Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trialBMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n84 (Published 20 January 2021) Cite this as: BMJ 2021;372:n84
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Tocilizumab for COVID-19: Difficulties in Interpreting the Results of RCTs vs. Observational Studies
The anti-inflammatory properties of tocilizumab may have benefit for subjects with COVID-19. However, identifying appropriate therapies for the disease proves to be extremely challenging. The complex natural history of COVID-19, which includes an early "viral" phase overlapping a later "inflammatory" phase, may result in potential therapies being effective only during limited timeframes, which are currently difficult to identify. Additionally, critically ill patients suffer systemic and multi-organ complications, and are also prone to secondary infections.
Bacterial co-infection is common in subjects with severe COVID-19, and associated with worse outcome.  One of the reasons for the success of tocilizumab in retrospective and observational studies, such as the large study by Gupta et al.  may be a selection bias for the control group. It is highly probable that immunosuppressive medications such as tocilizumab will only be administered to subjects without evidence of bacterial co-infection. Thus, in retrospective studies the control group will include more subjects with such secondary infections, which have inherently worse outcomes. If this is the case, the perceived benefit of tocilizumab may simply be the confounding effect of unmatched study groups. This may explain some of the critical differences in the results between prospective, randomized controlled trials, and retrospective, observational trials.
In our hospital, we consider tocilizumab for critically ill subjects with COVID-19, after excluding concomitant bacterial infection using molecular diagnostic tests from lower respiratory tract specimens. We believe that such tests offer a high negative predictive value for co-infection with a rapid turnover time, although at the cost of "false positive" results. 
Understanding and interpreting the results of COVID-19 trials has other potential difficulties. For example, the time since the beginning of symptoms to hospital admission can affect outcome as was demonstrated by Alaa et al . Therefore, different policies of referral to hospital is another variable that is not commonly taken into account.
Even though Veiga et al. report no benefit, and possible harm, from tocilizumab in subjects with COVID-19 , as beautifully summarized in the Editorial , the role of tocilizumab in COVID-19 is still undefined and we will have to await the results of further studies.
1. Zhou F, Yu T, Du R, et al. Clinical Course and Risk Factors for Mortality of Adult Inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study. Lancet 2020; 395:1054-62.
2. Gupta S, Wang W, Hayek SS, et al. Association between Early Treatment with Tocilizumab and Mortality among Critically Ill Patietns with COVID-19. JAMA Intern Med 2021; 181:41-51.
3. Kolenda C, Ranc AG, Boisset S, et al. Assessment of Respiratory Bacterial Coinfections Among Severe Acute Respiratory Syndrome Coronavirus 2-Positive Patients Hospitalized in Intensive Care Units Using Conventional Culture and BioFire, FilmArray Pneumonia Panel Plus Assay. Open Forum Infec Dis 2020; 7(11):ofaa484. doi: 10.1093/ofid/ofaa484. eCollection 2020 Nov.
4. Alaa A, Qian Z, Rashbass J et al. Retrospective Cohort Study of Admission Timing and Mortality Following COVID-19 Infection in England. BMJ Open 2020; 10(11):e042712.
5. Veiga VC, Prats JAGG, Farias DLC, et al. Effect of Tocilizumab on Clinical Outcomes at 15 days in Patients with Severe or Critical Coronavirus Disease 2019: Randomised Controlled Trial. BMJ 2021; 372:n84. doi: 10.1136/bmj.n84.
6. McCreary EK and Meyer NJ. COVID-19 Controversies: The Tocilizumab Chapter. BMJ 2021; 372:n244. doi: 10.1136/bmj.n244.
Competing interests: No competing interests
Re: Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial
Is tocilizumab invalid? Or used at a wrong timing in COVID-19 patients
Viviane C Veiga et al. reported that COVID-19 patients could not benefit from tocilizumab therapy. Instead, the application of tocilizumab might increase mortality . Thus, the trial was stopped early. Although the study showed potential risks of tocilizumab, these results should not prevent its application to other COVID-19 patients. John H. Stone et al. reported that tocilizumab did not prevent intubation or death in moderately COVID-19 patients. But in terms of safety, the incidence of serious infections in the tocilizumab group was lower (13[8.1%] vs. 14[17.1%]; P=0.03) . Multiple clinical trials had verified the safety of tocilizumab [2,3,4]. Moreover, due to the wide confidence intervals of this study, some benefit (or harm) from tocilizumab might exist .
In the study of Carlos Salama et al. , the incidence of mechanical ventilation or death by 28 days in patients received tocilizumab (12.0%; 95% confidence interval [CI], 8.5 to 16.9) was significantly lower than in placebo group (19.3%; 95% CI, 13.3 to 27.4) (hazard ratio, 0.56; 95% CI, 0.33 to 0.97; P=0.04). Shruti Gupta et al. performed early tocilizumab administration (within 2 days of ICU admission) in 3924 critical COVID-19 patients . The results showed the death rate of patients treated with tocilizumab significantly decreased.
John H. Stone considered that interleukin-6 and other inflammatory proteins increasing reflect the host's response to infection, rather than a leading part of inflammation amplifying . However, another possibility is that the application of tocilizumab is too late to prevent the serious inflammation induced by Il-6. Actually, in almost all randomized trials, the tocilizumab is used after the symptoms last for many days [1-3]. This may also be the reason why the patients in Shruti Gupta’s study benefit from tocilizumab.
Therefore, tocilizumab should not be sentenced to be invalid. The clinical trial design and patient standards should be improved to explore the patient population that would benefit from tocilizumab.
1. Veiga VC, Prats J, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. Bmj 2021;372:n84.
2. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020;383(24):2333-2344.
3. Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;384(1):20-30.
4. Gupta S, Wang W, Hayek SS, et al. Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. JAMA Intern Med. 2021;181(1):41-51.
Competing interests: No competing interests
Severe COVID-19 is associated with cytokine mediated hyperinflammation with raised interleukin-6 (IL6) and C reactive protein (CRP) levels being highly predictive of worse outcomes . The results of Veiga et al in 129 patients with severe COVID-19 showed futility for the anti-IL6 agent tocilizumab compared to standard of care for the composite of death or mechanical ventilation on day 15 . Moreover, by day 15 there was an 84% (95%CI 27-98) increased likelihood of death associated with tocilizumab and the trial was consequently stopped.
Preliminary data from the REMAP-CAP trial in 755 critically ill patients with COVID-19 found that cardio-respiratory organ support free days up to day 21 were 29% (95%CI 20-53) more likely with tocilizumab versus standard of care and were 29% (95%CI 12-57) more likely to survive during hospitalisation .Taken together these data suggest that the benefit of anti-IL6 therapy is more apparent in critically ill patients with COVID-19 which included corticosteroids in the majority of participants. The presence of rising levels of IL6 or CRP after admission to hospital should point to the need to promptly escalate anti-inflammatory therapy with tocilizumab in critically ill patients who have failed to respond to prior corticosteroids.
1. Lipworth B, Chan R, Kuo CR. Predicting Severe Outcomes in COVID-19. J Allergy Clin Immunol Pract 2020;8(8):2582-84. doi: 10.1016/j.jaip.2020.06.039 [published Online First: 2020/07/03]
2. Veiga VC, Prats J, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. Bmj 2021;372:n84. doi: 10.1136/bmj.n84 [published Online First: 2021/01/22]
3. Gordon AC, Mouncey PR, Al-Beidh F, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report. medRxiv 2021:2021.01.07.21249390. doi: 10.1101/2021.01.07.21249390
Competing interests: No competing interests