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

Table 1 Summary of studies addressing interleukin-1 blockers on coronavirus disease 2019

Ref.	Patients	Intervention	Comparison	Outcome
CORIMUNO-19 Collaborative group[74], RCT	Hospitalized patient with mild-to-moderate pneumonia, non-ICU admitted	Anakinra (200 mg twice a day on days 1-3, 100 mg twice on day 4, 100 mg once on day 5) (n = 59)	Standard care (n = 55)	No difference in NIV/MV/death at day 4. Stopped early following the recommendation of the data and safety monitoring board
Cavalli et al[75], observational	Pneumonia with moderate-to-severe ARDS and hyperinflammation (non-MV, non-ICU admitted)	Anakinra (high dose: 5 mg/kg twice a day intravenously, n = 29; or low dose: 100 mg twice a day subcutaneously, n = 7)	Standard care (retrospective cohort) (n = 16)	Survival. High-dose anakinra: 72%, SC: 56%, P = 0.009
Huet et al[76], observational	Bilateral pneumonia (non-ICU admitted)	Anakinra (100 mg twice daily for 72 h, followed by 100 mg daily for 7 d) (n = 52)	Standard care (historical group) (n = 44)	Death/MV. Anakinra: HR = 0.22 (95%CI: 0.11-0.41), P < 0.0001. Death. Anakinra: HR = 0.30 (95%CI: 0.12-0.71), P = 0.0063. MV: Anakinra: HR = 0.22 (95%CI: 0.09-0.56), P = 0.0015
Kooistra et al[77], observational	ICU admitted pneumonia (MV: 100%)	Anakinra (300 mg iv, followed by 100 mg iv/6 h) (n = 21)	Standard care (n = 39)	No differences in duration of MV, ICU length of stay, or mortality

RCT: Randomized clinical trial; ICU: Intensive care unit, NIV: Non-invasive ventilation; MV: Mechanical ventilation; ARDS: Acute respiratory distress syndrome; HR: Hazard ratio; SC: Standard of care; CI: Confidence interval.

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.

Table 3 Coronavirus disease 2019 patients treated with tocilizumab and corticosteroids

Ref.	Tocilizumab group	Control
Salama et al[110], RCT	80.3%	87.5%
Rosas et al[113], RCT	36.1%	54.9%
Stone et al[90], RCT	11%	6%
Salvarani et al[111], RCT	10%	7.6%
Mariette et al[112], RCT	33%	61%
RECOVERY Collaborative Group[115], RCT	82%	82%
REMAP-CAP Investigators et al[116], RCT	> 80%
Veiga et al[114], RCT	69%	73%
Gupta et al[189], observational	18.7%	12.6%
Somers et al[108], observational	29%	20%
Fisher et al[109], observational	73.3%	78.6%
Biran et al[102], observational	46%	42%
Guaraldi et al[101], observational	30%	17%
Rossotti et al[105], observational	Not reported
Rojas-Marte et al[107], observational	43%	33%

RCT: Randomized clinical trial.

