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. 2021;181(1):12-15. 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.

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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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