In this randomized, controlled, open-label trial, we investigated the effect of tocilizumab on mortality and the need for IMV in adults with severe COVID-19 pneumonia and high IL-6 serum levels. Our primary analysis revealed a trend towards a lower rate of death or need for IMV in the tocilizumab group compared to the SOC group, although this difference was not statistically significant. It may be clinically significant, especially when considering that the trial was discontinued earlier, and the expected sample size was not reached, limiting the trial’s statistical power. Secondary outcomes showed similar trends favoring tocilizumab, including fewer days of IMV and shorter hospital stays. These results are novel since the study focusses on patients who might benefit the most from the IL-6 blockade strategy by selecting subjects with high IL-6 serum levels.

Our findings support previous studies that reported benefits of tocilizumab in reducing mortality and the need for mechanical ventilation. The RECOVERY trial [8] randomized 4116 hospitalized patients presenting hypoxia and systemic inflammation to receive tocilizumab versus SOC and found benefits in mortality and secondary outcomes. Similarly, in their study Salama et al. concluded that tocilizumab reduced the likehood of progression to mechanical ventilation or death [20]. The REMAP-CAP [9] focused in critically ill patients receiving organ support and assigned 865 subjects to receive an IL-6 antagonist or SOC. They found efficacy of IL-6 receptor antagonists in increasing the median of organ support-free days and in other secondary outcomes. Nevertheless, in none of these studies was it required to have elevated IL-6 to participate. The difference in the rate of the primary outcome was broader in our study than previous trials. Consistently, in the meta-analysis, the estimated RR for our study was half of the pooled estimate, driven by large trials such as RECOVERY and REMAP-CAP. This could be due to the selection of participants in whom the excessive inflammation and higher risk of progression were related to an increased IL-6. Consequently, this subpopulation could have a greater benefit from an IL-6 blockade strategy [9].

For instance, Stone et al. concluded that tocilizumab was not effective for preventing intubation or death in patients with moderate illness [11]. The difference with our results may be also explained by the fact that in their study, median IL-6 level was 24.4 pg/mL while in ours participants the median IL-6 serum levels was 76.4 pg/mL. A similar phenomenon occurs with the study by Salvarani et al., in which median IL-6 serum level in the participants was 42.1 pg/mL [19].

Interestingly, Wang et al. designed a clinical trial similar to ours, in which patients with high IL-6 serum levels were randomized to receive tocilizumab in addition to the standard of care. The primary outcome was clinical improvement, which was not statistically different in both groups. Despite the fact that this study was designed to select patients who might benefit most of an IL-6 blockade, IL-6 serum levels were only slightly above the normal limit (25 pg/mL), which might have diluted this effect [22].

Other trials not using personalized medicine driven by IL-6 serum levels were unable to demonstrate the benefit of tocilizumab. Rosas et al. concluded that the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo. Although in this trial, only 22% of the patients received glucocorticoids at inclusion in contraposition with our trial, in which 83% received concomitant steroids [10]. In their trial, Soin et al. did not find differences in illness progression in patients treated with tocilizumab but they included a highly heterogeneous sample population with patients presenting different ranges of severity [23].

Our study supports the safety and tolerability of tocilizumab, as no serious AEs were documented and only 6.1% of participants in the tocilizumab group presented a grade 2 or 3 AE. Notably, there were more transaminase elevations in the tocilizumab arm, but all were mild and transient, not requiring further intervention. This is consistent with the observed data reported in the package insert from the European Medicines Agency [24]. Moreover, there were no bacterial infections in These results enforce the statement that tocilizumab is useful in hospitalized patients with COVID-19. the tocilizumab group. Results from other clinical trials showed similar results, stressing the fact that the use of a limited number of doses in the context of a severe COVID-19 have a safety profile similar to other populations receiving tocilizumab.

The meta-analysis shows a lower proportion of death or IMV in patients treated with tocilizumab. The results are consistent among studies and the meta-analysis shows low heterogeneity due to the high quality of the trials included. Interestingly, 8 out of 9 clinical trials showed RR below one, indicating a protective effect of tocilizumab against death or IMV. Results in the trials administering tocilizumab regardless of the IL-6 inflammatory status showed a RR spinning around 0.8, while personalized medicine strategy based on IL-6 serum levels has a RR of 0.4 (95%CI 0.14–1.14) [25, 26].

The main strength of our study is the selection of a population at high risk of poor prognosis and with a highly likelihood of improving based on the tocilizumab mechanism of action. IL-6 serum level measurements can be easily implemented, and turnaround time can be less than few hours, allowing for the implementation of our personalized medicine strategy. Moreover, the randomized controlled design presents advantages by reducing biases and improving the reliability of the findings.

However, there are some limitations that need to be stated. First, the small sample size, that did not reach the calculated sample size, limits the interpretation of the results. In addition, patients were included during a two-year period, during which standard-care treatment and SARS-Cov2 variants changed, however this bias may have influenced both groups in the same proportion. On the other hand, our study included participants with infections from different strains over the time, and we did not find any differences regarding the time period in which participants were included in both efficacy and safety outcomes. Tocilizumab treatment may be equally effective regardless the circulating strain, and is unlikely that its efficacy could be compromised over the time. Finally, the last limitation is that during the study period, immunization was implemented, potentially affecting the outcomes and introducing variability in patient responses, but again patients were equally vaccinated in both groups.

Tocilizumab may reduce the risk of death or IMV in patients with severe COVID-19 pneumonia. This benefit could be higher among people with high IL-6 serum levels. A personalized treatment strategy driven by IL-6 serum levels in patients with severe COVID-19 pneumonia could maximize the benefits of tocilizumab and reduce the number of patients needed to treat to prevent a poor outcome, while optimizing the allocation of resources. Finally, tocilizumab in patients with severe COVID-19 pneumonia and high IL-6 serum levels is safe and well tolerated.