Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1) and has led to more than 6 million deaths around the world (2). COVID-19 can range from a simple asymptomatic viral infection to acute respiratory distress syndrome (ARDS) requiring intensive care; 15%–20% of hospitalized patients develop severe pneumonia (3, 4). Currently, the standard of care for in-hospitalized patients requiring oxygen is based on corticosteroids (5, 6), which have broad-spectrum anti-inflammatory actions. Despite the extensive use of dexamethasone, 15%–30% of patients remain refractory to corticosteroids and require intubation or progress to death (5–7).

Tocilizumab (an interleukin (IL)-6 receptor antagonist) and anakinra (an IL-1 receptor antagonist) have been proven effective in reducing mortality in patients with severe inflammatory COVID-19 (8–12). In France, since 2021, the French High Council for Public Health (HCSP) recommends adding anti-IL-6 or anti-IL-1 drugs in patients requiring high-flow oxygen therapy and having a marked inflammatory state in the absence of improvement (C-reactive protein (CRP) >75 mg/L) after 48 h of the standard of care, including dexamethasone (13). However, to date, there is no evidence showing which anti-IL drug is the most effective. Scarce data have compared the efficacy of tocilizumab versus anakinra in dexamethasone-refractory COVID-19 patients (14, 15). We aimed to retrospectively compare the outcomes of dexamethasone-refractory COVID-19 patients treated with tocilizumab or anakinra using propensity score matching.

Patients received tocilizumab (8 mg/kg, 800 mg maximum) intravenously over a 1-h infusion once or repeated after 24 h, according to the opinion of the attending clinician. Patients were treated with subcutaneous anakinra 100 mg/day until clinical improvement (maximum 10 days) or with 300 mg/day for 5 days and then tapering 200 mg/day for 2 days and 100 mg/day for 1 day. All patients were treated with dexamethasone (6 mg/day, administered intravenously, until oxygen discontinuation). Patients could also have received anti-spike monoclonal antibodies [casirivimab/imdevimab (Ronapreve®), or sotrovimab (Xevudy®) according to the SARS-CoV-2 variants], antibiotics, and prophylactic (enoxaparin 40 mg/day), intermediate (enoxaparin 40 mg twice a day), or therapeutic (tinzaparin 175 anti-Xa IU/kg/day) thromboprophylaxis according to the current recommendations from the French Society of Critical Care (16) until discharge.

Patients were considered under immunosuppressive therapy when they took anti-rejection therapy, immunosuppressive therapy, corticosteroids > 10 mg/day, biotherapy, or chemotherapy before COVID-19. Patients were considered with a secondary infection when they needed a new antibiotic 48 h after the introduction of the anti-IL drug or when a new bacterial infection was identified (by culture or molecular testing).

This study was approved by the Institutional Review Board of Assistance Publique - Hôpitaux de Marseille (GDPR number PADS22-339). The study was conducted in compliance with good clinical practices and the Declaration of Helsinki principles. Formal approval from an ethics committee was not required for this observational study.

Quantitative variables were described using means and standard deviations (SD); categorical variables were described using numbers and percentages. Quantitative data were compared using Student’s t-test or the Mann–Whitney U test, while qualitative data were compared with the chi-square or Fisher’s exact test when appropriate. A propensity score matching was performed to minimize confounding effects due to the non-random allocation. The propensity score matching function matched the two groups of patients with an anti-IL drug (tocilizumab or anakinra) as the dependent variable. Based on risk factors described in the literature (17–21), propensity score matching of 1:1 was performed with age, sex, vaccine status (partial/full versus none), the extent of lung involvement, comorbidities (hypertension, cancer, chronic kidney disease, diabetes, and obesity), a high-flow requirement before anti-IL introduction, CRP level at the anti-IL drug introduction, use of anti-spike monoclonal antibodies, and thromboprophylaxis as covariates using the optimal method. To confirm the results found with the optimal method, we performed the nearest neighbor propensity score matching method (caliper = 0.25). After matching, McNemar’s test was used to test the association of the mortality rate/rate of high-flow oxygen requirement with the anti-IL drug between matched pairs. The tests were two-sided. p-Values <0.05 were considered significant. All analyses were performed with R software (R Foundation for Statistical Computing, Vienna, Austria), and the propensity score was performed with the MatchIt package.

