Time to Reassess Tocilizumab’s Role in COVID-19 Pneumonia | Critical Care Medicine | JAMA Internal Medicine | JAMA Network
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Editorial
October 20, 2020

Time to Reassess Tocilizumab’s Role in COVID-19 Pneumonia

Author Affiliations
  • 1Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill
JAMA Intern Med. Published online October 20, 2020. doi:10.1001/jamainternmed.2020.6557

In this issue of JAMA Internal Medicine, 3 important articles1-3 explore the use of tocilizumab in coronavirus disease 2019 (COVID-19) pneumonia. Tocilizumab is a humanized monoclonal antibody that binds human interleukin 6 (IL-6) receptors. It is used routinely in inflammatory arthritis, giant cell arteritis, and cytokine release syndrome after chimeric antigen receptor T-cell therapy. Its use recently proliferated after early observations from China showed increased risk of death in patients with COVID-19 and elevated IL-6 levels,4 and nonrandomized studies5,6 suggested benefit from tocilizumab treatment. In many centers across the United States, off-label use of tocilizumab became standard of care for patients with COVID-19 and evidence of hyperinflammation. However, practice patterns have varied, and guidelines from the National Institutes of Health7 and the Infectious Disease Society of America8 now recommend against the use of tocilizumab except in the context of a clinical trial. Although an increasing number of observational studies9-11 have suggested mortality benefit, data from randomized clinical trials (RCTs) of tocilizumab in COVID-19 are sorely needed to inform clinical practice.

The studies reported by Salvarani et al for the RCT-TCZ-COVID-19 Study Group (RCT-TCZ-COVID-19)1 and Hermine et al for the CORIMUNO-19 Collaborative Group (CORIMUNO-TOCI-1)2 provide clinicians with their first look at peer-reviewed RCT results. In addition, preliminary results from COVACTA12 and EMPACTA,13 2 multicenter, randomized, double-blind, placebo-controlled trials, have just been released. These studies, complemented by the largest observational study of tocilizumab in COVID-19 published to date, from the Study of the Treatment and Outcomes in Critically Ill Patients With COVID-19 (STOP-COVID) investigators,3 supply the raw material needed for a critical appraisal of tocilizumab use in COVID-19. For clinicians practicing on the front lines of the COVID-19 pandemic and weary of the deluge of research findings coming their way, now is the time to step back and reconsider the proper placement of tocilizumab in their COVID-19 treatment algorithms.

How should we interpret, and more importantly operationalize, findings from these studies? In the following discussion, several considerations that should influence our conclusions are highlighted.

Observational Studies and Residual Confounding

Even the best observational studies can be affected by residual confounding. With more than 60 000 COVID-19 publications listed in PubMed and multiple clinical trials under way, our choice of COVID-19 therapeutics can and should rely on the best possible evidence from randomized trials. In contrast to findings from STOP-COVID3 and a growing number of observational studies,9-11 none of the tocilizumab randomized trials reported mortality benefit at 28 or 30 days,1-3,12,13 and only 2 of these2,13 reported outcomes meeting predefined thresholds for clinical efficacy (Table).

Table.  Comparison of Major Tocilizumab COVID-19 Studies Reported to Date
Comparison of Major Tocilizumab COVID-19 Studies Reported to Date

The STOP-COVID tocilizumab study3 stands out from other observational studies owing to its large size and focus on patients admitted to intensive care units (ICUs) at leading academic centers across the United States. The investigators used observational data from a large, multisite study and adjusted for confounding using a Cox proportional hazards model with inverse probability weighting. Reduced time to death and risk of death at 30 days were observed in patients treated with tocilizumab. However, there are potentially important differences in treatment groups at baseline (tocilizumab-treated patients were younger and had fewer comorbidities but were more likely to have hypoxemia and elevated levels of inflammatory markers). The authors appropriately acknowledge and attempt to adjust for these differences, but even careful statistical methods cannot completely overcome the risk of residual confounding in observational studies.

Despite their inherent limitations, carefully conducted retrospective clinical studies can provide critical insights into proper clinical management, especially when results of RCTs are unavailable. The STOP-COVID investigators3 rapidly collected and analyzed data in the midst of a global pandemic and should be applauded for their efforts to establish a generalizable evidence base for COVID-19 management decisions. Nonetheless, randomized trials will ultimately determine tocilizumab’s role in COVID-19.

Not All Randomized Trials Are Equal

The trials reported by the RCT-TCZ-COVID-19 Study Group1 and the CORIMUNO-19 Collaborative Group2 are similar in size, enrolled participants with similar clinical severity, and are strengthened by their multisite designs. Both are limited by the lack of blinding and placebo controls. However, the similarities stop there, because these trials included very different study populations that deserve careful consideration.

