Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial

Maryam Edalatifard, Maryam Akhtari, Mohammadreza Salehi, Zohre Naderi, Ahmadreza Jamshidi, Shayan Mostafaei, Seyed Reza Najafizadeh, Elham Farhadi, Nooshin Jalili, Masoud Esfahani, Besharat Rahimi, Hossein Kazemzadeh, Maedeh Mahmoodi Aliabadi, Tooba Ghazanfari, Mohammadreza Sattarian, Hourvash Ebrahimi Louyeh, Seyed Reza Raeeskarami, Saeidreza Jamalimoghadamsiahkali, Nasim Khajavirad, Mahdi Mahmoudi, Abdolrahman Rostamian, Maryam Edalatifard, Maryam Akhtari, Mohammadreza Salehi, Zohre Naderi, Ahmadreza Jamshidi, Shayan Mostafaei, Seyed Reza Najafizadeh, Elham Farhadi, Nooshin Jalili, Masoud Esfahani, Besharat Rahimi, Hossein Kazemzadeh, Maedeh Mahmoodi Aliabadi, Tooba Ghazanfari, Mohammadreza Sattarian, Hourvash Ebrahimi Louyeh, Seyed Reza Raeeskarami, Saeidreza Jamalimoghadamsiahkali, Nasim Khajavirad, Mahdi Mahmoudi, Abdolrahman Rostamian

Abstract

Introduction: There are no determined treatment agents for severe COVID-19. It is suggested that methylprednisolone, as an immunosuppressive treatment, can reduce the inflammation of the respiratory system in COVID-19 patients.

Methods: We conducted a single-blind, randomised controlled clinical trial involving severe hospitalised patients with confirmed COVID-19 at the early pulmonary phase of the illness in Iran. The patients were randomly allocated in a 1:1 ratio by the block randomisation method to receive standard care with methylprednisolone pulse (intravenous injection, 250 mg·day-1 for 3 days) or standard care alone. The study end-point was the time of clinical improvement or death, whichever came first. Primary and safety analysis was done in the intention-to-treat (ITT) population.

Results: 68 eligible patients underwent randomisation (34 patients in each group) from April 20, 2020 to June 20, 2020. In the standard care group, six patients received corticosteroids by the attending physician before the treatment and were excluded from the overall analysis. The percentage of improved patients was higher in the methylprednisolone group than in the standard care group (94.1% versus 57.1%) and the mortality rate was significantly lower in the methylprednisolone group (5.9% versus 42.9%; p<0.001). We demonstrated that patients in the methylprednisolone group had a significantly increased survival time compared with patients in the standard care group (log-rank test: p<0.001; hazard ratio 0.293, 95% CI 0.154-0.556). Two patients (5.8%) in the methylprednisolone group and two patients (7.1%) in the standard care group showed severe adverse events between initiation of treatment and the end of the study.

Conclusions: Our results suggest that methylprednisolone pulse could be an efficient therapeutic agent for hospitalised severe COVID-19 patients at the pulmonary phase.

Conflict of interest statement

Conflict of interest: M. Edalatifard has nothing to disclose. Conflict of interest: M. Akhtari has nothing to disclose. Conflict of interest: M. Salehi has nothing to disclose. Conflict of interest: Z. Naderi has nothing to disclose. Conflict of interest: A. Jamshidi has nothing to disclose. Conflict of interest: S. Mostafaei has nothing to disclose. Conflict of interest: S.R. Najafizadeh has nothing to disclose. Conflict of interest: E. Farhadi has nothing to disclose. Conflict of interest: N. Jalili has nothing to disclose. Conflict of interest: M. Esfahani has nothing to disclose. Conflict of interest: B. Rahimi has nothing to disclose. Conflict of interest: H. Kazemzadeh has nothing to disclose. Conflict of interest: M. Mahmoodi Aliabadi has nothing to disclose. Conflict of interest: T. Ghazanfari has nothing to disclose. Conflict of interest: M. Sattarian has nothing to disclose. Conflict of interest: H. Ebrahimi Louyeh has nothing to disclose. Conflict of interest: S.R. Raeeskarami has nothing to disclose. Conflict of interest: S. Jamalimoghadamsiahkali has nothing to disclose. Conflict of interest: N. Khajavirad has nothing to disclose. Conflict of interest: M. Mahmoudi has nothing to disclose. Conflict of interest: A. Rostamian has nothing to disclose.

Copyright ©ERS 2020.

Figures

FIGURE 1
FIGURE 1
Appropriate time for methylprednisolone administration and inclusion/exclusion criteria of the patients. Patients in the intervention group received methylprednisolone pulse (intravenous injection, 250 mg·day−1 for 3 days) at the early pulmonary phase of the disease before connection to the ventilator and intubation. ICU: intensive care unit; SpO2: arterial oxygen saturation measured by pulse oximetry; CRP: C-reactive protein; IL: interleukin; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; PCT: pro-calcitonin; ARDS: acute respiratory distress syndrome; GI: gastrointestinal.
FIGURE 2
FIGURE 2
Randomisation, enrolment and treatment assignment.
FIGURE 3
FIGURE 3
Kaplan–Meier estimator of survival rate between the methylprednisolone and standard care groups. Log-rank test: p

