Table 2.
Available Evidence, Excluding Case Reports, for Use of Immunomodulatory Therapy in Patients With COVID-19
| Reference (Year) | Study Design (Location) | Patient Population | Intervention | Outcome(s) | Limitations/Critique |
|---|---|---|---|---|---|
| Tocilizumab | |||||
| Xu et al (2020) [14, 15] | Retrospective (Hefei, China) | Demographic data (n = 21) • Age, mean: 57 years • Male: 80% • Hypertension: 60% • Diabetes mellitus: 27% • Cerebrovascular disease: 5% • COPD: 5% • IL-6 concentration, mean (±SD): 153.44 (296.63) pg/mL • CRP concentration, mean (±SD): 75.06 (66.80) mg/L Severe (81%), defined as any of the following: • RR ≥30 bpm • SpO2 ≤93% on RA • PaO2/FiO2 ≤300 mmHg Critical (19%), defined as ICU admission plus any of the following: • MV • Shock • Organ failure |
• Tocilizumab 4–8 mg/kg (recommended dose 400 mg) IV once + SOCa | • Normalized body temperature within 24 hours: 100% • Decreased O2 requirements: 75% • Improvement in chest CT: 90.5% • No reports of adverse effects, pulmonary infections, clinical deterioration, or death • IL-6 concentration post-tocilizumab, mean (±SD) ◦ Day 1:129.18 (131.79) pg/mL ◦ Day 3: 300.98 (341.90) pg/mL ◦ Day 5: 274.90 (414.08) pg/mL • CRP concentration post-tocilizumab, mean (±SD) ◦ Day 1: 38.13 (54.21) mg/L ◦ Day 3: 10.61 (13.79) mg/L ◦ Day 5: 2.72 (3.60) mg/L |
• Small sample size • Nonrandomized • Limited description of methods and results • Time to tocilizumab administration unknown • 3 patients received a second dose of tocilizumab 400 mg IV within 12 hours due to sustained fever |
| Luo et al (2020) [29] | Retrospective (Wuhan, China) | Demographic data (n = 15) • Age, mean: 73 years • Male: 86% • Hypertension: 43% • Diabetes mellitus: 24% • Cerebrovascular disease: 20% • IL-6 concentration, mean (±SD): 111.1 (170.0) pg/mL • CRP concentration, mean (±SD): 131.81 (77.44) mg/L Moderately ill: 13% Seriously ill: 40% Critically ill: 47% |
• Tocilizumab IV on study day 0 | • Clinical improvement: 7% • Clinical stabilization: 60% • Disease aggravation: 13% • Death: 20% • IL-6 concentrations post-tocilizumab, mean (±SD) ◦ Day 1: 338.3 (383.4) pg/mL ◦ Day 3: 314.5 (317.3) pg/mL ◦ Day 5: 3196.8 (2191.4) pg/mL ◦ Day 7: 739.8 (1290.0) pg/mL • CRP concentration post-tocilizumab, mean (±SD) ◦ Day 1: 74.44 (30.24) mg/L ◦ Day 3: 21.61 (16.81) mg/L ◦ Day 5: 28.02 (22.18) mg/L ◦ Day 7: 14.15 (32.13) mg/L |
• Small sample size • Nonrandomized • Limited description of methods and results • Suboptimal reporting of safety profile • Initial tocilizumab doses included 80 mg (n = 2), 100 mg (n = 1), 240 mg (n = 1), 320 mg (n = 1), 400 mg (n = 3), 480 mg (n = 6), and 600 mg (n = 1) • 8 patients received tocilizumab in combination with methylprednisolone 20 mg to 80 mg IV every 12 to 24 hours • 5 patients received 2 or more doses of tocilizumab |
| Klopfenstein et al (2020) [32] | Retrospective, case-control comparing tocilizumab vs SOC (Trévenans, France) | Demographic data (tocilizumab group [n = 20] vs SOC group [n = 25]) • Age >70 years: 75% vs 44%, P = .036 • Charlson comorbidity index, mean (± SD): 5.3 (2.4) vs 3.4 (2.6), P = .014 • CRP concentration: 158 mg/L vs 105 mg/L, P = .017 |
• Tocilizumab • SOCb |
• Composite endpoint of death and/or ICU admission: 25% vs 72%, P = .002 • Death: 25% vs 48%, P = .066 • Receipt of invasive MV: 0% vs 32%, P = .006 |
• Small sample size • Nonrandomized • Scant demographic data available • Limited description of methods and results • Suboptimal reporting of safety profile • On average, tocilizumab administered 13 days after symptom onset, 7 days after admission, and after failure of SOC • Tocilizumab dosing regimen not defined |
| Toniati et al (2020) [28] | Case series (Brescia, Italy) | Demographic data (n = 100) • Age, median (IQR): 62 (57–71) years • Male: 88% • Hypertension: 46% • Diabetes mellitus: 17% • COPD: 9% • IL-6 concentration, median (IQR): 41 (10–102) pg/mL • CRP concentration, median (IQR): 113 (45–169) mg/L • BCRSS score, median (IQR): 3 (3–7) ◦ NIV: 57% ◦ MV: 43% |
