Abstract
During severe and critical COVID-19, therapeutic options remain scarce. Among interventions, the use of interleukin-6 receptor inhibitor (IL-6Ri) is especially controversial due to persistent uncertainty about their efficacy and safety. To compare the occurrence of secondary infections, digestive and hematological complication function of the administration of IL-6Ri we conducted a multicentric retrospective French observational study. All severe or critical COVID-19 requiring hospital admission were included. Among 2587 patients requiring hospital admission, 1603 had a severe COVID-19 and 984 a critical one requiring ICU admission. 224 received at least one dose of tocilizumab or sarilumab. Incidence of secondary infection was 29.5% in the IL-6Ri group vs. 19.5% without IL-6Ri (p = 0.0004) in the whole population. This result remained consistent after adjustment, without multiple imputation (MI) and after MI (adjusted OR: 1.47 [1.25; 1.72]; p < 0.0001)). Incidence of hematological or digestive complication were similar between groups. Mortality of patients admitted in ward was higher in the IL-6Ri group (18.7% vs 10.5%, p = 0.0155). No difference in 28 days, ICU, hospital of 90 days mortality was noticed among ICU patients.
Clinical trial registration: This study was registred on ClinicalTrial.gov: NCT05017441.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-026-36864-w.
Keywords: Covid-19, Tocilizumab, Nosocomial infections, Ventilator-associated pneumonia, Neutropenia, Mortality
Subject terms: Infectious diseases, Viral infection, Outcomes research, Phase IV trials
Introduction
Since the onset of Coronavirus disease 2019 (COVID-19), numerous therapeutic interventions have been proposed, particularly for severe manifestations of the disease. The efficacy of corticosteroids in severe and critical COVID-19 cases has been swiftly established1–3. Concurrently, the pronounced inflammatory response observed in severe cases4 has prompted exploration of cytokine pathway inhibitors as potential therapeutic targets.
Elevated levels of circulating interleukin-6 (IL-6) in critically ill patients, and its correlation with severe hypoxemia, have highlighted the IL-6 pathway as a promising target for intervention5,6. However, randomized trials investigating IL-6 receptor inhibitors have yielded conflicting results, leading to ongoing uncertainty about their clinical relevance7, despite numerous meta-analyses7–10. Moreover, the safety of targeting the IL-6 pathway in septic patients remains to be specifically investigated.
IL-6 receptor (IL-6R) antagonists have been extensively used in chronic inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, and Castleman’s disease11,12. Long-term experience with IL-6 pathway inhibition has highlighted an increased risk of infectious diseases, estimated at approximately 5.5 events per 100 patient-years7,11. Additionally, altering the IL-6 pathway may compromise digestive mucosa regeneration, mediated by signal transduction through the gp130 protein12,13. This could potentially lead to upper digestive tract hemorrhage, especially when combined with systemic corticosteroids.
Conversely, the potential risks associated with the acute administration of IL-6 inhibitors are not yet well-documented. This is particularly true in cases of cytokine release syndrome following chimeric antigen receptor T-cell (CAR-T) therapy, or in severe and critical COVID-19 cases7,14,15. While recent meta-analyses of therapeutic trials have not reported an increased risk of infections16–18, this remains a topic of debate7,14.
The aim of our study was to highlight the potential complications associated with the IL-6 receptor inhibitors in use at the time, specifically tocilizumab and sarilumab.
Results
Participants
A total of 2587 patients were included in the study over a 22-month period. Of these, 1603 spent their all stay in medical ward (referred to as the “Ward group”), while 984 required an ICU admission at some point during their hospital stay (Fig. 1). The populations are described in Tables 1 and 2 and supplementary table 1 and Table 2.
Fig. 1.
Flowchart.
Table 1.
Characteristics of the population: ward group.
| Total (N = 1603) | No IL-6R inhibitor (n = 1512) | Tocilizumab or Sarilumab (n = 91) | OR [IC95%] | p | |
|---|---|---|---|---|---|
| Inclusion center | – | ||||
| Center 1 | 927 (58.2%) | 888 (59.0%) | 39 (43.3%) | 1 | 0.0083 |
| Center 2 | 666 (41.8%) | 615 (40.9%) | 51 (56.7%) | 1.89 [1.23; 2.90] | |
| Center 3 | 1 (0.06%) | 1 (0.07%) | 0 (0.00%) | – | |
| Age (years), mean (SD) | 64.99 (16.8) | 64.77 (16.9) | 68.69 (15.3) | – | 0.0299 |
| Sex (Female) | 657 (41.1%) | 620 (41.1%) | 37 (41.1%) | – | > 0.99 |
| BMI (kg/m2), median [Q1;Q3] | 27.1 [23.83;31.00] | 27.1[23.72;30.86] | 27.8 [25.39;31.99] | – | 0.08 |
| BMI (kg/m2) | – | ||||
| < = 25 | 413 (34.1%) | 397 (35.0%) | 16 (20.2%) | 1 | 0.0192 |
| ]25—30] | 432 (35.6%) | 395 (34.9%) | 37 (46.8%) | 2.32 [1.27; 4.25] | |
| > 30 | 367 (30.3%) | 341 (30.1%) | 26 (32.9%) | 2.32 [1.27;3.59] | |
| Smoking habits (Yes) | 271 (17.0%) | 263 (17.5%) | 8 (8.9%) | – | 0.08 |
| Alcohol habits | 121 (7.6%) | 116 (7.7%) | 5 (5.5%) | – | 0.24 |
| Hypertension | 740 (46.2%) | 687 (45.5%) | 53 (58.2%) | 1.67 [1.09; 2.57] | 0.0176 |
| Ischemic cardiopathy | 174 (10.9%) | 162 (10.7%) | 12 (13.3%) | – | 0.44 |
| Chronic heart failure | 71 (4.4%) | 65 (4.3%) | 6 (6.6%) | – | 0.29 |
| Diabetes mellitus | 355 (22.2%) | 329 (21.8%) | 26 (28.6%) | – | 0.13 |
| Immunosuppressive treatment | 84 (5.2%) | 83 (5.5%) | 1 (1.1%) | – | 0.09 |
| Infectious immunodepression | 22 (1.4%) | 22 (1.5%) | 0 (0.00%) | – | 0.63 |
| Gastric or duodenal peptic ucler | 39 (2.4%) | 37 (2.4%) | 2 (2.2%) | – | > 0.99 |
| COPD/SAS/Asthma | 301 (18.8%) | 279 (18.5%) | 22 (24.2%) | – | 0.18 |
| Long-term oxygen therapy | 12 (0.7%) | 12 (0.8%) | 0 (0.00%) | – | > 0.99 |
| Chronic renal failure | 124 (7.7%) | 115 (7.6%) | 9 (9.9%) | – | 0.43 |
| Dialysis | 15 (0.9%) | 15 (1.0%) | 0 (0.00%) | – | > 0.99 |
| Cancer / hematological malignancies | 212 (13.2%) | 201 (13.3%) | 11 (12.1%) | – | 0.74 |
| Stroke | 124 (7.7%) | 118 (7.8%) | 6 (6.6%) | – | 0.67 |
| Proton pump inhibitors | 339 (21.3%) | 318 (21.2%) | 21 (23.3%) | – | 0.64 |
| Anticoagulation | 198 (12.5%) | 186 (12.4%) | 12 (13.3%) | – | 0.81 |
| Antiaggregant therapy | 325 (20.5%) | 306 (20.5%) | 19 (20.9%) | – | 0.93 |
BMI: Body mass index; COPD: chronic obstructive pulmonary diseases; SAS: sleep apnea syndrome.