Table 4 Summary of studies using corticosteroids in coronavirus disease 2019

Ref.	Patients	Treatment regimen	Population	Mortality2	ICU administration	In-hospital stay	Secondary infections
RECOVERY Collaborative Group et al[177], RCT	11303	DXM 6 mg daily × 10 d	In-hospital	Decrease 2.8% RR 0.83	NS	Increase discharged 28 d (3.7%)	NA
RECOVERY Collaborative Group et al[177], RCT	1007	DXM 6 mg daily × 10 d	MV	Decrease 12.1% RR 0.64	NA	Increased discharged 28 d (9.7% RR 1.48)	NA
Tomazini et al[176], RCT	299	DXM 20 mg × 5d + DXM 10 mg × 5d	ICU patients	Decrease 2.4% (alive or ventilator-free)		NA	DXM 21.9% vs 29.1% standard. (7.9% vs 9.5% bacteremia)
Jeronimo et al[178], RCT	416	MPD (0.5 mg/kg twice daily) × 5d	In-hospital	NS	NS (MV)	NS	No significant differences
Dequin et al[179], RCT	149	HCT 200 mg daily × 7d then decrease dose × 7d (14 d)	ICU patients	NS		NS	NA
Angus et al[180], RCT	384	HCT 50 or 100 mg/6 h × 7 d	ICU patients	93% and 80% of superiority in organ support free		NS	NA
Edalatifard et al[181], RCT	68	MPD 250 mg × 3 d	In-hospital	Decrease 37%	No patients on MV	Decrease 4.6 d	2.9% (1 pt) in MPD vs 0% (0 pt) standard
Corral-Gudino et al[188], RCT1	85	MPD 40 mg/12 h × 3 d, then MPD 20 mg/12 h × 3 d	In-hospital	Decrease 24% composite death, ICU Adm or NIV		NS	NA
Kim et al[186], MA	49569	Variable regimens	ICU patients	OR 0.54 (0.40-0.73)	NA	NS	NA
Van Paassen et al[187], MA	20197	Variable regimens	In- hospital	OR 0.72 (0.57-0.87)	RR 0.71 (0.54-0. 97)	NS	NA

¹Preprint, not peer-reviewed.

²Absolute risk of mortality reduction in randomized clinical trial or odds ratio in meta-analysis.

ICU: Intensive care unit; RCT: Randomized clinical trial; MA: Meta-analysis; DXM: Dexamethasone; MPD: Methylprednisolone; HCT: Hydrocortisone; NS: Non-significant; NA: Not applicable; Adm: Admission; MV: Mechanical ventilation; NIV: Non-invasive ventilation; RR: Relative risk; OR: Odds ratio.

Table 5 Summary of randomized clinical trials and observational studies including critically ill patients addressing intravenous immunoglobulin and hyperimmune immunoglobulin on coronavirus disease 2019

Ref.	Patients	Intervention	Comparison	Outcome
Xie et al[193], observational	Severe/critical pneumonia and. Lymphocyte count < 0.5 × 109/L (18.9% on MV, 13.8% on NIV/HFNC)	IVIG (20 g/d)	> 48 h after admission (n = 28) vs < 48 h after admission (n = 30)	Reduction in 28-d mortality (23% vs 57%, P = 0.009), need for MV (6.67% vs 32.14%, P = 0.001) and LOS (11.5 ± 1.0 vs 16.9 ± 1.6 d, P = 0.005) in the < 48 h group
Tabarsi et al[194], RCT	Severe pneumonia (36.9% on MV, 78.6% ICU-admitted)	IVIG (400 mg/kg/24 h for 3 d) (n = 52)	Standard care (n = 32)	No difference in mortality (46.1% vs 43.7%, P = 0.83), need for MV (40.4% vs 31.2%, P = 0.39) or ICU admission (75% vs 84.4 %, P = 0.3)
Gharebaghi et al[195], RCT	Severe pneumonia with persisting symptoms or need for supplementary oxygen to maintain SaO2 > 90% after 48 h of treatment	IVIG (20 g daily for three days) (n = 30)	Standard care (n = 29)	Lower in-hospital mortality (20% vs 48.3%, P = 0.022). Mortality. IVIG: OR = 0.003 (95%CI: 0.001-0.815, P = 0.042)
Agarwal et al[200], RCT	Moderate pneumonia	Convalescent plasma (200 mL, 2 doses) (n = 235)	Standard care (n = 229)	Disease progression or mortality: No difference
Li et al[201], RCT	Severe/critical pneumonia (NIV/HFNO: 42.7%, MV/ECMO: 24.3%)	Convalescent plasma (4-13 mL/kg) (n = 52)	Standard care (n = 51)	No improvement in time to clinical improvement within 28 d

RCT: Randomized clinical trial; MV: Mechanical ventilation; NIV: Non-invasive ventilation; LOS: Length of stay; HNFO: High nasal flow oxygen therapy; ICU: Intensive care unit; OR: Odds ratio; IVIG: Intravenous immunoglobulin; ECMO: Extracorporeal membrane oxygenation; CI: Confidence interval.