• Tocilizumab 8 mg/kg (maximum dose 800 mg) IV × 2 doses, 12 hours apart + SOCc | 24–72 hours post-tocilizumab • Clinical and respiratory improvement: 58% • Clinical stabilization: 37% • Clinical worsening: 5% (of which 80% died) 10 days post-tocilizumab • Clinical and respiratory improvement or stabilization: 77% • Clinical worsening: 23% (of which 87% died) • IL-6 concentration, median (IQR): 1812 (375–2600) pg/mL • CRP concentration, median = 2 (IQR, 1–5) mg/L • BCRSS score, median = 2 (IQR, 1–4) |
• Nonrandomized • Limited description of methods and results • Used BCRSS, a 9-category, locally developed bedside respiratory severity scale (scores range from 0 [asymptomatic] to 8 [critically ill requiring MV and ICU management]) • Median (IQR) time from symptom onset to tocilizumab administration was 12 (9–14) days • Median (IQR) time from admission to tocilizumab administration was 5 (3–8) days • 13 patients received a third dose of tocilizumab 24 hours after the second based on clinical response • 3 adverse events were noted during the 10-day follow-up: 2 fatal cases of septic shock, 1 nonfatal case of gastrointestinal perforation |
| Roumier et al (2020) [33] | Retrospective, case-control comparing patients treated with tocilizumab vs patients not treated with tocilizumab (Suresnes, France) | Demographic data (tocilizumab group [n = 30] vs control group [n = 29]) • Age, mean (±SD): 58.8 (12.4) vs 71.2 (15.4) years, P = .001 • Male: 80% vs 79.3%, P = .947 • Hypertension: 20% vs 62.1%, P = .008 • Diabetes mellitus: 23.3% vs 34.5%, P = .343 • COPD: 13.3% vs 24.1%, P = .284 • ICU admission: 23.3% vs 34.5%, P = .079 • CRP concentration, mean (±SD): 189 (104.4) mg/L vs 167.4 (106.8) mg/L, P = .426 |
• Tocilizumab 8 mg/kg IV × 1 dose | Unadjusted analysis • Requirement of MV: 33.3% vs 55.2%, P = .089 • Death: 10% vs 31%, P = .04 Weighted analysis • Requirement of MV: 43.1% vs 64%, P = .025 • Death: 17.2% vs 18.7%, P = .837 |
• Nonpeer reviewed publication • Limited description of methods and results • Scant data on control group available • Suboptimal reporting of safety profile • Mean time from symptom onset to receipt of tocilizumab was 14.1 days • Patients could receive a second dose of tocilizumab if insufficient response, but number of patients who received second dose is unknown • 2 patients treated with tocilizumab also received HCQ 200 mg every 8 hours and azithromycin 250 mg every 12 hours on day 1, then every 6 hours thereafter |
| Sciascia et al (2020) [34] | Prospective open, single-arm multicenter (Torino, Italy) | Demographic data (n = 63) • Age, mean (±SD): 62.6 (12.5) years • Male: 88% • Hypertension: 38% • Diabetes mellitus: 9.5% • COPD: 4.7% Inclusion criteria: • SARS-CoV-2 PCR-confirmed COVID-19 infection • Pulmonary involvement defined as SpO2 ≤93% on RA or PaO2/FiO2 ≤300 mmHg • Hyperinflammation and hypercoagulable, defined as at least 3 of the following: ◦ CRP > 10× ULN ◦ Ferritin > 1000 ng/mL ◦ D-Dimer 10× ULN ◦ LDH 2× ULN |
• Tocilizumab 8 mg/kg IV (n = 34) • Tocilizumab 324 mg SQ (n = 29) |
• Mortality at 14 days: 11% o IV vs SQ: 12.9% vs 10.3%, OR = 1.16 (95% CI, 0.24–5.65), P = .858143 | • Limited description of methods and results • Suboptimal reporting of safety profile • Time to tocilizumab administration unknown • 52 patients received a second dose of tocilizumab within 24 hours of first dose • All patients were treated with concomitant antiviral therapy, of which 71.4% and 28.6% received LPV/r and DRV/c, respectively • No moderate or severe adverse events were observed |
| Colaneri et al (2020) [35] | Retrospective case-control comparing patients treated with tocilizumab vs patients not treated with tocilizumab (Pavia, Italy) | Demographic data (tocilizumab group [n = 21] vs control group [n = 91]) • Age, median (IQR): 62.33 (18.68) vs 63.74 (16.32) years • Male: 90% vs 69% • Hypertension: 38% vs 22% • Diabetes mellitus: 10% vs 9% • CRP concentration, median (IQR): 21.38 (13.40) mg/L vs 14.88 (14.41) mg/L |