Salvarani et al1 enrolled hospitalized patients in Italy with severe COVID-19 who required oxygen by nasal cannula but did not yet require ICU-level care. Their objective was to study the effect of early tocilizumab administration (≤8 hours of randomization). The trial was stopped early by the data and safety board for futility, after initial analyses did not find evidence of improvement in primary outcomes (development of a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen <150 mm Hg, ICU admission, or death). Two important characteristics of their population and treatment groups deserve extra attention.

First, the study population had very few deaths, with 2.4% overall mortality 30 days after randomization in the intention-to-treat analysis. This mortality rate is surprisingly low for a study of hospitalized patients with severe COVID-19, especially in Italy. Recent estimates indicate an overall case fatality rate of 13.2% among all comers (outpatients and hospitalized patients) with confirmed COVID-19 in Italy.14 The trial’s low mortality rate is likely driven by its exclusion criteria; participants were excluded if they were ineligible for ICU admission owing to comorbidities and clinical criteria that varied by site. The concept of ICU ineligibility will be unfamiliar to most US clinicians but was an unfortunate reality during Italy’s pandemic response. Second, 14 of 60 patients assigned to the usual care treatment group ultimately received tocilizumab owing to clinical worsening. This was permitted per study protocol, and per-protocol and intention-to-treat analysis results were similar, but treatment with tocilizumab in both the intervention and comparator groups complicates interpretation of the results. Although these 2 characteristics limit the trial’s generalizability, the value of its prospective, randomized design cannot be understated.

The other prospective, randomized trial reported herein, CORIMUNO-19-TOCI-1,2 enrolled hospitalized patients in France with moderate or severe COVID-19 pneumonia and oxygen requirement but who did not require high-flow oxygen by nasal cannula, noninvasive ventilation, or mechanical ventilation (World Health Organization clinical progression scale [WHO-CPS] score of 5). In layman’s terms, they studied a population of patients with COVID-19 who were sick enough to require oxygen by low-flow nasal cannula and who would typically be managed on the floor (ie, not in the ICU) in US hospitals. The parent CORIMUNO trial also enrolled patients with more severe disease, but these patients were not included in the present study. Unlike the other randomized trials, the investigators used Bayesian statistical methods to assess efficacy.

One of 2 predefined thresholds for treatment efficacy was met; the posterior probability of improved survival without the need for noninvasive or mechanical ventilation by day 14 in the treatment group (their late outcome) was 95.05%, just exceeding the threshold of greater than 95%.2 Reduced risk of a WHO-CPS score of greater than 5 at day 4 (their early outcome) was not observed. In contrast to the study by Salvarini et al,1 the overall 28-day mortality rate was 11.5% and more in line with what might be expected in well-resourced hospitals in the global North. The narrow focus of CORIMUNO-19-TOCI-1 and its more representative patient population make its findings easier to generalize. Its findings suggest that tocilizumab may improve outcomes at 14 days, but the significance of this finding is unclear in light of newly released preliminary results from the COVACTA12 and EMPACTA13 trials.

COVACTA12 and EMPACTA13 are double-blind, placebo-controlled RCTs sponsored by F Hoffman-La Roche Ltd, tocilizumab’s manufacturer, and conducted at sites worldwide. Peer-reviewed analyses are not yet available, but early press releases reported mixed results. The COVACTA study,12 conducted across North America and Europe, reported failure to meet predefined efficacy thresholds and no mortality difference at day 28. Tocilizumab-treated patients had reduced hospital lengths of stay, but other secondary outcomes were negative. The EMPACTA study of patients largely from minority racial and ethnic groups across the Americas and Africa13 reported efficacy in its primary end point, reduction of mechanical ventilation or death by day 28. However, secondary outcomes were negative, and no difference in mortality was observed at day 28.

Aware that the antiviral remdesivir has been widely adopted without clear evidence of mortality benefit, one might ask, “Is reduced risk of mechanical ventilation in some patient populations enough to motivate tocilizumab use?” Findings from the CORIMUNO-TOCI-12 and EMPACTA13 studies suggest that tocilizumab may reduce the need for mechanical ventilation and, by extension, ICU-level care in some patients with severe COVID-19. However, the answer will depend on in-depth analysis of results from COVACTA,12 EMPACTA,13 and other studies nearing completion.

Things May Change

As with everything in the COVID-19 era, things may change. At least 5 other RCTs of tocilizumab in COVID-19 are under way.15-19 These include double-blinded, randomized, placebo-controlled trials, as well as the massive, pragmatic Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial17 being conducted across the United Kingdom. Studies focused on different patient populations and outcomes will better define tocilizumab’s role in COVID-19 management.