During the study period, 259 patients were treated with anti-IL drugs; 19 patients were excluded because they received tocilizumab and anakinra (n = 16) or JAK inhibitor and anakinra (n = 3), and five patients were excluded because of a lack of follow-up data. A total of 235 patients were included in the analysis. The main characteristics of the population are presented in Table 1. The mean age was 72 ± 15 years (range, 28–99), with 143 male patients (60.9%). The main comorbidities were hypertension (51.5%), type 2 diabetes (34.0%), obesity (23.4%), overweight (19.4%), chronic kidney disease (18.7%), coronary artery disease (14.0%), pulmonary diseases (chronic obstructive pulmonary disease, asthma, or obstructive sleep apnea, 13.6%), and active cancer (13.2%). Of the total patients, 21 (8.9%) received previous immunosuppressive therapy, and 116 (49.4%) had a “not to be resuscitated” status.

Table 1 Description of the cohort.

Vaccine status was available for 229 patients: 61 patients (26.6%) received at least one dose of vaccine, 12 patients (5.2%) were partially vaccinated (only one dose of vaccine), and 49 (21.4%) were fully vaccinated (two doses of vaccine). Assessment of SARS-CoV-2 variants was available in 111 patients: 25 (22.5%) carried the alpha variant, 5 (4.5%) carried the beta variant, 51 (45.9%) carried the delta variant, and 30 (27.0%) carried the omicron variant. Lung CT showed typical lesions of COVID-19 in 212 out of 220 patients (96.4%), consisting of minimal, moderate, and severe lesions in 11.8%, 34.5%, and 50.0%, respectively. Of 152 patients (64.7%) who received antibiotics, 117 of them (49.8%) received third-generation cephalosporin, 83 patients (35.3%) received azithromycin, 56 patients (23.8%) received piperacillin–tazobactam, and 11 patients (4.7%) received carbapenem. Sixty-six patients (28.1%) received only one antibiotic, 61 patients (26.0%) received two antibiotics, 21 patients (8.9%) received three antibiotics, and four patients (1.7%) received four antibiotics. Of 235 patients, 231 (98.3%) were treated with low-molecular-weight heparin at prophylactic, intermediate, or therapeutic doses of 36.2%, 27.7%, and 34.5%, respectively; 22 patients (9.4%) were treated with monoclonal anti-spike antibodies; 150 patients (63.8%) were treated with an anti-IL drug once under high-flow oxygen. At the time of anti-IL introduction, ferritin was 1,496 ± 1,442 µg/L (range, 96–10,555), and C-reactive protein was 123 ± 77 mg/L (range, 8–351).