Table 2.
Characteristics of the population: ICU group.
| ICU Group | Total (N = 984) | No IL-6R inhibitor (n = 851) | Tocilizumab or Sarilumab (n = 133) | OR [IC95%] | p |
|---|---|---|---|---|---|
| Inclusion center | |||||
| Center 1 | 434 (44.3%) | 355 (42.0%) | 79 (59.4%) | 1 | < 0.0001 |
| Center 2 | 289 (29.5%) | 242 (28.6%) | 47 (35.3%) | 0.87 [0.59;1.30] | |
| Center 3 | 256 (26.1%) | 249 (29.4%) | 7 (5.3%) | 0.13 [0.06;0.28] | |
| Age (years), mean (SD) | 61.3 (13.15) | 61.4 (13.19) | 60.9 (12.89) | – | 0.62 |
| Sex (Female) | 306 (31.1%) | 254 (29.9%) | 52 (39.1%) | 0.66 [0.45;0.97] | 0.0328 |
| BMI (kg/m2), median [Q1;Q3] | 28.28 [24.98;32.28] | 28.07 [24.90;31.83] | 29.90 [25.39;34.55] | 0.0078 | |
| BMI (kg/m2) | |||||
| < = 25 | 240 (25.6%) | 213 (26.4%) | 27 (20.6%) | 1 | 0.019 |
| ]25—30] | 336 (35.9%) | 297 (36.8%) | 39 (29.8%) | 1.04 [0.62;1.74] | |
| > 30 | 361 (38.5%) | 296 (36.7%) | 65 (49.6%) | 1.73 [1.07;2.81] | |
| Smoking habits (Yes) | 188 (19.1%) | 170 (20.0%) | 18 (13.5%) | 2.51 [0.83;7.65] | 0.0011 |
| Alcohol habits | 62 (6.3%) | 56 (6.6%) | 6 (4.5%) | 2.68 [0.78;9.15] | 0.0011 |
| Hypertension | 505 (51.4%) | 449 (52.8%) | 56 (42.1%) | 0.65 [0.45;0.94] | 0.0215 |
| Ischemic cardiopathy | 86 (8.7%) | 78 (9.2%) | 8 (6.0%) | – | 0.23 |
| Chronic heart failure | 17 (1.7%) | 13 (1.5%) | 4 (3.0%) | – | 0.27 |
| Diabetes mellitus | 294 (29.9%) | 260 (30.6%) | 34 (25.6%) | – | 0.24 |
| Immunosuppressive treatment | 59 (6.0%) | 54 (6.3%) | 5 (3.8%) | – | 0.24 |
| Infectious immunodepression | 13 (1.3%) | 11 (1.3%) | 2 (1.5%) | – | 0.69 |
| Gastric or duodenal peptic ucler | 15 (1.5%) | 15 (1.8%) | 0 (0.0%) | – | 0.24 |
| COPD/SAS/Asthma | 174 (17.7%) | 151 (17.8%) | 23 (17.3%) | – | 0.89 |
| Long-term oxygen therapy | 4 (0.4%) | 4 (0.5%) | 0 (0.0%) | – | > 0.99 |
| Chronic renal failure | 87 (8.9%) | 80 (9.4%) | 7 (5.3%) | – | 0.12 |
| Dialysis | 32 (3.3%) | 29 (3.4%) | 3 (2.3%) | – | 0.61 |
| Cancer / hematological malignancies | 101 (10.3%) | 93 (10.9%) | 8 (6.1%) | – | 0.09 |
| Stroke | 49 (4.9%) | 46 (5.4%) | 3 (2.3%) | – | 0.12 |
| Proton pump inhibitors | 179 (18.4%) | 158 (18.8%) | 21 (15.8%) | – | 0.41 |
| Anticoagulation | 86 (8.9%) | 80 (9.5%) | 6 (4.5%) | – | 0.06 |
| Antiaggregant therapy | 179 (18.4%) | 155 (18.4%) | 24 (18.2%) | – | 0.94 |
BMI: Body mass index; COPD: chronic obstructive pulmonary diseases; SAS: sleep apnea syndrome.
COVID-19 severity
In the ward group, 23 (25.6%) of IL-6Ri treated patients required HFNO, for a median length of 7.00 [4.00; 10.00]. In absence of IL-6Ri, 99 (6.58%) had high oxygen therapy for a median length of 5.00 [2.00; 7.00] days (Table 3, Supplementary Table 4). Median hospital length of stay (LOS) was 10.00 [7.00; 15.00] among patients who received IL-6Ri and 7.0 [4.0; 11.0] days in patients who did not.
Table 3.
