0.045)	TCZ 21% vs placebo 25.9%
Stone et al[90], RCT	242	TCZ (8 mg/kg, max 800 mg, 1 dose)	Placebo	MV or death. TCZ: 10.6%, SC: 12.5% (NS). Clinical worsening. TCZ: 19.3%, SC: 17.4% (NS)	TCZ 8.15% vs placebo 17.1%
Salvarani et al[111], RCT	123	TCZ (8 mg/kg, max 800 mg, 1-2 doses)	Standard of care	NS	TCZ 1.7% vs TE 6.3%
Mariette et al[112], RCT	131	TCZ (8 mg/kg, max 800 mg, 1-2 doses)	Standard of care	NIV/MV/death at day 4. TCZ: 19%, SC: 28% (NS). Survival without HFNO/NIV/MV at day 14. TCZ: 24%, SC: 36% (probability: 95%). 28 d mortality. TCZ: 10.9%, SC: 11.9% (NS)	TCZ 3.2% vs TE 16.4%
RECOVERY Collaborative Group[115], RCT	4166	TCZ (different regimes)	Standard of care	28 d mortality: TCZ: RR = 0.86 (95%CI: 0.77-0.96, P = 0.006)	Not available
REMAP-CAP Investigators et al[116], RCT	826	TCZ (8 mg/kg, max 800 mg, 1-2 doses) (n = 366). Sarilumab (400 mg) (n = 48)	Standard of care	Days free of respiratory/hemodynamic support at day 21. TCZ: 10 d, sarilumab: 11 d, SC: 0 d. Hospital mortality. TCZ: 28%, sarilumab: 22.2% SC: 35.8% (probability TCZ better: 99.6%, probability sarilumab better: 99.5%)	TCZ 0.2% vs TE 0%
Veiga et al[114], RCT	129	TCZ (8 mg/kg, max 800 mg)	Standard of care	Stopped early due to higher mortality in TCZ patients	PB 15% vs SC 16%
Tleyjeh et al[121], MA	9850	TCZ (variable regimen)	Standard of care	Mortality: TCZ: OR = 0.58 (0.51-0.66)	TCZ: RR = 0.63 (0.38-1.06)
Gupta et al[106], OS	3491	TCZ (regimen not specified)	Standard of care	Hospital mortality. TCZ: HR = 0.71 (95%CI: 0.56-0.92)	TCZ 32.3% vs SC 31.1%
Somers et al[108], OS	154	TCZ (8 mg/kg, max 800 mg)	Standard of care	Mortality. TCZ: HR = 0.54 (95%CI: 0.35-0.84)	TCZ 54% vs SC 26%. Pneumonia 45% vs 20%. Bacteremia 14% vs 9%
Fisher et al[109], OS	115	TCZ (400 mg)	Standard of care	30 d mortality. TCZ: OR = 1.04 (95%CI: 0.27-3.75)	TCZ 28.9% vs SC 25.7%
Biran et al[102], OS	764	TCZ (400 mg, 1-2 doses)	Standard of care	Hospital mortality. TCZ: HR = 0.64 (95%CI: 0.47-0.87, P = 0.004)	TCZ 17% vs SC 13%
Guaraldi et al[101], OS	544	TCZ (8 mg/kg, max 800 mg, 2 doses) (n = 179)	Standard of care	Death/MV. TCZ: HR = 0.61 (95%CI: 0.4-0.92), P = 0.020	TCZ 13% vs SC 4%
Rossotti et al[105], OS	222	TCZ (8 mg/kg, max 800 mg, 1-2 doses) (n = 74)	Standard of care	Survival rate TCZ: HR = 2.004 (95%CI: 1.050-3.817), P = 0.035. Survival rate in critically ill patient. HR = 30.055 (95%CI: 1.420-636.284), P = 0.029	TCZ 24.4%; SC: NA
Rojas-Marte et al[107], OS	193	TCZ (regimen not specified)	Standard of care	Mortality TCZ: 52%, SC: 62%, P = 0.09. Mortality in non-ventilated patients: TCZ: 6.1%, SC: 26.5%, P = 0.024	Bacteremia: TCZ 12.5% vs SC 23.7%. Fungemia: TCZ 4.2% vs SC 3.1%

TCZ: Tocilizumab; RCT: Randomized clinical trial; MA: Metha-analysis; OS: Observational study; MV: Mechanical ventilation; ICU: Intensive care unit; NIV: Non-invasive ventilation; LOS: Long of stay; HNFO: High nasal flow oxygen therapy; ECMO: Extracorporeal extracorporeal membrane oxygenation; SC: Standard of care; NS: Non-significative; RR: Relative risk; OR: Odds ratio; CI: Confidence interval; HR: Hazard ratio; NA: Not applicable.