A total of 126 (53.6%) patients received tocilizumab, and 109 (46.4%) patients received anakinra (Table 1). The two cohorts were similar in age, gender, and main comorbidities (hypertension, coronaropathy disease, obesity, overweight, and cancer). There were some differences between the two cohorts in terms of vaccine status (fully vaccinated patients: 15.1% of the tocilizumab group vs. 29.1% of the anakinra group, p = 0.01), extent of lung involvement (42.0% of intermediate lesions in the tocilizumab group vs. 25.7% in the anakinra group, p = 0.011; 41.2% of severe lesions in the tocilizumab group vs. 60.4% in the anakinra group, p = 0.0045), SARS-CoV-2 variants (47.8% of alpha variant in the tocilizumab group vs. 4.6% in the anakinra group, p < 0.001; 2.2% of omicron variant in the tocilizumab group vs. 44.6% in the anakinra group, p < 0.001), comorbidities (9.5% of the tocilizumab group had pulmonary diseases vs. 18.3% of the anakinra group, p = 0.049; 11.9% of the tocilizumab group had chronic kidney disease vs. 24.4% of the anakinra group, p = 0.0040; 4.0% of the tocilizumab group were under immunosuppressive therapy vs. 14.7% of the anakinra group, p = 0.0041), severity of clinical state (82.5% of the tocilizumab group were under high-flow oxygen before anti-IL introduction vs. 42.2% of the anakinra group, p < 0.001), thromboprophylaxis management (45.2% of the tocilizumab group received prophylactic dose of low-molecular-weight heparin vs. 25.7% of the anakinra group, p = 0.0019), or associated therapies (0% of the tocilizumab group received anti-spike monoclonal antibody vs. 20.2% of the anakinra group, p < 0.001; 44.4% of the tocilizumab group received antibiotics vs. 88.1% of the anakinra group, p < 0.001).

After propensity score matching using the optimal method (Table 2), 79 patients treated with tocilizumab and 79 patients treated with anakinra had similar characteristics (except for anti-spike monoclonal antibodies; no patients in the tocilizumab group received anti-spike monoclonal antibodies vs. 26.6% of the anakinra group, p < 0.001; for high-flow oxygen introduction before anti-IL introduction, 73.4% were under high-flow oxygen at tocilizumab introduction vs. 43.0% at anakinra introduction). Because of the imbalance of covariates between the two groups, we performed a propensity score matching using the nearest neighbor method (Table 3). Similar characteristics were found in 36 patients treated with tocilizumab and 36 patients treated with anakinra.

Table 2 Patient characteristics after matching (optimal method).

Table 3 Patient characteristics after matching (nearest neighbor method).

The 28-day mortality was similar between the two groups (29.4% in the tocilizumab group vs. 31.2% in the anakinra group, p = 0.76), as was in-hospital mortality (31.7% in the tocilizumab group vs. 33.0% in the anakinra group, p = 0.83). High-flow oxygen was required in similar proportions (17.5% in the tocilizumab group vs. 18.3% in the anakinra group, p = 0.86). Among patients without a “not to be resuscitated” status (n = 119), the transfer rate into intensive care units (ICUs) was similar between the two groups (30.8% in the tocilizumab group vs. 22.2% in the anakinra group, p = 0.30). The secondary infections following anti-IL drugs were quite scarce (6.3% in the tocilizumab group vs. 9.2% in the anakinra group, p = 0.44) (Table 4).

Table 4 Outcomes of the cohort.

After propensity score matching using the optimal method, the 28-day mortality (29.1% in the tocilizumab group vs. 30.4% in the anakinra group, p = 1) and the rate of high-flow oxygen requirement (10.1% in the tocilizumab group vs. 21.5% in the anakinra group, p = 0.081) did not differ between the two groups. Using the nearest neighbor method, we found a similar 28-day mortality (33.3% in the tocilizumab group vs. 30.6% in the anakinra group, p = 1) and a similar rate of high-flow oxygen requirement (5.6% in the tocilizumab group vs. 13.9% in the anakinra group, p = 0.43) between the pseudo-populations.

These results follow the few data available about this subject. IL-1 and IL-6 are two cytokines mainly involved in cytokine storm initiation and amplification, particularly in COVID-19 ARDS (22). Anakinra is an IL-1-receptor antagonist blocking the effect of both IL-1α and IL-1β. IL-1β leads to the production of IL-6 (23). However, tocilizumab blocks IL-6-mediated signal transduction by targeting both the membrane and soluble forms of the IL-6 receptor (24). Thus, it seems logical that the use of tocilizumab or anakinra could be effective in COVID-19. A large amount of data in the literature confirm the efficacy of the two anti-IL drugs (10, 25–27).