Therapeutic interventions and clinical evolution during hospital stay: Ward group.
| Total (N = 1603) | No IL-6R inhibitor (N = 1512) | Tocilizumab or Sarilumab (N = 91) | OR [IC95%] | p | |
|---|---|---|---|---|---|
| Type of IL-6R inhibitor | |||||
| Sarilumab | 11 (0.7%) | 0 (0.00%) | 11 (12.1%) | – | – |
| Tocilizumab | 80 (5.0%) | 0 (0.00%) | 80 (87.9%) | – | – |
| New anticoagulation | 1461 (91.5%) | 1370 (91.03%) | 91 (100.0%) | 1 | 0.0028 |
| Anticoagulation. type | |||||
| Curative | 367 (25.1%) | 346 (25.26%) | 21 (23.1%) | 1 | < 0.0001 |
| Preventive | 652 (44.6%) | 635 (46.35%) | 17 (18.7%) | 0.44 [0.23; 0.85] | |
| Intermediate dose preventive | 442 (30.2%) | 389 (28.39%) | 53 (58.2%) | 2.24 [1.33; 3.80] | |
| Corticosteroids | 857 (53.5%) | 778 (51.46%) | 79 (86.8%) | 6.21 [3.36; 11.49] | < 0.0001 |
| Proton pump inhibitors | 126 (7.9%) | 97 (6.42%) | 29 (31.9%) | 6.82 [4.19; 11.10] | < 0.0001 |
| Chloroquine/ Hydroxychloroquine | 76 (4.7%) | 76 (5.03%) | 0 (0.0%) | – | 0.0195 |
| Anakinra | 58 (3.6%) | 58 (3.85%) | 0 (0.0%) | – | 0.07 |
| Lopinavir/ritonavir | 4 (0.2%) | 4 (0.27%) | 0 (0.0%) | – | > 0.99 |
| Standard supplemental oxygen (days), median [Q1;Q3] | 4.00 [2.00; 8.00] | 4.00 [2.00; 7.00] | 7.50 [5.00; 11.00] | – | < 0.0001 |
| High flow nasal oxygen | 122 (7.6%) | 99 (6.58%) | 23 (25.6%) | 4.88 [2.91; 8.16] | < 0.0001 |
| If HFNO. length(days), median [Q1;Q3] | 5.00 [3.00; 8.00] | 5.00 [2.00; 7.00] | 7.00 [4.00; 10.00] | – | 0.0186 |
| Length of hospital stay (days), median [Q1;Q3] | 7.00 [4.00; 11.00] | 7.00 [4.00; 11.00] | 10.00 [7.00; 15.00] | – | < 0.0001 |
HFNO: high-flow nasal oxygen; IL-6Ri : interleukin-6 receptor inhibitor.
In ICU patients, HNFO was initially required in 521 (61.66%) and 111 (83.46%) in the absence or treatment with IL-6Ri, respectively. Non-invasive ventilation was implemented in 112 (13.29%) and 10 (7.52%).
and invasive mechanical ventilation in 498 (58.59%) and 67 (50.38%), respectively (Table 3 and 4, and supplementary Table 3–5).
Table 4.
Therapeutic interventions and clinical evolution during hospital stay: ICU Group.
| Total (N = 984) | No IL-6R inhibitor (N = 851) | Tocilizumab or Sarilumab (N = 133) | OR [IC95%] | p | |
|---|---|---|---|---|---|
| Type of IL-6R inhibitor | |||||
| Sarilumab | 112 (11.4%) | 0 (0.0%) | 112 (84.2%) | – | – |
| Tocilizumab | 21 (2.1%) | 0 (0.0%) | 21 (15.8%) | – | – |
| Anticoagulation | 806 (82.6%) | 674 (79.9%) | 132 (99.2%) | 33.10 [4.59; 238.43] | < 0.0001 |
| Anticoagulation type | – | – | |||
| Curative | 262 (32.5%) | 229 (34.0%) | 33 (25.0%) | 1 | 4.00 × 10–4 |
| Preventive | 122 (15.1%) | 112 (16.6%) | 10 (7.6%) | 0.62 [0.29; 1.30] | |
| Intermediate dose preventive | 422 (52.4%) | 333 (49.4%) | 89 (67.4%) | 1.85 [1.20; 2.86] | |
| Corticosteroids | 620 (63.0%) | 508 (59.7%) | 112 (84.2%) | 3.60 [2.22; 5.85] | < 0.0001 |
| Proton pump inhibitors | 123 (12.5%) | 74 (8.7%) | 49 (36.8%) | 6.12 [4.00; 9.36] | < 0.0001 |
| Chloroquine / hydroxychloroquine | 41 (4.2%) | 39 (4.6%) | 2 (1.5%) | – | 0.1 |
| High flow nasal oxygen | 632 (64.62%) | 521 (61.66%) | 111 (83.46%) | 3.14 [1.95;5.06] | < 0.0001 |
| If HFNO: length(days), median [Q1;Q3] | 3.00 [1.00;5.00] | 3.00 [1.00;5.00] | 3.00 [1.00;5.00] | ||
| Non-invasive ventilation | 122 (12.50%) | 112 (13.29%) | 10 (7.52%) | 0.53 [0.27;1.04] | 0,06 |
| If NIV: length(days), median [Q1;Q3] | |||||
| Invasive mechanical ventilation | 565 (57.48%) | 498 (58.59%) | 67 (50.38%) | 0.72 [0.50;1.03] | 0,07 |
| If invasive mechanical ventilation. length (days), median [Q1;Q3] | 14.00 [7.50;29.00] | 14.00 [7.00;29.00] | 17.00 [8.00;29.00] | 0.55 | |
| Prone position | 416 (42.4%) | 359 (42.3%) | 57 (42.9%) | – | 0.9 |
| Muscular blockers | 512 (52.1%) | 450 (52.9%) | 62 (46.6%) | – | 0.17 |
| VV or VA ECMO (N = 982) | 64 (6.5%) | 52 (6.1%) | 12 (9.0%) | – | 0.21 |
| Cardiac arrest (N = 972) | 72 (7.4%) | 63 (7.5%) | 9 (6.8%) | – | 0.78 |
| Catecholamines (N = 980) | 399 (40.7%) | 348 (41.1%) | 51 (38.3%) | – | 0.55 |
| Dialysis (N = 978) | 165 (16.9%) | 150 (17.7%) | 15 (11.4%) | – | 0.08 |
| Total length of ward stay, (days, median [Q1;Q3]) | 7.00 [2.00;13.00] | 6.00 [2.0013.00] | 9.00 [4.00; 14.00] | – | 0.0132 |
| Length of ward stay before ICU admission (days, median [Q1;Q3]) | 1.00 [1.00;4.00] | 1.00 [1.004.00] | 2.00 [1.00; 4.00] | – | 0.0335 |
| Length of ICU stay (days, median [Q1;Q3]) | 9.00 [4.00;20.25] | 9.00 [4.0021.00] | 9.00 [4.00; 20.00] | – | 0.88 |
| Length of hospital stay (days), median [Q1;Q3] | 19.00 [11.00;33.00] | 18.00 [11.0033.00] | 20.00 [13.00; 33.00] | – | 0.29 |
| SAPS II (N = 961), mean (SD) | 40.5 (18.32) | 41.6 (18.80) | 33.70 (13.0) | – | < 0.0001 |
HFNO: high-flow nasal oxygen; ICU: Intensive care unit; IL-6Ri: interleukin-6 receptor inhibitor; NIV: non-invasive ventilation; VV or VA ECMO: veno-venous or veno-arterial extracorporeal membrane oxygenation.
