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

Jonathan B. Parr

doi:10.1001/jamainternmed.2020.6557

Editorial

October 20, 2020

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

Jonathan B. Parr, MD, MPH¹

Author Affiliations Article Information

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

Original Investigation

Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19

Shruti Gupta, MD, MPH; Wei Wang, PhD; Salim S. Hayek, MD; Lili Chan, MD, MSCR; Kusum S. Mathews, MD, MPH, MSCR; Michal L. Melamed, MD, MHS; Samantha K. Brenner, MD, MPH; Amanda Leonberg-Yoo, MD, MS; Edward J. Schenck, MD, MS; Jared Radbel, MD; Jochen Reiser, MD, PhD; Anip Bansal, MD; Anand Srivastava, MD, MPH; Yan Zhou, MD; Diana Finkel, DO; Adam Green, MD, MBA; Mary Mallappallil, MD; Anthony J. Faugno, MD; Jingjing Zhang, MD, PhD; Juan Carlos Q. Velez, MD; Shahzad Shaefi, MD, MPH; Chirag R. Parikh, MD, PhD; David M. Charytan, MD, MSc; Ambarish M. Athavale, MBBS, MD; Allon N. Friedman, MD; Roberta E. Redfern, PhD; Samuel A. P. Short, BA; Simon Correa, MD, MMSc; Kapil K. Pokharel, MBBS; Andrew J. Admon, MD, MPH, MSc; John P. Donnelly, PhD; Hayley B. Gershengorn, MD; David J. Douin, MD; Matthew W. Semler, MD; Miguel A. Hernán, MD, DrPH; David E. Leaf, MD, MMSc; STOP-COVID Investigators
Original Investigation

Effect of Tocilizumab on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia

Carlo Salvarani, MD; Giovanni Dolci, MD; Marco Massari, MD; Domenico Franco Merlo, PhD; Silvio Cavuto, BSc; Luisa Savoldi, BSc; Paolo Bruzzi, MD, PhD; Fabrizio Boni, MD; Luca Braglia, BSc; Caterina Turrà, MSc; Pier Ferruccio Ballerini, MD; Roberto Sciascia, MD; Lorenzo Zammarchi, MD; Ombretta Para, MD; Pier Giorgio Scotton, MD; Walter Omar Inojosa, MD; Viviana Ravagnani, MD; Nicola Duccio Salerno, MD; Pier Paolo Sainaghi, MD; Alessandro Brignone, MD; Mauro Codeluppi, MD; Elisabetta Teopompi, MD, PhD; Maurizio Milesi, MD; Perla Bertomoro, MD; Norbiato Claudio, MD; Mario Salio, MD; Marco Falcone, MD; Giovanni Cenderello, MD; Lorenzo Donghi, MD; Valerio Del Bono, MD; Paolo Luigi Colombelli, MD; Andrea Angheben, MD; Angelina Passaro, MD; Giovanni Secondo, MD; Renato Pascale, MD; Ilaria Piazza, MD; Nicola Facciolongo, MD; Massimo Costantini, MD, PhD; RCT-TCZ-COVID-19 Study Group
Original Investigation

Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia

Olivier Hermine, MD, PhD; Xavier Mariette, MD, PhD; Pierre-Louis Tharaux, MD, PhD; Matthieu Resche-Rigon, MD, PhD; Raphaël Porcher, PhD; Philippe Ravaud, MD, PhD; CORIMUNO-19 Collaborative Group; Serge Bureau; Maxime Dougados; Annick Tibi; Elie Azoulay; Jacques Cadranel; Joseph Emmerich; Muriel Fartoukh; Bertrand Guidet; Marc Humbert; Karine Lacombe; Matthieu Mahevas; Frédéric Pene; Valérie Pourchet-Martinez; Frédéric Schlemmer; Yazdan Yazdanpanah; Gabriel Baron; Elodie Perrodeau; Damien Vanhoye; Cécile Kedzia; Lauren Demerville; Anne Gysembergh-Houal; Alexandre Bourgoin; Sarah Dalibey; Matthieu Resche-Rigon; Nabil Raked; Lakhdar Mameri ; Stéphanie Alary; Samir Hamiria; Thinhinane Bariz; Hala Semri; Dhiaa Meriem Hai; Moustafa Benafla; Mohamed Belloul; Pernelle Vauboin; Saskia Flamand; Claire Pacheco; Anouk Walter-Petrich; Emilia Stan; Souad Benarab; Corine Nyanou; Claire Montlahuc; Lucie Biard; Robin Charreteur; Celine Dupré; Kévin Cardet; Blandine Lehmann; Kamyl Baghli; Claire Madeleine; Eric D'Ortenzio; Oriane Puéchal; Caroline Semaille; Laurent Savale; Anatole Harrois; Samy Figuereido; Jacques Duranteau; Nadia Anguel; Xavier Monnet; Christian Richard; Jean-Louis Teboul; Philippe Durand; Pierre Tissieres; Mitja Jevnikar; David Montani; Stéphan Pavy; Nicolas Noel; Olivier Lambotte; Lelia Escaut; Stéphane Jauréguiberry; Elodie Baudry; Christiane Verny; Edouard Lefèvre; Mohamad Zaidan; Clotilde Le Tiec Le Tiec; Céline Verstuyft Verstuyft; Anne-Marie Roques; Lamiae Grimaldi; Domitille Molinari; Gaël Leprun; Alain Fourreau; Laurent Cylly; Myriam Virlouvet; Ramdane Meftali; Solène Fabre; Marion Licois; Asmaa Mamoune; Yacine Boudali; Sophie Georgin-Lavialle; Patricia Senet; Angèle Soria; Antoine Parrot; Hélène François; Nathalie Rozensztajn; Emmanuelle Blin; Pascaline Choinier; Juliette Camuset; Jean-Simon Rech; Antony Canellas; Camille Rolland-Debord; Nadège Lemarié; Nicolas Belaube; Marine Nadal; Martin Siguier; Camille Petit-Hoang; Julie Chas; Elodie Drouet; Matthieu Lemoine; Audrey Phibel; Lucie Aunay; Eliane Bertrand; Sylviane Ravato; Marie Vayssettes; Anne Adda; Celine Wilpotte; Pélagie Thibaut; Julie Fillon; Isabelle Debrix; Soraya Fellahi; Jean-Philippe Bastard; Guillaume Lefèvre; Vincent Fallet; Jacques-Eric Gottenberg ; Yves Hansmann; Emmanuel Andres; Sophie Bayer ; Guillaume Becker ; Frédéric Blanc; Stéphane Brin; Vincent Castelain; Emmanuel Chatelus ; Eva Chatron; Olivier Collange; François Danion; Frédéric De Blay ; Eric Demonsant ; Pierre Diemunsch; Sophie Diemunsch; Renaud Felten; Bernard Goichot ; Valentin Greigert; Aurélien Guffroy ; Bob Heger ; Anne Hutt; Charlotte Kaeuffer ; Loic Kassegne; Anne Sophie Korganow; Pierrick Le Borgne; Nicolas Lefebvre ; Tristan Martin ; Paul Michel Mertes; Catherine Metzger ; Nicolas Meyer ; Gabriel Nisand ; Eric Noll; Mathieu Oberlin; Sophie Ohlmann-Caillard; Vincent Poindron ; Julien Pottecher ; Yvon Ruch ; Cédric Sublon ; Hakim Tayebi ; François Weill ; Arsène Mekinian; Dorothée Chopin; Olivier Fain; Marc Garnier; Jessica Krause Le Garrec; Marjolaine Morgand; Jerome Pacanowski; Tomas Urbina; Chloe Mcavoy; Maria Pereira; Gladys Aratus; Laurence Berard; Tabassome Simon; Anne Daguenel Nguyen; Marie Antignac; Céline Leplay; Jean-Benoit Arlet; Jean-Luc Diehl ; Florence Bellenfant ; Anne Blanchard ; Alexandre Buffet; Bernard Cholley ; Antoine Fayol ; Edouard Flamarion ; Anne Godier; Thomas Gorget; Sophie-Rym Hamada ; Caroline Hauw-Berlemont ; Jean- Sébastien Hulot ; David Lebeaux ; Marine