For now, however, findings from the randomized trials described herein do not support routine tocilizumab use in COVID-19. Differences in mortality attributable to tocilizumab at day 28 or 30 were not observed across all randomized trials. Only 2 of the 4 trials reported evidence of efficacy, one based on a single primary outcome measure that barely met its predefined efficacy threshold. Although observational studies by the STOP-COVID investigators3 and others9-11 report mortality benefit and other positive outcomes, priority should be given to the randomized trial results when developing clinical algorithms.

There is an important caveat relevant to these and other therapeutic trials in COVID-19: longer-term outcomes may tell a different story. We know that the hyperinflammatory state induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in some patients is a major driver of COVID-19 morbidity and mortality. Prolonged hospitalization and rehabilitation are common among patients hospitalized with severe COVID-19. It is possible that blunting the immune response with tocilizumab will reduce morbidity and mortality over the long haul. It is also possible that treatment-related adverse events and secondary infections will become more apparent over time, although these were rare in the studies described herein.

Conclusions

Newly released randomized trials suggest a potential role for tocilizumab in COVID-19 but do not show clear evidence of efficacy, in contrast to observational studies. Their findings do not support the routine use of tocilizumab for COVID-19 in most settings. I plan to wait out the torrent of positive observational studies and reconsider tocilizumab’s use in COVID-19 if, and only if, more compelling data from randomized trials emerges.

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Article Information

Corresponding Author: Jonathan B. Parr, MD, MPH, Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, 111 Mason Farm Rd, Campus Box 7036, Chapel Hill, NC 27599 (jonathan_parr@med.unc.edu).

Published Online: October 20, 2020. doi:10.1001/jamainternmed.2020.6557

Conflict of Interest Disclosures: Dr Parr reported receiving grant support from the World Health Organization and Gilead Sciences, Inc, and nonfinancial support from Abbott Laboratories, all outside the scope of the current work. No other disclosures were reported.

Additional Contributions: Ashley Marx, PharmD, University of North Carolina at Chapel Hill Eshelman School of Pharmacy, provided comments on a draft of this commentary, for which she was not compensated.

References
1.
Salvarani  C, Dolci  G, Massari  M,  et al; for the RCT-TCZ-COVID-19 Study Group.  Effect of tocilizumab vs standard of care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial.   JAMA Intern Med. Published online October 20, 2020. doi:10.1001/jamainternmed.2020.6615Google Scholar
2.
Hermine  O, Mariette  X, Tharaux  P-L, Resche-Rigon  M, Porcher  R, Ravaud  P; for the CORIMUNO-19 Collaborative Group.  Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial.   JAMA Intern Med. Published online October 20, 2020. doi:10.1001/jamainternmed.2020.6820Google Scholar
3.
Gupta  S, Wang  W, Hayek  SS,  et al; for the STOP-COVID Investigators.  Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19.   JAMA Intern Med. Published online October 20, 2020. doi:10.1001/jamainternmed.2020.6252Google Scholar
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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(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3 PubMedGoogle ScholarCrossref
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Xu  X, Han  M, Li  T,  et al.  Effective treatment of severe COVID-19 patients with tocilizumab.   Proc Natl Acad Sci U S A. 2020;117(20):10970-10975. doi:10.1073/pnas.2005615117 PubMedGoogle ScholarCrossref
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Luo  P, Liu  Y, Qiu  L, Liu  X, Liu  D, Li  J.  Tocilizumab treatment in COVID-19: a single center experience.   J Med Virol. 2020;92(7):814-818. doi:10.1002/jmv.25801 PubMedGoogle ScholarCrossref
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National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. Updated September 1, 2020. Accessed August 31, 2020. https://www.covid19treatmentguidelines.nih.gov/
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Bhimraj  A, Morgan  RL, Shumaker  AH,  et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Updated September 21, 2020. Accessed August 31, 2020. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
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Guaraldi  G, Meschiari  M, Cozzi-Lepri  A,  et al.  Tocilizumab in patients with severe COVID-19: a retrospective cohort study.   Lancet Rheumatol. 2020;2(8):e474-e484. doi:10.1016/S2665-9913(20)30173-9 PubMedGoogle ScholarCrossref
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Somers  EC, Eschenauer  GA, Troost  JP,  et al.  Tocilizumab for treatment of mechanically ventilated patients with COVID-19.   Clin Infect Dis. Published online July 11, 2020. doi:10.1093/cid/ciaa954 PubMedGoogle Scholar
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    2 Comments for this article
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    Is a 'Cytokine storm' relevant to CoVID19?
    Camilo Colaco, PhD | ImmunoBiology Ltd
    The potential role for tocilizumab in COVID-19 is dependent on the proposal that a 'Cytokine Storm' driven by IL6 results in ARDS that is widely believed to be the pathophysiology of CoVID19. This proposal is, however, not supported by studies that measure levels of IL6 in CoVID patients as a previous JAMA editorial discussed (1). As I pointed out in my comments on that editorial, a pulmonary intravascular coagulopathy (PICS) is an alternative explanation for the pathophysiology of CoVID19 than ARDS (2) and more consistent with the biomarkers observed in patients, including the elevated d-dimer levels that have been reported consistently from the first clinical studies (3). It is important to recognize this in order to focus future studies on more useful therapeutic studies, such as the treatment of the coagulopathy characteristic of PICS (3) as effective treatments for CoVID19 are desperately needed to reduce the global impact on mortality. With respect to the misdirection of ARDS, it is interesting that even the efficacy of the widely used anti-coagulant LMW heparin in CoVID has been ascribed to the mitigation of a cytokine storm (4), though the important aspect of this retrospective analysis shows that it appears to be more effective than the studies that are the subject of the current editorial.