However, to date, randomized trials comparing the efficacy of different agents are lacking. The effect of tocilizumab and anakinra seems similar among all the meta-analyses (28–31). One Turkish study compared many patients receiving tocilizumab or anakinra using propensity score matching (15). The authors concluded a lower mortality and ICU transfer rate in the anakinra group. However, in this cohort, patients received very high doses of anakinra (600 mg daily mean versus 100 mg daily in most studies) and were also treated with hydroxychloroquine and favipiravir. Finally, the patients in the tocilizumab group received less corticosteroid than in the anakinra group, which is a major bias. Langer-Gould et al. (32) compared 52 patients treated with tocilizumab to 41 patients treated with anakinra using a propensity score matching and found no statistical difference in mortality. Some other studies, with a few participants, have directly compared tocilizumab to anakinra. Iglesias-Julian et al. (33) showed the same mortality under tocilizumab or anakinra. Patoulias et al. (14) performed a meta-analysis on three non-randomized studies comparing 125 patients under tocilizumab to 112 patients under anakinra and found lower mortality in the anakinra group. Unfortunately, they did not adjust their results with confounding factors. To the best of our knowledge, here, we report one of the largest cohorts of patients treated with tocilizumab compared to anakinra using an adjustment on confounding factors.

We acknowledge some limitations of this study. First, it was retrospective, but we could compare the patients using propensity score matching despite the absence of randomization. We used a combination of clinical, biological, and radiological prognosis factors to build our propensity score matching. Second, the patients were recruited over a large period, including patients infected by different variants of SARS-CoV-2. We could not add variants in the propensity score matching because there were too much missing data, which would have led to the inability to build the propensity score matching. Furthermore, we included a few patients with the omicron variant, which is now dominating. However, there is no evidence that the SARS-CoV-2 omicron variant changes the response to the anti-inflammatory therapy (34, 35). In effect, even if the omicron variant is less severe than the others, thanks to the propensity score matching, we could compare patients with COVID-19 with the same severity (according to the extent of lung involvement, the CRP level, or the rate of high-flow requirement before anti-IL introduction, which are well-known factors of severity). We also acknowledge the lack of assessment of inflammatory biomarkers such as interleukin-6 and soluble urokinase plasminogen activator receptor (suPAR) at baseline. Nevertheless, their utility was not clear, hyperinflammation was defined by CRP and ferritin levels, and IL-6 and suPAR are not routinely available biomarkers in all the centers. Furthermore, the two groups could not be matched on anti-spike monoclonal antibodies (using the optimal method) because no patients in the tocilizumab group have received these treatments (they were not available during the second and third waves when most patients receiving tocilizumab were included). Therefore, we performed a second propensity score matching, in which the use of anti-spike monoclonal antibodies was balanced between the two groups. Despite the small sample size, similar results were found with this method. Moreover, the rate of antibiotic prescriptions was different between the two groups. However, there is no evidence in the literature showing that antibiotics influence the response to anti-IL drugs or the evolution of COVID-19 (36–38).

Since the efficacy of tocilizumab seems to be similar to the efficacy of anakinra, clinicians should consider the cost of the treatment to choose it. In France, the cost of a 10-day anakinra course is lower than that of an 8 mg/kg dose of tocilizumab. In our study, the average cost of tocilizumab per patient was 1,052€/1,124 USD compared to 189€/202 USD per patient treated with anakinra. Moreover, the half-life of anakinra [a few hours (39)] is lower than that of tocilizumab [14–21 days (40)]. In patients with secondary infection due to the anti-IL drug, the infection would be easier to manage with a short half-life therapy such as anakinra than with tocilizumab.

Despite the small sample sizes of groups after propensity score matching, our study showed the same efficacy and secondary infection risk of tocilizumab and anakinra to treat severe COVID-19. Thus, anakinra and tocilizumab represented equivalent therapies in conjunction with corticosteroids. Our results need to be confirmed in larger randomized studies in order to choose the most effective and personalized treatment plans for each patient.

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