Median duration of invasive mechanical ventilation was 14.00 [7.00;29.00] in absence of treatment with IL-6Ri and 17.00 [8.00;29.00] in treated patients. Neuromuscular blockade was administered to 450 (52.9%) and 62 (46.6%) respectively and prone positioning was required in 359 (42.29%) and 57 (42.86%), respectively.
An ECMO support was implemented in 52 (6.12%)in absence of treatment with IL-6Ri 12 (9.02%) of treated patients (Table 4, Supplementary Table 6). Length of ICU stay was 9.0 in both groups (9.00 [4.0021.00] vs 9.00 [4.00; 20.00], respectively). The median time from hospital admission to ICU admission was 1.0 day [1.0–4.0] in the non-treated group and 2.00 [1.00; 4.00] in the IL-6Ri treated group (Table 4, Supplementary Tables 3–5).
COVID-19 specific therapeutic interventions
With the exception of corticosteroids, COVID-19-specific treatments were initiated during the patient’s ward stay. Both IL-6R inhibitors were initiated prior to ICU transfer in the majority of cases (9 out of 133 cases (6.7%) during ICU stay).
A total of 224 patients (8.7%) received at least one dose of tocilizumab or sarilumab. Tocilizumab was administered to 192 patients (7.4%) and sarilumab to 32 patients (1.2%) (Table 3 and 4, Fig. 1, Supplementary Tables 1–5).
In the ward group, corticosteroids were prescribed in association with an IL-6Ri in 79 (86.8%) of patients and without cytokine inhibitor in 778 (51.46%). Other treatments are detailed in Table 4 and supplementary Table 5. In the ICU group the repartition was 112 (84.2%) and 508 (59.7%).
Both in ICU and Ward groups, patients treated with IL-6R inhibitors received significantly more corticosteroids, proton pump inhibitors, and intermediate-dose preventive anticoagulation (Table 3 and 4 Supplementary Table 4–6).
Outcomes
Mortality in the whole population with and without IL-6Ri was 48 (21.4%) and 395 (17.7%) respectively (p = 0.07) (Table 5, 6 and supplementary table 7).
Table 5.
Patients outcome: ward group.
| Total (N = 1603) | No IL-6R inhibitor | Tocilizumab or Sarilumab | p | |
|---|---|---|---|---|
| Ward group | ||||
| Hospital mortality | 176 (11.0%) | 159 (9.9%) | 17 (18.7%) | 0.0155 |
| Day 90 mortality | 180 (1.4%) | 161 (10.0%) | 17(18.7%) |
Table 6.
Patients outcome: ICU group.
| Total (N = 984) | No IL-6R inhibitor | Tocilizumab or Sarilumab | p | |
|---|---|---|---|---|
| ICU group | ||||
| Day 28 mortality | 8 (3.0%) | 8 (3.4%) | 0 (0%) | 0.8 |
| ICU mortality | 248 (25.2%) | 217 (27.7%) | 31 (23.3%) | 0.58 |
| Hospital mortality | 267 (27.1%) | 236 (27.7%) | 31 (23.3%) | 0.29 |
| Day 90 mortality | 271 (27.5%) | 240 (24.4%) | 31(23.3%) | 0.24 |
In the Ward group, 1427 (89.0%) were discharged alive. mortality was higher in patients receiving IL-6R inhibitors (17 (18.7%) vs. 159 (10.5%); p < 0.02) (Table 5 and supplementary table 7). The length of hospital stay was significantly longer in patients receiving IL-6R inhibitors compared to those who did not (10.0 [7.0; 15.0] vs. 7.0 [4.0; 11.0]; p < 0.0001) (Table 3, Supplementary Table 4).
In the ICU group, hospital mortality was similar in both groups (23.3% vs. 27.7%; p = 0.29) (Table 6, Supplementary Table 7). No difference in the length of ICU or hospital stay was observed (20.0 [13.0; 33.0] vs. 18.0 [11.0; 33.0]; p = 0.29) (Table 4, Supplementary Table 5 and 6).
Infectious complications
The infectious complications are described in Tables 7 and 8, Supplementary Table 8.
Table 7.