Livrozet ; Adrien Michon; Arthur Neuschwander ; Marie-Aude Pennet; Benjamin Planquette ; Brigitte Ranque ; Olivier Sanchez ; Geoffroy Volle ; Sandrine Briois ; Mathias Cornic ; Virginie Elisee ; Denis, Jesuthasan; Juliette Djadi-Prat ; Pauline Jouany ; Ramon Junquera ; Mickael Henriques ; Amina Kebir ; Isabelle Lehir ; Jeanne Meunier ; Florence Patin ; Valérie Paquet; Anne TréHan ; Véronique Vigna ; Brigitte Sabatier; Damien Bergerot ; Charlène Jouve ; Camille Knosp ; Olivia Lenoir; Nassim Mahtal; Léa Resmini; Xavier Lescure; Jade Ghosn; Antoine Bachelard ; Timothee Bironne; Raphael Borie ; Agathe Bounhiol; Catherine Boussard ; Jeanne Chauffier ; Solaya Chalal; Lynda Chalal; Malikhone Chansombat ; Paul Crespin; Bruno Crestani ; Olivia Daconceicao; Laurene Deconinck; hilippe Dieude; Antoine Dossier; Marie Dubert ; Greggory Ducrocq; Axelle Fuentes ; Anne Gervais; Marie Gilbert; Valentina Isernia ; Sophie Ismael; Veronique Joly; Zelie Julia; Sylvie Lariven; Sylvie Le Gac; Diane Le Pluart ; Francoise Louni; Awa Ndiaye; Thomas Papo; Marion Parisey; Bao Phung ; Annabelle Pourbaix; Anne Rachline; Christophe Rioux; Aurelie Sautereau ; Gabriel Steg; Hassan Tharini; Simon Valayer; Dorothee Vallois; Paul Vermes; Thomas Volpe; Yann Nguyen; Vasco Honsel; Emmanuel Weiss; Anaïs Codorniu; Virginie Zarrouk; Victoire De Lastours; Matthieu Uzzan; Naura Gamany; Roza Rahli; Zeina Louis; David Boutboul; Lionel Galicier; Yaël Amara; Gabrielle Archer; Amira Benattia; Anne Bergeron; Louise Bondeelle; Nathalie De Castro; Melissa Clément; Michaël Darmont; Blandine Denis; Clairelyne Dupin; Elsa Feredj; Delphine Feyeux; Adrien Joseph; Etienne Lengliné; Pierre Le Guen; Geoffroy Liégeon; Gwenaël Lorillon; Asmaa Mabrouki; Eric Mariotte; Grégoire Martin De Frémont; Adrien Mirouse; Jean-Michel Molina; Régis Peffault De Latour; Eric Oksenhendler; Julien Saussereau; Abdellatif Tazi; Jean-Jacques Tudesq; Lara Zafrani; Isabelle Brindele; Emmanuelle Bugnet; Karine Celli Lebras; Julien Chabert; Lalia Djaghout; Catherine Fauvaux; Anne Lise Jegu; Ewa Kozaliewicz; Martine Meunier; Marie-Thérèse Tremorin; Claire Davoine; Isabelle Madeleine; Sophie Caillat-Zucman; Constance Delaugerre; Florence Morin; Damien Sene; Ruxandra Burlacu; Benjamin Chousterman; Bruno Megarbane; Pascal Richette; Jean-Pierre Riveline; Aline Frazier; Eric Vicaut; Laure Berton; Tassadit Hadjam; Miguel Alejandro Vasquez-Ibarra; Clément Jourdaine; Aude Jacob; Julie Smati; Stéphane Renaud; Philippe Manivet; Claire Pernin; Lydia Suarez; Luca Semerano; Sebastien Abad; Ruben Benainous; Coralie Bloch Queyrat; Nicolas Bonnet; Sabrina Brahmi; johann Cailhol; Yves Cohen; Celine Comparon; Hugues Cordel; Robin Dhote; Nathalie Dournon; Boris Duchemann; Nathan Ebstein; Benedicte Giroux-Leprieur; Jeanne Goupil De Bouille; Anne Jacolot; Hilario Nunes; Johanna Oziel; Vanessa Rathouin; Marthe Rigal; Dominique Roulot; Claire Tantet; Yurdagul Uzunhan; Nathalie Costedoat-Chalumeau; Zakaria Ait Hamou; Sarah Benghanem; Philippe Blanche; Etienne Canoui; Nicolas Carlier; Benjamin Chaigne; Adrien Contejean; Bertrand Dunogue; Pierre Dupland; Aurélie Durel - Maurisse; Remy Gauzit; Paul Jaubert; Hassan Joumaa; Mathieu Jozwiak; Solen Kerneis; Marie Lachatre; Hélène Lafoeste; Paul Legendre; Liem Binh Luong Nguyen; Jonathan Marey; Caroline Morbieu; Luc Mouthon; Lee Nguyen; Lola-Jade Palmieri; Alexis Regent; Tali-Anne Szwebel; Benjamin Terrier; Corinne Guerin; Jérémie Zerbit; Kahina Cheref; Kamil Chitour; Mamadou Salif Cisse; Ada Clarke; Gaelle Clavere; Isabelle Dusanter; Caroline Gaudefroy; Moez