Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial

Journal of Allergy and Clinical Immunology

Volumn 146, Issue 1, 2020, Pages 137-146.e3

  Cao, Yang ^a   Wei, Jia ^a   Zou, Liang ^b   Jiang, Tiebin ^c   Wang, Gaoxiang ^a   Chen, Liting ^a   Huang, Liang ^a   Meng, Fankai ^a   Huang, Lifang ^a   Wang, Na ^a   Zhou, Xiaoxi ^a   Luo, Hui ^a   Mao, Zekai ^a   Chen, Xing ^a   Xie, Jungang ^a   Liu, Jing ^c   Cheng, Hui ^b   Zhao, Jianping ^a   Huang, Gang ^d   Wang, Wei ^a   Zhou, Jianfeng ^a   more..

^a HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY   (China)

^b WUHAN NO 1 HOSPITAL   (China)

^c THE THIRD XIANGYA HOSPITAL OF CENTRAL SOUTH UNIVERSITY   (China)

^d CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER   (United States)

Author keywords

COVID 19; cytokine storm; efficacy; randomized controlled trial; Ruxolitinib; safety

Indexed keywords

ALANINE AMINOTRANSFERASE; ALKALINE PHOSPHATASE; ALPHA2 INTERFERON; ANTIBIOTIC AGENT; ANTIVIRUS AGENT; ASCORBIC ACID; ASPARTATE AMINOTRANSFERASE; C REACTIVE PROTEIN; CORTICOSTEROID; GAMMA GLUTAMYLTRANSFERASE; GAMMA INTERFERON; HYPERTENSIVE FACTOR; IMMUNOGLOBULIN M; INTERLEUKIN 12P40; INTERLEUKIN 6; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; MACROPHAGE INFLAMMATORY PROTEIN 1BETA; NERVE GROWTH FACTOR BETA SUBUNIT; RUXOLITINIB; VASCULOTROPIN; JANUS KINASE INHIBITOR; PYRAZOLE DERIVATIVE;

ACUTE HEART FAILURE; ADULT; AGED; ARTICLE; CAUSE OF DEATH; CHIMERIC ANTIGEN RECEPTOR IMMUNOTHERAPY; CLINICAL FEATURE; COMPUTER ASSISTED TOMOGRAPHY; CONTROLLED STUDY; CORONAVIRUS DISEASE 2019; DECREASED APPETITE; DEMOGRAPHY; DISEASE SEVERITY; DIZZINESS; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; EXTRACORPOREAL OXYGENATION; FEMALE; FEVER; HEADACHE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTENSION; HYPERTRIGLYCERIDEMIA; HYPOALBUMINEMIA; HYPOCALCEMIA; HYPOCHLOREMIA; HYPOKALEMIA; LYMPHOCYTOPENIA; MAJOR CLINICAL STUDY; MALE; MORTALITY; MULTICENTER STUDY; NAUSEA; NEUTROPENIA; OXYGEN THERAPY; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; PROSPECTIVE STUDY; RANDOMIZED CONTROLLED TRIAL; RASH; RESPIRATORY FAILURE; SECONDARY INFECTION; SEPSIS; SHOCK; SINGLE BLIND PROCEDURE; THORAX RADIOGRAPHY; THROMBOCYTOPENIA; TOXICITY; BETACORONAVIRUS; CLINICAL TRIAL; CORONAVIRUS INFECTION; MIDDLE AGED; PANDEMIC; TREATMENT OUTCOME; VIRUS PNEUMONIA;

AGED; BETACORONAVIRUS; CORONAVIRUS INFECTIONS; FEMALE; HUMANS; JANUS KINASE INHIBITORS; MALE; MIDDLE AGED; PANDEMICS; PNEUMONIA, VIRAL; PYRAZOLES; SINGLE-BLIND METHOD; TREATMENT OUTCOME;

EID: 85086647427     PISSN: 00916749     EISSN: 10976825     Source Type: Journal    
DOI: 10.1016/j.jaci.2020.05.019     Document Type: Article

References (41)

1. Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 382 (2020), 1199–1207.
2. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 382 (2020), 727–733.
3. Mahase, E., Covid-19: WHO declares pandemic because of “alarming levels” of spread, severity, and inaction. BMJ, 368, 2020, m1036.
4. Lai CC, Liu YH, Wang CY, Wang YH, Hsueh SC, Yen MY, et al. Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): facts and myths [published online ahead of print March 4, 2020]. J Microbiol Immunol Infect. https://doi.org/10.1016/j.jmii.2020.02.012.
5. Guan, W.J., Ni, Z.Y., Hu, Y., Liang, W.H., Ou, C.Q., He, J.X., et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 382 (2020), 1708–1720.
6. Wang, Y., Liu, Y., Liu, L., Wang, X., Luo, N., Ling, L., Clinical outcome of 55 asymptomatic cases at the time of hospital admission infected with SARS-coronavirus-2 in Shenzhen, China. J Infect Dis 221 (2020), 1770–1774.
7. Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 323 (2020), 1061–1069.
8. Du Y, Tu L, Zhu P, Mu M, Wang R, Yang P, et al. Clinical features of 85 fatal cases of COVID-19 from Wuhan: a retrospective observational study [published online ahead of print April 3, 2020]. Am J Respir Crit Care Med. https://doi.org/10.1164/rccm.202003-0543OC.
9. Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395 (2020), 507–513.
10. Cao Y, Liu X, Xiong L, Cai K. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis [published online ahead of print April 3, 2020]. J Med Virol. https://doi.org/10.1002/jmv.25822.
11. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. Available at: https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19. (Accessed 12 May 2020)
12. Chien, J.Y., Hsueh, P.R., Cheng, W.C., Yu, C.J., Yang, P.C., Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology 11 (2006), 715–722.
13. Wang, C.H., Liu, C.Y., Wan, Y.L., Chou, C.L., Huang, K.H., Lin, H.C., et al. Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS. Respir Res, 6, 2005, 42.
14. Wong, C.K., Lam, C.W., Wu, A.K., Ip, W.K., Lee, N.L., Chan, I.H., et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 136 (2004), 95–103.
15. Zhang, Y., Li, J., Zhan, Y., Wu, L., Yu, X., Zhang, W., et al. Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect Immun 72 (2004), 4410–4415.
16. Zhang, C., Wu, Z., Li, J.W., Zhao, H., Wang, G.Q., The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents, 55, 2020, 105954.
17. Channappanavar, R., Perlman, S., Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 39 (2017), 529–539.
18. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395 (2020), 497–506.
19. Peiris, J.S., Chu, C.M., Cheng, V.C., Chan, K.S., Hung, I.F., Poon, L.L., et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 361 (2003), 1767–1772.
20. Stebbing, J., Phelan, A., Griffin, I., Tucker, C., Oechsle, O., Smith, D., et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis 20 (2020), 400–402.
21. Gu, J., Gong, E., Zhang, B., Zheng, J., Gao, Z., Zhong, Y., et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med 202 (2005), 415–424.
22. Ajayi, S., Becker, H., Reinhardt, H., Engelhardt, M., Zeiser, R., von Bubnoff, N., et al. Ruxolitinib. Recent Results Cancer Res 212 (2018), 119–132.
23. Meng, G., Wang, J., Wang, X., Wang, Y., Wang, Z., Ruxolitinib treatment for SR-aGVHD in patients with EBV-HLH undergoing allo-HSCT. Ann Hematol 99 (2020), 343–349.
24. Ahmed, A., Merrill, S.A., Alsawah, F., Bockenstedt, P., Campagnaro, E., Devata, S., et al. Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. Lancet Haematol 6 (2019), e630–e637.
25. Kiladjian, J.J., Zachee, P., Hino, M., Pane, F., Masszi, T., Harrison, C.N., et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol 7 (2020), e226–e237.
26. China National Health Commission. Diagnosis and treatment of pneumonitis caused by new coronavirus (trial version 5). 2020, China National Health Commission, Beijing Available at: http://www.nhc.gov.cn/yzygj/s7653p/202002/3b09b894ac9b4204a79db5b8912d4440.shtml. (Accessed 12 May 2020)
27. Jagasia, M., Perales, M.A., Schroeder, M.A., Ali, H., Shah, N.N., Chen, Y.B., et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label, phase 2 trial. Blood 135 (2020), 1739–1749.
28. National Cancer Institute. Common terminology criteria for adverse events v5.0. Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. (Accessed 24 April 2020)
29. Yan, X.-h., Bao, Y.-w., Zhu, T., Ai, T., Tang, D., Evolution characteristics of thoracic lesions on CT of COVID-19 in recovery stage [in Chinese]. Radiol Pract 35 (2020), 428–432.
30. Li, X., Zeng, W., Li, X., Chen, H., Shi, L., Li, X., et al. CT imaging changes of corona virus disease 2019 (COVID-19): a multi-center study in Southwest China. J Transl Med, 18, 2020, 154.
31. Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., et al. A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19. N Engl J Med 382 (2020), 1787–1799.
32. Coronavirus disease (COVID-2019) R&D. Geneva: World Health Organization. Available at: http://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus/en/. (Accessed 12 May 2020)
33. Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., Zhang, C., et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 8 (2020), 420–422.
34. Yao, X.H., Li, T.Y., He, Z.C., Ping, Y.F., Liu, H.W., Yu, S.C., et al. A pathological report of three COVID-19 cases by minimally invasive autopsies [in Chinese]. Zhonghua Bing Li Xue Za Zhi, 49, 2020, E009.
35. Crayne, C.B., Albeituni, S., Nichols, K.E., Cron, R.Q., The immunology of macrophage activation syndrome. Front Immunol, 10, 2019, 119.
36. Kotch, C., Barrett, D., Teachey, D.T., Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome. Expert Rev Clin Immunol 15 (2019), 813–822.
37. Chen, H., Wang, F., Zhang, P., Zhang, Y., Chen, Y., Fan, X., et al. Management of cytokine release syndrome related to CAR-T cell therapy. Front Med 13 (2019), 610–617.
38. Schulz, O., Hammerschmidt, S.I., Moschovakis, G.L., Forster, R., Chemokines and chemokine receptors in lymphoid tissue dynamics. Annu Rev Immunol 34 (2016), 203–242.
39. Cooper, A.M., Khader, S.A., IL-12p40: an inherently agonistic cytokine. Trends Immunol 28 (2007), 33–38.
40. Menten, P., Wuyts, A., Van Damme, J., Macrophage inflammatory protein-1. Cytokine Growth Factor Rev 13 (2002), 455–481.
41. Olsson, A.K., Dimberg, A., Kreuger, J., Claesson-Welsh, L., VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol 7 (2006), 359–371.