References

    1. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun 2020; 109: 102433. doi:10.1016/j.jaut.2020.102433
    1. de Wit E, van Doremalen N, Falzarano D, et al. . SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol 2016; 14: 523–534. doi:10.1038/nrmicro.2016.81
    1. Wang W, Tang J, Wei F. Updated understanding of the outbreak of 2019 novel coronavirus (2019-nCoV) in Wuhan, China. J Med Virol 2020; 92: 441–447. doi:10.1002/jmv.25689
    1. Guan WJ, Ni ZY, Hu Y, et al. . Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382: 1708–1720. doi:10.1056/NEJMoa2002032
    1. Musa S. Hepatic and gastrointestinal involvement in coronavirus disease 2019 (COVID-19): what do we know till now? Arab J Gastroenterol 2020; 21: 3–8. doi:10.1016/j.ajg.2020.03.002
    1. Shi Y, Wang Y, Shao C, et al. . COVID-19 infection: the perspectives on immune responses. Cell Death Differ 2020; 27: 1451–1454. doi:10.1038/s41418-020-0530-3
    1. Chen N, Zhou M, Dong X, et al. . Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395: 507–513. doi:10.1016/S0140-6736(20)30211-7
    1. Huang C, Wang Y, Li X, et al. . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506. doi:10.1016/S0140-6736(20)30183-5
    1. Mehta P, McAuley DF, Brown M, et al. . COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395: 1033–1034. doi:10.1016/S0140-6736(20)30628-0
    1. Buttgereit F, Straub RH, Wehling M, et al. . Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum 2004; 50: 3408–3417. doi:10.1002/art.20583
    1. Sung JJY, Wu A, Joynt GM, et al. . Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak. Thorax 2004; 59: 414–420. doi:10.1136/thx.2003.014076
    1. Tsang OTY, Chau TN, Choi KW, et al. . Coronavirus-positive nasopharyngeal aspirate as predictor for severe acute respiratory syndrome mortality. Emerg Infect Dis 2003; 9: 1381–1387. doi:10.3201/eid0911.030400
    1. Arabi YM, Mandourah Y, Al-Hameed F, et al. . Corticosteroid therapy for critically ill patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med 2018; 197: 757–767. doi:10.1164/rccm.201706-1172OC
    1. Moher D, Hopewell S, Schulz KF, et al. . CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869. doi:10.1136/bmj.c869
    1. Ding Z, Li X, Lu Y, et al. . A randomized, controlled multicentric study of inhaled budesonide and intravenous methylprednisolone in the treatment on acute exacerbation of chronic obstructive pulmonary disease. Respir Med 2016; 121: 39–47. doi:10.1016/j.rmed.2016.10.013
    1. Bigler D, Jonsson T, Olsen J, et al. . The effect of preoperative methylprednisolone on pulmonary function and pain after lung operations. J Thorac Cardiovasc Surg 1996; 112: 142–145. doi:10.1016/S0022-5223(96)70189-7
    1. Muir J, Godard P, Leophonte P, et al. . Seventy-two hour comparison of methylprednisolone suleptanate and methylprednisolone sodium succinate in patients with acute asthma. Br J Clin Pract 1996; 50: 440–445.
    1. Lee N, Allen Chan KC, Hui DS, et al. . Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients. J Clin Virol 2004; 31: 304–309. doi:10.1016/j.jcv.2004.07.006
    1. Lee DT, Wing YK, Leung HC, et al. . Factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study. Clin Infect Dis 2004; 39: 1247–1249. doi:10.1086/424016
    1. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006; 3: e343. doi:10.1371/journal.pmed.0030343
    1. RECOVERY Collaborative Group Dexamethasone in hospitalized patients with Covid-19 – preliminary report. N Engl J Med 2020; in press [10.1056/NEJMoa2021436].
    1. Veronese N, Demurtas J, Yang L, et al. . Use of corticosteroids in coronavirus disease 2019 pneumonia: a systematic review of the literature. Front Med 2020; 7: 170. doi:10.3389/fmed.2020.00170
    1. Liu K, Fang YY, Deng Y, et al. . Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J 2020; 133: 1025–1031. doi:10.1097/CM9.0000000000000744
    1. Ling Y, Xu S-B, Lin Y-X, et al. . Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients. Chin Med J 2020; 133: 1039–1043. doi:10.1097/CM9.0000000000000774
    1. Zha L, Li S, Pan L, et al. . Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19). Med J Aust 2020; 212: 416–420. doi:10.5694/mja2.50577
    1. Wu C, Chen X, Cai Y, et al. . Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; 180: 934–943. doi:10.1001/jamainternmed.2020.0994
    1. Wang Y, Jiang W, He Q, et al. . A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther 2020; 5: 57. doi:10.1038/s41392-020-0158-2
    1. Epstein SK, Singh N. Respiratory acidosis. Respir Care 2001; 46: 366–383.
    1. Goodwin JE, Geller DS. Glucocorticoid-induced hypertension. Pediatr Nephrol 2012; 27: 1059–1066. doi:10.1007/s00467-011-1928-4
    1. Liu F, Li L, Xu M, et al. . Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol 2020; 127: 104370. doi:10.1016/j.jcv.2020.104370

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