Jallouli; Sami Kolta; Catherine Le Bourlout; Nathalie Marin; Nathalie Menage; Alexandre Moores; Isabelle Peigney; Cédric Pierron; Samira Saleh-Mghir; Mathilde Vallet; Marc Michel; Giovanna Melica; Jean-Daniel Lelievre; Elena Fois; Pascal Lim; Marie Matignon; Constance Guillaud; Alaki Thiemele; David Schmitz; Marion Bouhris; Syllia Belazouz; Laetitia Languille; Armand Mekontso-Dessaps; Thiziri Sadaoui; Julien Mayaux; Patrice Cacoub; Jean-Christophe Corvol; Céline Louapre; Sara Sambin; Louise-Laure Mariani; Carine Karachi; Florence Tubach; Candice Estellat; Linda Gimeno; Karine Martin; Aïcha Bah; Vixra Keo; Sabrine Ouamri; Yasmine Messaoudi; Nessima Yelles; Pierre Faye; Sébastien Cavelot; Cecile Larcheveque ; Laurence Annonay; Jaouad Benhida; Aida Zahrate-Ghoul; Soumeya Hammal; Ridha Belilita; Marie Lecronier; Alexandra Beurton; Luc Haudebourg; Robin Deleris; Julien Le Marec; Sara Virolle; Safaa Nemlaghi; Côme Bureau; Pierre Mora; Martin De Sarcus; Olivier Clovet; Baptiste Duceau ; Paul Henri Grisot ; Marie hélène Pari ; Jérémy Arzoine; Ulrich Clarac; Morgane Faure; Julie Delemazure; Maxence Decavele; Elise Morawiec; Alexandre Demoule; Martin Dres ; Mathieu Vautier; Yves Allenbach; Olivier Benveniste; Gaelle Leroux; Aude Rigolet; Perrine Guillaume-Jugnot; Fanny Domont; Anne Claire Desbois; Cloé Comarmond; Nicolas Champtiaux; Segolene Toquet; Amine Ghembaza; Matheus Vieira; Georgina Maalouf; Gonçalo Boleto; Yasmina Ferfar; Fanny Charbonnier; Claire Aguilar; Fanny Alby-Laurent; Marie-Alexandra Alyanakian; Prissile Bakouboula; Christine Broissand; Carole Burger; Clara Campos-Vega; Nathalie Chavarot; Laure Choupeaux; Caroline Elie; Benjamin Fournier; Sophie Granville; Elodie Issorat; Claire Rouzaud; Damien Vimpere; Guillaume Geri; Nawal Derridj; Naima Sguiouar; Hakim Meddah; Mourad Djadel; Helene Chambrin-Lauvray; Jean-Charles Duclos-Vallée; Faouzi Saliba; Sophie-Caroline Sacleux; Ilias Koumis; Jean-Marie Michot; Annabelle Stoclin; Emeline Colomba; Fanny Pommeret; Chistophe Willekens; Rosa Da Silva; Valérie Dejean; Yasmina Mekid; Ines Ben-Mabrouk; Caroline Pradon; Laurence Drouard; Valérie Camara-Clayette; Alexandre Morel; Gilles Garcia; Abolfazl Mohebbi; Férial Berbour; Mélanie Dehais; Anne-Lise Pouliquen; Alison Klasen; Loren Soyez-Herkert; Jonathan London; Younes Keroumi; Emmanuelle Guillot; Guillaume Grailles; Younes El Amine; Fanny Defrancq; Hanane Fodil; Chaouki Bouras; Dominique Dautel; Nicolas Gambier; Thierno Dieye; Boris Bienvenu; Victor Lancon; Laurence Lecomte; Kristina Beziriganyan; Belkacem Asselate; Laure Allanic; Elena Kiouris; Marie-Hélène Legros; Christine Lemagner; Pascal Martel; Vincent Provitolo; Félix Ackermann; Mathilde Le Marchand; Aurélie Clan Hew Wai; Dimitri Fremont; Elisabeth Coupez; Mireille Adda; Frédéric Duée; Lise Bernard; Antoine Gros; Estelle Henry; Claire Courtin; Anne Pattyn; Pierre-Grégoire Guinot; Marc Bardou; Agnes Maurer; Julie Jambon; Amélie Cransac; Corinne Pernot; Bruno Mourvillier; Amélie Servettaz; Gaetan Deslée; Alain Wynckel; Philippe Benoit; Eric Marquis; Damien Roux; Coralie Gernez; Cécile Yelnik; Julien Poissy; Mandy Nizard; Fanette Denies; Hélène Gros; Jean-Jacques Mourad; Emmanuelle Sacco; Sophie Renet

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.

2 Comments for this article

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October 21, 2020

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

November 8, 2020

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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