• Tocilizumab + SOCd • SOCd |
• Mortality: OR = 0.78 (95% CI, 0.06–9.34) • ICU admission: OR = 0.11 (95% CI, 0.00–3.38) • CRP concentration post-tocilizumab, median (IQR): 0.63 (0.45) mg/L vs 6.07 (16.42) mg/L |
• Small sample size • Nonrandomized • Limited description of methods and results • Suboptimal reporting of safety profile • Tocilizumab dosing regimen not defined • Time to tocilizumab administration unknown • Severity of illness poorly described • No adverse effects were reported |
| Siltuximab | |||||
| Gritti et al (2020) [38]e | Retrospective (Bergamo, Italy) | Demographic data (n = 21) • Age, median: 64 years • Male: 86% • Hypertension: 43% • Diabetes mellitus: 24% • Cerebrovascular disease: 5% • IL-6 concentration, median (range): 139.5 (113–239) pg/mL • CRP concentration, median (range): 23.4 (9.5–43.1) mg/L ARDS requiring CPAP or NIV: 100% |
• Siltuximab 11 mg/kg per day IV within 2 days of CPAP or NIV | • Clinical condition improved: 33% • Clinical condition unchanged: 43% • Clinical condition worsened: 24% |
• Nonpeer reviewed publication • Small sample size • Nonrandomized • Limited description of methods and results • Suboptimal reporting of safety profile • Median initial siltuximab dose was 900 mg (range 700–1200 mg) • 5 patients received a second dose of siltuximab at physician’s discretion, as part of a compassionate-use program approved by the hospital ethics board |
| Anakinra | |||||
| Aouba et al (2020) [85] | Retrospective case series (France) | Demographic data (n = 9) • Age, median (range): 55 (46–84) years • Male: 89% • Hypertension: 33% • Diabetes mellitus: 11% • CRP concentration, median (range): 177 (83–282) mg/L Inclusion criteria: • Hospitalized, non-ICU • O2 flow ≤6 L/min • CRP ≥50 mg/L |
• Anakinra 100 mg SQ every 12 hours × 3 days, then 100 mg SQ every 24 hours × 7 days | CRP concentration post-anakinra, median (range) • Day 6: 19.5 (11–65) mg/L • Day 11: 4.5 (1–16) mg/L All patients were alive at last follow-up |
• Small sample size • Nonrandomized • Limited description of methods and results • Follow-up period unknown • Severity of illness poorly described • Suboptimal reporting of safety profile • Median (range) time from symptom onset to anakinra administration was 8 (4–12) days • Treatment was discontinued in one patient who developed acute respiratory failure after the first dose |
| Cavalli et al (2020) [27] | Retrospective cohort study comparing low-dose anakinra vs high-dose anakinra vs SOC (Milan, Italy) | Demographic data (low-dose anakinra [n = 167], high-dose [n = 29], SOC [n = 16]) • Age, median (IQR): 68 (51–73) vs 62 (55–71) vs 70 (64–78) years • Male: 71% vs 83% vs 88% • Hypertension: 43% vs 52% vs 50% • Diabetes mellitus: 29% vs 21% vs 19% • COPD: 14% vs 3% vs 13% • CRP concentration, median (IQR): 139 (109–172) vs 164 (105–227) vs 188 (130–246) mg/L Inclusion criteria: • NIV • Moderate-to-severe ARDS • Hyperinflammation defined as CRP ≥100 mg/L or ferritin ≥900 ng/mL • No evidence of bacterial infection • No concomitant use of other anti-inflammatory agents or corticosteroids |
• Low-dose anakinra (100 mg SQ every 12 hours) + SOCe • High-dose anakinra (5 mg/kg IV every 12 hours + SOCe • SOCe |
21 days post-anakinra (high-dose anakinra vs SOC) • Discharged from the hospital: 45% vs 44% • Survival: 90% vs 56% (HR = 0.20 [95% CI, 0.04–0.63], P = .009) • MV-free survival: 72% vs 50% (HR = 0.5 [95% CI, 0.16–1.30], P = .15) |