Clinical course complications: Ward group.
| Total (N = 1603) | No IL-6R inhibitor (N = 1512) | Tocilizumab or Sarilumab (N = 91) | p | |
|---|---|---|---|---|
| Infection during hospital stay | 97 (6.0%) | 88 (5.8%) | 9 (9.9%) | 0.11 |
| Fungal infection | 2 (0.1%) | 2 (0.1%) | 0 (0.0%) | > 0.99 |
| Viral infection | 1 (0.1%) | 0 (0.0%) | 1 (1.1%) | 0.06 |
| Number of infectious episode (N = 95) Mean (SD) | 1.05 (0.3) | 1.07 (0.3) | 0.89 (0.3) | 0.06 |
| Urinary tract infection (N = 1602) | 53 (3.3%) | 50 (3.3%) | 3 (3.3%) | > 0.99 |
| Primitive bacteremia (N = 1600) | 5 (0.3%) | 5 (0.3%) | 0 (0.0%) | > 0.99 |
| Secondary bacteremia (N = 1600) | 10 (0.6%) | 9 (0.6%) | 1 (1.1%) | 0.44 |
| Catheter related infection (N = 1599) | 1 (0.1%) | 1 (0.1%) | 0 (0.0%) | > 0.99 |
| Pneumonia | 6 (0.4%) | 6 (0.4%) | 0 (0.0%) | > 0.99 |
| Any noninfectious adverse event | ||||
| Number of non-infectious adverse event (Median [Q1;Q3]) | ||||
| Hematological complication | 33 (2.1%) | 29 (1.9%) | 4 (4.4%) | 0.11 |
| Thrombopenia (N = 32) | 30 (93.7%) | 26 (92.9%) | 4 (100.0%) | > 0.99 |
| Length of thrombopenia (days) Median [Q1;Q3] | 2.00 [1.00;4.75] | 2.50 [1.00;5.75] | 1.50 [1.00;2.00] | 0.2 |
| Neutropenia | 5 (15.1%) | 5 (17.2%) | 0 (0.0%) | > 0.99 |
| Severe neutropenia | 1 (3.0%) | 1 (3.4%) | 0 (0.0%) | > 0.99 |
| Bleeding | ||||
| Number of bleeding episodes Mean (SD) | 12 (0.7%) | 11 (0.7%) | 1 (1.1%) | 0.51 |
| Gastroduodenal bleeding | 1 (8.3%) | 1 (9.1%) | 0 (0.0%) | |
| Digestive perforation (N = 76) | 1 (8.3%) | 0 (0.0%) | 1 (100.0%) | 0.08 |
Table 8.
Clinical course complications: ICU group.
| Total (N = 984) | No IL-6R inhibitor (N = 851) | Tocilizumab or Sarilumab (N = 133) | p | |
|---|---|---|---|---|
| Infection during hospital stay | 429 (43.6%) | 372 (43.7%) | 57 (42.9%) | 0.85 |
| Fungal infection | 32 (3.2%) | 27 (3.2%) | 5 (3.8%) | 0.79 |
| Viral infection | 30 (3.1%) | 26 (3.1%) | 4 (3.0%) | > 0.99 |
| Number of infectious episode, median [Q1;Q3] | 2.00 [1.00;3.00] | 2.00 [1.00;2.00] | 2.00 [1.00;3.00] | 0.82 |
| Urinary tract infection | 42 (4.3%) | 38 (4.5%) | 4 (3.0%) | 0.43 |
| Primitive bacteremia | 75 (7.7%) | 68 (8.0%) | 7 (5.3%) | 0.26 |
| Secondary bacteremia | 50 (5.1%) | 42 (5.0%) | 8 (6.1%) | 0.6 |
| Catheter-related infection | 30 (3.1%) | 29 (3.4%) | 1 (0.8%) | 0.11 |
| Ventilator-associated pneumonia | 356 (36.2%) | 305 (35.8%) | 51 (38.3%) | 0.58 |
| Hematological complication | 30 (3.1%) | 25 (2.9%) | 5 (3.8%) | 0.59 |
| Thrombopenia | 28 (93.3%) | 23 (92.0%) | 5 (100.0%) | > 0.99 |
| Length of thrombopenia (days), median [Q1;Q3] | 5.00 [3.00;10.50] | 5.00 [2.25;10.75] | 10.00 [10.00;10.00] | 0.13 |
| Neutropenia | 3 (10.0%) | 3 (12.0%) | 0 (0.0%) | > 0.99 |
| Severe neutropenia | 2 (6.9%) | 2 (8.3%) | 0 (0.0%) | > 0.99 |
| Bleeding | ||||
| Number of bleeding episodes, mean (SD) | 64 (6.5%) | 60 (7.1%) | 4 (3.0%) | 0.08 |
| Gastroduodenal bleeding (confirmed by oesogastric endoscopy) | 20 (31.2%) | 20 (33.3%) | 0 (0.0%) | 0.3 |
| Lower digestive tract bleeding | 7 (10.9%) | |||
| Digestive perforation | 1 (1.6%) | 1 (1.7%) | 0 (0.0%) | > 0.99 |
In the whole population, patients who received IL-6R inhibitors developed more hospital-acquired infections than those who did not (unadjusted OR: 1.73 [1.27; 2.34]; p = 0.0004). This result remained consistent after adjustment both with and without multiple imputation (adjusted OR: 2.12 [1.51; 2.97]; p < 0.0001 and adjusted OR: 1.47 [1.25; 1.72]; p < 0.0001, respectively) (Tables 7, 8 and 9, Supplementary Table 8 and 12).
Table 9.
Factors associated to infectious complications according to different statistical analysis methods in the total population.
