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Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes.
Chest. 2020 10; 158(4):1397-1408.Chest

Abstract

BACKGROUND

Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series.

RESEARCH QUESTION

The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19.

STUDY DESIGN AND METHODS

This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity.

RESULTS

Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002).

INTERPRETATION

A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.

Authors+Show Affiliations

Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, CT; Department of Allergy and Immunology, VA Medical Center, West Haven, CT. Electronic address: Christina.price@yale.edu.Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT; Division of Epidemiology of Microbial Diseases, Yale University School of Public Health, New Haven, CT.Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN.Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.Section of Hematology, Yale University School of Medicine, New Haven, CT.Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.Department of Pharmacy Services, Yale New Haven Hospital, New Haven, CT.Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN.Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT.Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, CT.Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, CT.Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.Department of Pharmacy Services, Yale New Haven Hospital, New Haven, CT.Section of Breast Oncology, Yale Cancer Center, New Haven, CT.Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT.Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, CT.Section of Hematology, Yale Cancer Center, New Haven, CT.Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT.Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, CT.Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT.Section of Hematology, Yale University School of Medicine, New Haven, CT.Department of Medical Oncology, Yale Cancer Center, New Haven, CT.Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT; Department of Pharmacy Services, Yale New Haven Hospital, New Haven, CT.Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT.Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.

Pub Type(s)

Journal Article
Observational Study

Language

eng

PubMed ID

32553536

Citation

Price, Christina C., et al. "Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes." Chest, vol. 158, no. 4, 2020, pp. 1397-1408.
Price CC, Altice FL, Shyr Y, et al. Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes. Chest. 2020;158(4):1397-1408.
Price, C. C., Altice, F. L., Shyr, Y., Koff, A., Pischel, L., Goshua, G., Azar, M. M., Mcmanus, D., Chen, S. C., Gleeson, S. E., Britto, C. J., Azmy, V., Kaman, K., Gaston, D. C., Davis, M., Burrello, T., Harris, Z., Villanueva, M. S., Aoun-Barakat, L., ... Malinis, M. (2020). Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes. Chest, 158(4), 1397-1408. https://doi.org/10.1016/j.chest.2020.06.006
Price CC, et al. Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes. Chest. 2020;158(4):1397-1408. PubMed PMID: 32553536.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes. AU - Price,Christina C, AU - Altice,Frederick L, AU - Shyr,Yu, AU - Koff,Alan, AU - Pischel,Lauren, AU - Goshua,George, AU - Azar,Marwan M, AU - Mcmanus,Dayna, AU - Chen,Sheau-Chiann, AU - Gleeson,Shana E, AU - Britto,Clemente J, AU - Azmy,Veronica, AU - Kaman,Kelsey, AU - Gaston,David C, AU - Davis,Matthew, AU - Burrello,Trisha, AU - Harris,Zachary, AU - Villanueva,Merceditas S, AU - Aoun-Barakat,Lydia, AU - Kang,Insoo, AU - Seropian,Stuart, AU - Chupp,Geoffrey, AU - Bucala,Richard, AU - Kaminski,Naftali, AU - Lee,Alfred I, AU - LoRusso,Patricia Mucci, AU - Topal,Jeffrey E, AU - Dela Cruz,Charles, AU - Malinis,Maricar, Y1 - 2020/06/15/ PY - 2020/05/08/received PY - 2020/06/02/revised PY - 2020/06/08/accepted PY - 2020/6/20/pubmed PY - 2020/10/22/medline PY - 2020/6/20/entrez KW - COVID-19 KW - cytokine release syndrome KW - disease severity KW - mechanical ventilation KW - survival KW - tocilizumab SP - 1397 EP - 1408 JF - Chest JO - Chest VL - 158 IS - 4 N2 - BACKGROUND: Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series. RESEARCH QUESTION: The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19. STUDY DESIGN AND METHODS: This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity. RESULTS: Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002). INTERPRETATION: A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings. SN - 1931-3543 UR - https://www.unboundmedicine.com/medline/citation/32553536/Tocilizumab_Treatment_for_Cytokine_Release_Syndrome_in_Hospitalized_Patients_With_Coronavirus_Disease_2019:_Survival_and_Clinical_Outcomes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0012-3692(20)31670-6 DB - PRIME DP - Unbound Medicine ER -