In our retrospective cohort study of critically ill COVID-19 patients, we found that patients who received tocilizumab did not have a significantly higher risk of acquiring multidrug-resistant bacteria such as MDR, XDR, PDR nor had higher risk of CRE. Moreover, the tocilizumab group had similar in-hospital mortality, 30 day ICU mortality, days on MV during ICU stay, ICU length of stay, and hospital length of stay to those who did not receive tocilizumab. However, patients who received tocilizumab did have a significantly higher risk of respiratory failure that required MV.
Our primary outcomes findings were observed after adjusting for the patient's comorbidities, history of hospitalization or invasive procedure within one year, history of antibiotics exposure in the last three months, systemic corticosteroids during ICU, and ICU LOS. The finding of no difference in secondary infections rate is similar to previous studies that conducted adjusted matched analyses for tocilizumab and controls and showed no difference between the arms only (26 in the treatment arm, 25 in the control arm; 95% CI for difference, − 0.15 to 0.13; P = 1.00) (20, 21). This was also demonstrated in another multicenter cohort study of 4485 adults with COVID-19 admitted to (ICUs) has found no differences in secondary infection rate (140 [32.3%] vs 1085 [31.1%]) (22, 23 ). This is also concurrent with a recent meta-analysis that evaluated tocilizumab use in critically ill patients and found no difference in secondary infection between tocilizumab and the control group (24). However, other published trials found lower rates of secondary infections with tocilizumab (7,10,11), while another study found higher rates of secondary infections with tocilizumab (25). The differences in outcomes in these studies could be attributed to the unadjusted analysis in some studies and if studied on critically ill patients or other hospitalized patients as critical care settings are more prone to infections. Further randomized studies are needed to confirm these findings.
We found no significant difference in 30-day ICU and in-hospital mortality rates between the two groups. Previous studies depicted mixed results in the mortality outcome. In one randomized control study comparing tocilizumab with usual care in non ICU COVID-19 patients with moderate to severe pneumonia, there was also no difference in mortality at 28-days (10). Similarly, a recent meta-analysis in ICU patients found no significant difference in mortality rates between the tocilizumab group and the comparator groups (24). Alternatively, a previous retrospective cohort study in ICU COVID-19 patients found significantly lower ICU mortality in the tocilizumab group but no difference in the 28-day mortality (23). Another retrospective cohort study for non-ICU patients found lower mortality with tocilizumab (25). In the recent RECOVERY trial that included non-ICU COVID-19 patients, there was a significant lower 28-days mortality in the tocilizumab group compared with placebo. However, it is important to note that this benefit may be attributed to the combination with corticosteroids, as more than 80% on included patients were recieveing corticosteroids at the same time, a confounder that we took in consideration and adjusted for it (26).
Furthermore, a randomized clinical trial evaluated tocilizumab versus usual care in ICU patients with COVID-19 and found no significant difference in 15-day, in-hospital and 28-days mortality between the two groups. However, this trial was prematurely interrupted after the first interim analysis due to an excess number of deaths at day 15 in the tocilizumab group (27). Overall, the mortality benefit with tocilizumab in an ICU setting is still debatable, but other potential clinical benefits could justify its use and improve COVID-19 patients course of illness.
Intersteningly, our study demonstrated that the progression of care towards the use of mechanical ventilator was higher among patients who received tocilizumab. This could be due to the increase in IL-6 levels and the cytokine storm shortly after the infusion, which was associated with worsening PaO2/FIO2 ratio and decline in the lung function as reported by Rossotti R, et al (28). These finding are contradicted by the result of two randomized controlled trials conducted by Hermine O, et al (10) and Salama C, et al (6), which showed that the use of tocilizumab was associated with reduced risk of intubation and need for mechanical ventilation.
In this study, tocilizumab use was not associated with any statistically significant differences in the ICU and hospital length of stay. In contrast to our findings is the reports from COVACTA trial (5) were they found that the median time until patients were discharged from the hospital or was 20 days in the tocilizumab group and 28 days in the placebo group. Also, they report shorter ICU Los, the median duration of ICU stay was 9.8 days in the tocilizumab group and 15.5 days in the placebo group, for a difference of 5.8 days.
Among patient who received tocilizumab, we found differences in inflammatory markers levels compared with the control group. The D-dimer levels were higher in the tocilizumab group compared with placebo. In line with this results, Rossotti et al. found that d -dimer rise by day 5, then it decreased but without returning to baseline values (28). This finding is consistent with previous observational studies (30,31) were C-reactive protein, IL-6 improved; however, D-dimer levels increased significantly and is concerning as it might increase the risk of thromboembolic events, which is increased among patient with covid-19 (32). Fibrinogen levels during ICU stay were lower in the tocilizumab group, which was expected as tocilizumab tends to decrease inflammatory markers.
Our study has some limitations that need to be addressed. The retrospective and observational nature of the study puts the study at risk for residual confounding, despite adjustment for possible confounders. Furthermore, the decision to prescribe tocilizumab to COVID-19 patients was guided by the institutional and the Ministry of Health treatment protocols which continued to change with the emergence of new data. Moreover, the subsequent doses of tocilizumab and the timing between them could affect some of the clinical outcomes, which warrant further studies.