| Variable | Non ajusted (n = 2587) | Non ajusted—full cases (n = 1946) |
Ajusted—full cases (n = 1946) |
Ajusted—Multiple Imputation (n = 2587) |
||||||
|---|---|---|---|---|---|---|---|---|---|---|
| n | OR [IC95%] | p-value | n | OR [IC95%] | p-value | OR [IC95%] | p-value | OR [IC95%] | p-value | |
| Anti-IL-6R (yes vs no) | 2587 | 1.73 (1.27–2.34) | 0,0004 | 1946 | 1.69 (1.22–2.33) | 0,0014 | 2.12 (1.51–2.97) | < 0.0001 | 1.47 (1.25–1.72) | < 0.0001 |
| Sex (Female vs Male) | 2582 | 0.69 (0.56–0.85) | 0,0005 | 1946 | 0.67 (0.53–0.84) | 0,0006 | 0.69 (0.54–0.89) | 0,0042 | 0.85 (0.76–0.95) | 0,0053 |
| Age (years) | 2585 | < 0.0001 | 1946 | < 0.0001 | 0,0007 | |||||
| [54; 65[ vs. [3; 54[ | 1.89 (1.42–2.52) | 1.76 (1.29–2.40) | 1.72 (1.23–2.39) | 1.23 (1.03–1.46) | 0,0194 | |||||
| [65; 75[ vs. [3; 54[ | 2.09 (1.58–2.77) | 1.98 (1.46–2.69) | 1.91 (1.36–2.69) | 1.30 (1.10–1.55) | 0,0023 | |||||
| [75; 100] vs. [3; 54[ | 1.19 (0.88–1.62) | 1.13 (0.81–1.59) | 1.33 (0.91–1.97) | 0.93 (0.76–1.13) | 0,4541 | |||||
| BMI (kg/m2) | 2149 | 0,0685 | 1946 | 0,1486 | 0,1900 | |||||
| ]25–30] vs. < = 25 | 1.14 (0.88–1.47) | 1.16 (0.89–1.52) | 0.96 (0.72–1.28) | 0.88 (0.76–1.03) | 0,1082 | |||||
| > 30 vs. < = 25 | 1.34 (1.04–1.73) | 1.31 (1.00–1.71) | 1.23 (0.91–1.66) | 1.18 (1.01–1.38) | 0,0386 | |||||
| Tabac habits (yes vs no) | 1.36 (1.07–1.74) | 0,0125 | 1946 | 1.36 (1.06–1.76) | 0,0167 | 1.02 (0.77–1.37) | 0,8774 | 1.03 (0.89–1.19) | 0,6572 | |
| HTA (yes vs no) | 2585 | 1.27 (1.05—1.54) | 0,0140 | 1946 | 1.12 (0.90—1.38) | 0,3079 | 0.96 (0.75—1.23) | 0,7374 | 1.04 (0.93—1.16) | 0,5303 |
| Ischaemic heart disease (yes vs no) | 2584 | 1.17 (0.86–1.59) | 0,3242 | 1946 | 1.12 (0.80–1.58) | 0,5131 | ||||
| Chronic heart failure (yes vs no) | 2585 | 0.67 (0.37–1.22) | 0,1896 | 1946 | 0.59 (0.29–1.21) | 0,1498 | 0.57 (0.27–1.23) | 0,1525 | 0.84 (0.61–1.16) | 0,2906 |
| Diabetes mellitus (yes vs no) | 2584 | 1.59 (1.29–1.96) | < 0.0001 | 1946 | 1.41 (1.12–1.77) | 0,0040 | 1.33 (1.03–1.72) | 0,0314 | 1.17 (1.04–1.32) | 0,0076 |
| Therapeutic immunosuppression (yes vs no) | 2585 | 1.00 (0.65–1.51) | 0,9833 | 1946 | 0.79 (0.50–1.27) | 0,3321 | ||||
| Infectious immunodepression (yes vs no) | 2585 | 1.81 (0.88–3.72) | 0,1060 | 1946 | 1.49 (0.68–3.29) | 0,3173 | 1.53 (0.67–3.51) | 0,3147 | 1.35 (0.92–1.97) | 0,1237 |
| peptic ulcer (yes vs no) | 2585 | 1.25 (0.66–2.35) | 0,4926 | 1946 | 1.28 (0.63–2.57) | 0,4932 | ||||
| COPD/ashtma (yes vs no) | 2585 | 0.97 (0.76–1.25) | 0,8356 | 1946 | 1.01 (0.77–1.32) | 0,9639 | ||||
| Long-term oxygen therapy (yes vs no) | 2583 | - | 0,9730 | 1944 | - | 0,9777 | ||||
| Chronic renal failure (yes vs no) | 2584 | 1.14 (0.81–1.60) | 0,4611 | 1945 | 0.97 (0.66–1.42) | 0,8785 | ||||
| Chronic dialysis (yes vs no) | 2585 | 2.26 (1.24–4.13) | 0,0081 | 1946 | 2.21 (1.15–4.24) | 0,0178 | 2.25 (1.12–4.55) | 0,0233 | 1.40 (1.01–1.94) | 0,0449 |
| Cancer (yes vs no) | 2582 | 1.17 (0.88–1.55) | 0,2790 | 1943 | 1.08 (0.78–1.48) | 0,6472 | ||||
| Stroke (yes vs no) | 2585 | 0.88 (0.59–1.31) | 0,5315 | 1946 | 0.77 (0.48–1.22) | 0,2683 | ||||
| Proton pump inhibitor (yes vs no) | 2563 | 1.11 (0.88–1.41) | 0,3708 | 1931 | 1.02 (0.78–1.33) | 0,8966 | ||||
| Anticoagulant therapy (yes vs no) | 2555 | 0.92 (0.67–1.25) | 0,5871 | 1925 | 0.82 (0.57–1.18) | 0,2876 | ||||
| Anti-platelet aggregant therapy (yes vs no) | 2557 | 1.09 (0.86–1.39) | 0,4657 | 1925 | 0.97 (0.74–1.27) | 0,8465 | ||||
| Initial admission in ICU | 2583 | 5.95 (4.29–8.27) | < 0.0001 | 1946 | 5.63 (3.82–8.28) | < 0.0001 | 3.63 (2.35–5.60) | < 0.0001 | 1.89 (1.57–2.28) | < 0.0001 |
The difference in severity of ICU and ward patients led to conduct a specific analysis of each population. In the ICU group, the incidence of hospital-acquired infections was similar with or without prior treatment with IL-6R inhibitors (43.7% vs. 42.9%; OR: 0.97 [0.67; 1.40]; p = 0.85) (Table 9, Supplementary Table 9 and 13). This result remained consistent after adjustment both with and without multiple imputation (adjusted OR: 2 1.07 [0.88 à 1.30)]; p = 0.5137 and 1.09 [0.73 à 1.64]; p = 0.662 respectively) (supplementary table 14). In the ward group, the loss of power led to a reduction in the effect of IL-6 on the infectious risk after adjustment with multiple imputation (1.34 [0.92 à 1.94]; p = 0.1262) (supplementary table 15). The combination of IL-6R inhibitors and corticosteroids did not modify the risk of secondary infection compared to corticosteroids alone (Table 10). No difference was observed based on the number of initial comorbidities (Supplementary Table 11).