    1. Sinha P, Matthay MA, Calfee CS. Is a “Cytokine Storm” Relevant to COVID-19? JAMA Intern Med. 2020;180(9):1152–1154. doi:10.1001/jamainternmed.2020.3313
    2. McGonagle D, O’Donnell JS, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatology Published online May 7, 2020. https://doi.org/10.1016/S2665-9913(20)30121-1 .
    3. Oudkerk M et.al. Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands. Radiology Published Online Apr 23 2020. https://doi.org/10.1148/radiol.2020201629
    4. Chen S et.al. The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID-19 patients: a retrospective clinical study. medRxiv 2020.03.28.20046144; https://doi.org/10.1101/2020.03.28.20046144.
    CONFLICT OF INTEREST: None Reported
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    A clinician' s perspective on the use of tocilizumab for COVID-19
    Abdullah Sayiner, M.D. | Ege University Faculty of Medicine
    Three randomized controlled trials (RCT) (1-3) and one large observational study (4) on the efficacy of tocilizumab in COVID-19 were almost simultaneously published in two important journals. As they reported conflicting results; from a simple clinician’ s perspective, I have tried to find whether there is a responder subgroup and thus looked at the differences between the one positive (1) and two negative RCT’s (2, 3). In the study by Stone et al. (3) the patients had to meet two of three clinical and one of five laboratory criteria. Thus, a COVID-19 patient with fever and pulmonary infiltrates and a CRP value > 50 mg/L could be eligible. This may have led to the inclusion of non-hyperinflamed patients and resulted in similar outcomes in the control group. The studies by Hermine et al (1) and Salvarani et al (2) had similar inclusion criteria, randomization was performed at similar times (10 and 7 days after the onset of symptoms, respectively), the two populations had similar oxygenation levels; however, the former positive study reported higher ferritin (1292 vs 646 ng/mL), and CRP levels (120 vs 105 mg/L) at baseline. LDH level was also high (401 U/L) in the former, but not reported in the latter study. The ferritin and LDH levels were also lower in the negative study by Stone et al (723 ng/mL and 351 U/L, respectively). In the observational study (4), which included patients with severe COVID-19 admitted to the ICU, the beneficial effects of tocilizumab were more pronounced in patients admitted to the ICU within 3 days of symptom onset, possibly pointing to a hyperinflammatory, rapidly progresive disease in such patients; however, the data were not analyzed for inflammatory biomarkers. These findings suggest that patients with more overt signs of inflammation may in fact benefit from anti-IL-6 treatment and that we need to better define the target population. One possible approach could be the use of validated prediction models for cytokine storm (5) in future studies.
    References
    1. Hermine O, Mariette X, Tharaux PL et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. doi: 10.1001/jamainternmed.2020.6820
    2. Salvarani C, Dolci G, Massari M et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia. A randomized clinical trial. JAMA Intern Med. doi: 10.1001/jamainternmed.2020.6615
    3. Stone JH, Frigault MJ, Serling-Boyd NJ et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. New Eng J Med. doi: 10.1056/NEJMoa2028836
    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. doi: 10.1001/jamainternmed.2020.6252
    5. Caricchio R, Gallucci M, Dass C et al. Preliminary predictive criteria for COVID-19 cytokine storm. Ann Rheum Dis. doi: 10.1136/annrheumdis.2020.218323
    CONFLICT OF INTEREST: None Reported
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