• Nonrandomized • Limited description of methods and results • Selection of treatment regimens unclear • Low-dose anakinra did not improve clinical status or CRP concentrations and was abandoned in favor of high-dose • Treatment continued until sustained clinical benefit, defined as 75% decrease in CRP, respiratory improvement for at least 2 days, or until death, bacteremia, adverse effects which equated to median (IQR) 9 (7–11) days with high-dose anakinra • Patients treated with high-dose who sustained clinical benefit were transitioned to anakinra 100 mg SQ every 12 hours × 3 days to prevent relapse • 7 patients discontinued high-dose anakinra due to adverse events after median (IQR) 9 (8–10) days of treatment • 3 patients discontinued high-dose anakinra due to increases in transaminases >3× ULN • 4 patients receiving high-dose anakinra developed Staphylococcus epidermidis bacteremia • 3 patients who did not improve after receiving high-dose anakinra were noted to have pulmonary emboli • All patients were treated with concomitant LPV/r and HCQ |
| Meplazumab | |||||
| Bian et al (2020) [128] | Prospective, single center, open-label case-control comparing patients treated with meplazumab vs patients not treated with meplazumab (Xi’an, China) | Demographic data (meplazumab group [n = 17] vs control group [n = 11]) • Age, median (IQR): 51 (49–67) vs 64 (43–67) years, P = .981 • Male: 64.7% vs 45.5%, P = .441 • Hypertension: 35.3% vs 27.3%, P = 1.0 • Diabetes mellitus: 17.6% vs 0%, P = .258 • COPD: 5.9% vs 0%, P = 1.0 Severity of illness • Common, defined as fever, respiratory symptoms, radiographic pneumonia: 23.5% vs 36.4% • Severe, defined as dyspnea, RR ≥30 bpm, SpO2 ≤93% on RA, or PaO2/FiO2 ≤300 mmHg: 35.3% vs 36.4% • Critical, defined as respiratory failure requiring MV, shock, multiorgan dysfunction/failure: 41.2% vs 27.3% |
• Meplazumab 10 mg IV × 1 dose on days 1, 2, and 5 + SOCd • SOCd |
Virologic Clearance Rate • Day 7: 76.5% vs 27.3% (P = .019) • Day 14: 94.1% vs 54.4% (P = .022) • Median: 3 days vs 13 days, P = .014 (HR = 0.37 [95% CI, 0.155–0.833]) Clinical improvement defined as normalized vital signs: • Day 7: 17.6% vs 0% • Day 14: 47.1% vs 27.3% • Day 21: 82.4% vs 54.5% • Day 28: 94.1% vs 81.8% |
• Nonpeer reviewed publication • Small sample size • Limited description of methods and results • All patients in both groups were treated with concomitant LPV/r and recombinant INFα-2b • 94.1% and 63.6% (P = .062) received concomitant systemic corticosteroids, respectively • 100% and 90.9% (P = .393) received concomitant antibiotics, respectively • Increased ALT and AST ≥2× ULN occurred in 2 patients receiving meplazumab |
Abbreviations: ALT, alanine aminotransferase; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; BCRSS, Brescia COVID-19 respiratory severity scale; CI, confidence interval; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CPAP, continuous positive airway pressure; CRP, C-reactive protein; CT, computerized tomography; DRV/c, darunavir/cobicistat; FiO2, percentage of inspired oxygen; HCQ, hydroxychloroquine; ICU, intensive care unit; IL, interleukin; INF, interferon; IQR, interquartile range; LPV/r, lopinavir/ritonavir; MV, mechanical ventilation; NIV, noninvasive ventilation; OR, odds ratio; PaO2, partial pressure of arterial oxygen; PCR, polymerase chain reaction; PMH, past medical history; RR, respiratory rate; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SD, standard deviation; SOC, standard of care; SpO2, peripheral oxygen saturation; SQ, subcutaneous; ULN, upper limit of normal.
aSOC included LPV/r 200/50 mg/tablet, 2 tablets PO every 12 hours × 10 days, INF-α 5 million units via inhalation every 12 hours, ribavirin 500 mg IV every 8 to 12 hours × 10 days, symptomatic therapy, ± methylprednisolone 1–2 mg/kg per day × 3–5 days in patients with rapid progression in respiratory dysfunction and/or imaging and excessive inflammatory response.
bSOC included HCQ or LPV/r ± systemic corticosteroids (doses and frequencies undefined).
cSOC included antiviral therapy [LPV/r 200/50 mg/tablet, 2 tablets PO every 12 hours or remdesivir 100 mg IV every 24 hours], antibacterial prophylaxis [azithromycin, ceftriaxone, or PTZ], HCQ 400 mg every 24 hours, and dexamethasone 20 mg every 24 hours. SOC included HCQ 200 mg PO every 12 hours + methylprednisolone 1 mg/kg (maximum dose of 80 mg) tapered × 10 days.
dSOC was undefined.
eSOC included HCQ 200 mg PO every 12 hours, LPV/r 200/50 mg/tablet, 2 tablets PO every 12 hours.