Table 10.
Effect of IL-6R inhibitor and corticosteroids on infection and survival.
| Total (N = 224) | Tocilizumab or Sarilumab with corticosteroids (N = 191) | Tocilizumab or Sarilumab without corticosteroids (N = 33) | p | |
|---|---|---|---|---|
| Infection during hospital stay | 66 (29.5%) | 10 (30.3%) | 56 (29.3%) | 0.91 |
| Fungal infection | 5 (2.2%) | 1 (3.0%) | 4 (2.1%) | 0.55 |
| Viral infection | 5 (2.2%) | 0 (0.0%) | 5 (2.6%) | > 0.99 |
| Number of infectious episode, mean (SD) | 1.00 [1.00;2.00] | 1.50 [1.00;2.75] | 1.00 [1.00;2.00] | 0.62 |
| Urinary tract infection | 7 (3.1%) | 0 (0.0%) | 7 (3.7%) | 0.60 |
| Primitive bacteremia | 7 (3.1%) | 1 (3.0%) | 6 (3.1%) | > 0.99 |
| Secondary bacteremia | 9 (4.0%) | 2 (6.1%) | 7 (3.7%) | 0.62 |
| Catheter related infection | 1 (0.4%) | 1 (3.0%) | 0 (0.0%) | 0.15 |
| Ventilator-associated pneumonia | 51 (22.8%) | 9 (27.3%) | 42 (22.0%) | 0.5 |
| ICU admission | 133 (59.4%) | 21 (63.6%) | 112 (58.6%) | 0.59 |
| Hospital mortality | 48 (21.4%) | 5 (15.1%) | 43 (22.5%) | 0.34 |
Other complications
No difference in hematological abnormalities or digestive complication was observed between groups (Tables 7, 8 and 9, Supplementary Table 10).
Discussion
In our multicenter study, an IL-6R inhibitors were prescribed in 8.6%. The prolonged uncertainty regarding the relevance of IL-6 pathway inhibition 7 led to variable administration during the study period, resulting in a low percentage of patients who actually received an IL-6R inhibitor. This was particularly noticeable in the ICU, where the delayed onset of inflammation and relatively low levels of IL-6 compared to typical acute respiratory distress syndrome or septic shock28,29 often prevented the administration of these IL-6R inhibitors. As more studies emerged, guidelines were modified based on recent syntheses19,30. Both suggest the use of tocilizumab in severe COVID-19, but, balance the potential improvements and the prevention of adverse events19. However, the incidence and severity of these complications remain unclear7.
We found an increased risk of secondary infections associated with the administration of IL-6R inhibitor in the overall patient population (OR: 1.73 [1.27; 2.34]; p = 0.0004). Impairment of immune defenses due to the disruption of the IL-6 pathway is well-documented during long-term treatment of moderate chronic inflammatory diseases11,31. Conversely, the effect of a short period of treatment, remains poorly documented. The inability of a single dose to sufficiently dampen the cytokine response seems probable32 but previous smaller observational studies yielded divergent results. Marco Ripa et al. found an increased risk of infections. However, the involvement of IL-6R inhibitors was uncertain, and the multivariate analysis did not confirm this link33. In another early study in Chicago, the administration of tocilizumab was associated with the risk of secondary bacterial infections34. Unfortunately, the groups were highly heterogeneous, leading to a disequilibrium that blurred the conclusions. Recent meta-analyses offer similarly conflicting conclusions16,35–37.
Many secondary episodes were of viral origin. The central role of IL-6 in viral infection control, by reducing the production of acute phase proteins and modifying B lymphocytes differentiation and T cell maturation, may explain these results31,38. The absence of observed SARS-CoV-2 clearance compromise during clinical use of tocilizumab39 tends to reduce the relevance of this hypothesis. However, the timing of use, potential exhaustion of the inflammatory response, and alteration of the respiratory tract mucosa by the initial viral aggression may secondarily favor a new respiratory viral disease. The delay between admission and tocilizumab administration may play a role in the infectious risk40. Moreover, the association between IL-6R inhibition and specific visceral infections remains unclear. We observed a raw difference in secondary bacteremia that did not reach statistical significance that aligns with previous observations41,42.
Unexpectedly, while previous studies demonstrated an increased risk of infection in ICU patients40–42, we did not identify such a difference in our critical care patients. Administration beyond two days of hospital admission or two days of HFNO requirement has been associated with infectious complications43. In our study, IL-6R inhibitors were all administered on the first day of hospital admission. This may partly explain the discrepancy in the reported infectious risk between studies and may have contributed to the absence of infections during ICU stay. Conversely, as previously discussed7, the absence of a deleterious effect is often associated with a lack of beneficial effect in the same studies7,39. A recent meta-analysis reached a similar conclusion8. The absence of beneficial effects on survival, organ support requirements during ICU stay, or duration of mechanical ventilation observed in our study may partly explain the lack of deleterious effects from IL-6 pathway inhibition.
Most patients concurrently received corticosteroids, making it challenging to evaluate the separate effects of these drugs44. The absence of systematic corticosteroid use allowed for an adjustment that confirmed the involvement of tocilizumab, independent of its potential synergistic effect on the immune response 44.
The limited clinical effect of IL-6 pathway inhibitors in our severe and critical population is further supported by the absence of deleterious digestive and hematological effects widely described in chronic inflammatory diseases and COVID-1917,45.
Our study has several limitations. First, the retrospective design may result in less comprehensive side effect documentation. However, the severity of the complications of interest makes it unlikely that they were omitted from patient files. Furthermore, the incidence of adverse events in our cohort is similar to previous studies and higher than in many randomized trials. Second, the small number of patients treated with IL-6R inhibitors limits the conclusions that can be drawn. This usage however, reflected clinical reality and uncertainty about the benefits and risks of tocilizumab and sarilumab. Third, the lack of information on HFNO use or ICU admission during this critical pandemic period, along with the absence of data on ICU or tracheal intubation withholding, prevents us from drawing conclusions about the potential efficacy of IL-6R inhibition.
Conversely, our cohort has several strengths. The multicenter recruitment of severe patients from both wards and ICUs enabled the inclusion of the largest group of patients who received an IL-6R inhibitor in a tolerability study. The retrospective design minimized bias in the reporting of adverse events associated with the administration of controversial therapies. A specific analysis of tocilizumab allowed for the distinction of adverse events associated with the only IL-6R inhibitor shown to have a benefit during severe COVID-19. The multivariate analysis highlighted risk factors associated with an increased probability of secondary infection during IL-6R inhibitor treatment, which should be considered in the risk–benefit analysis of IL-6R inhibitor therapy in this context.
Methods
Study design
We conducted a retrospective, multicenter cohort study from March 1st, 2020, to December 31st, 2021.
The study adhered to the STROBE (STrengthening the Reporting of Observational Studies in Epidemiology) guidelines for reporting observational studies.
Settings and participants
Eight medical (3 internal medicine and 2 pulmonary departments) and 4 critical care wards of three regional university hospitals in Paris were involved in this study. All consecutive adult patients admitted in one of the participant departments for a documented severe COVID-19, as defined by the IDSA guidelines19 were included in the study.
COVID-19 was confirmed by a positive SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay from nasal or oropharyngeal swabs, or lower respiratory tract samples (in invasively ventilated patients). Patients without laboratory-confirmed COVID-19 were excluded from the study.
Patients were categorized into two groups: the “ward group” who spent their entire hospital stay in a ward (without any admission to intensive care), and the “ICU group” who required ICU admission at any point during their hospital stay and spent part of their all stay in internal medicine or pulmonary department after (and sometimes before) ICU stay.
Patients were admitted to the ICU if they required noninvasive or invasive mechanical ventilation or if they experienced any other acute organ failure. Details are provided in the supplementary material.
Data collection and proceeding
Data were collected using a standardized electronic form. Major adverse event included nosocomial infections, myelotoxicity and digestive tract hemorrhage. Hospital acquired and ventilator-associated pneumonia were defined according to the European20,21 and American guidelines22. Other ICU-acquired infections were diagnosed by the attending physician following established guidelines23. Primary bacterial bloodstream infection and central line associated bloodstream infection were defined as in the EUROBACT study24.
Upper digestive tract hemorrhage was confirmed by endoscopic demonstration of an esophageal, gastric or duodenal lesion25–27. Lower intestinal hemorrhage was defined by the presence of melena or hematochezia and confirmed by colonoscopy27. Thrombopenia was defined as a platelet count below 150 G/l; neutropenia was defined as a neutrophils count below 1 500 /mm3, with severe neutropenia below 500 /mm3.
The primary outcome was the proportion of hospital-acquired infectious episodes during the hospital stay. Secondary outcomes included the occurrence of leukopenia, thrombocytopenia, digestive hemorrhage or perforation, as well as the length of stay in the intensive care unit (ICU) and hospital, and the duration of mechanical ventilation. The exposure variable was the administration of tocilizumab or sarilumab during the hospital stay. Details are provided in the supplementary material.
Ethical considerations
The study was carried out in accordance with the Declaration of Helsinki and French law and was approved by our institutional review board (GERM—Groupe Ethique & Recherche Médicale—; IRB n°00,012,157). The requirement for written informed consent was waived by the GERM—Groupe Ethique & Recherche Médicale; participants were informed about the study, and their non-opposition to the use of anonymized data was noted. The processing of patient data complied with the reference methodology 004 of the French Commission Nationale de l’Informatique et des Libertés (French National Data Protection Agency).
Statistical analysis
Patient characteristics were described for the entire population and stratified by the use of IL-6 inhibitors (tocilizumab or sarilumab). Categorical variables are presented as counts (percentages), and continuous variables as mean (± standard deviation) or median with interquartile range [Q1; Q3], depending on their distribution. Categorical variables were compared between groups using the Pearson Chi-squared test or Fisher’s exact test, while continuous variables were compared using the Student’s t-test or the Wilcoxon rank-sum test. As there were no formal recommendations for the use of tocilizumab or sarilumab, their prescription was based on patient-specific characteristics and the judgment of the attending physician. To address potential bias introduced by these prescription methods, a logistic regression model was employed to examine the relationship between the use of these medications and hospital-acquired infectious episodes. Details are provided in the supplementary material.
Conclusion
In this multicenter French cohort study, the administration of an IL-6R inhibitor to severe COVID-19 patients was associated with an increased incidence of secondary infections. No digestive, or hematological complications were associated with IL-6R inhibitor administration. Broader international studies are needed to confirm these findings.
Supplementary Information
Acknowledgements
This work was supported by the Groupe Hospitalier Paris Saint‑Joseph All data generated or analyzed during this study are included in this study or its supplementary material files. Further inquiries can be directed to the corresponding author
Author contributions
Conceptualization: CL, TFB, AP, MT, FP. Methodology: MC, AF, GC, FP. Inclusions, review and editing: CL, TFB, AP, FP, LS, DM, OV, FB, LW, AP, SL, NR, PRB, MT, NJ, CB, JD. First draft: CL, TFB, FP. Secondary statistical analysis MY.
Funding
This work was supported by the Groupe Hospitalier Paris Saint‑Joseph.
Data availability
Datasets used/analyzed in this study are accessible upon reasonable request to the corresponding author.
Declarations
Competing interests
The authors declare no competing interests.
Ethics approval
The study was carried out in accordance with the Declaration of Helsinki and French law. The TOCSIN study was approved by our institutional review board (GERM; IRB n°00012157). Patients were informed about the study and their non-opposition to the collection and use of non-identifying data for research purposes was obtained. The processing of patient data complied with the reference methodology 004 of the French Commission Nationale de l’Informatique et des Libertés (French National Data Protection Agency).
Footnotes
Prior publication: This work was submitted on MedRxiv: 10.1101/2025.03.04.25323313.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Datasets used/analyzed in this study are accessible upon reasonable request to the corresponding author.