Early, low-dose, short-term methylprednisolone decreased the mortality in critical COVID-19 patients: A multicenter retrospective cohort study
Authors: Jingjing Ji, Ming Wu, Li Zhong, Zheying Liu, Conglin Wang, Ziyun Shao, Qifeng Xie, Zhifeng Liu
Journal: Journal of Infection (2020)

We read with interest the recent paper by Yang et al., concluding that corticosteroids overall have a negative impact on COVID-19 outcomes from a meta-analysis 1Zhenwei Yang Jialong Liu Yunjiao Zhou Xixian Zhao Qiu Zhao Jing Liu The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis.J Infect. 2020; 81: e13-e20https://doi.org/10.1016/j.jinf.2020.03.062Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar. Critical COVID-19, characterized by refractory hypoxemia caused by acute respiratory distress syndrome (ARDS), is a life-threatening multi-organ dysfunction syndrome resulted from host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Glucocorticoid (GC) was one of the anti-inflammatory medications used in critical patients 2Guo-Wei Tu Yi Shi Yi-Jun Zheng Min-Jie Ju Hong-Yu He Guo-Guang Ma et al.Glucocorticoid attenuates acute lung injury through induction of type 2 macrophage.J Transl Med. 2017; 15: 181https://doi.org/10.1186/s12967-017-1284-7Crossref PubMed Scopus (96) Google Scholar. Efficacy of glucocorticoids has been reported in numerous clinical studies in the treatment of coronavirus pneumonia 3Wen Zhang Yan Zhao Fengchun Zhang Qian Wang Taisheng Li Zhengyin Liu et al.The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the Perspectives of clinical immunologists from China.Clin Immunol. 2020; 214108393https://doi.org/10.1016/j.clim.2020.108393Crossref PubMed Scopus (940) Google Scholar. Yang and colleagues demonstrated that patients treated with GC had a higher mortality 1Zhenwei Yang Jialong Liu Yunjiao Zhou Xixian Zhao Qiu Zhao Jing Liu The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis.J Infect. 2020; 81: e13-e20https://doi.org/10.1016/j.jinf.2020.03.062Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, suggesting that not all patients could benefit from GC treatment. Present study aimed to evaluate the effect of GC on different patient population. Since critical patients were more likely to receive GC therapy, only severe type and critical type patients, according to clinical classification of the Chinese Recommendations for Diagnosis and Treatment of Novel Coronavirus (SARSCoV2) infection (Trial 7th version)4National Health Commission of the People`s Republic of China. Chinese recommendations for diagnosis and treatment of novel coronavirus (SARSCoV2) infection (Trial 7th version) 2020.Google Scholar, were enrolled in present study. We retrospective collected the clinical and outcome data of critical COVID-19 patients, and taking methylprednisolone (MP) treatment, the most used GC during clinical treatment, as an exposure factor analyzed the outcome. This study provides information on MP clinical application in treatment of SARS-CoV-2 infection, including patient selection and administration time and dosage. Present multicenter retrospective cohort study was performed in 4 government designated treatment centers for COVID-19 patients in 3 cities in China, Wuhan, Guangzhou, and Shenzhen. The data collection period was from December 2019 to March 2020. This study was approved by the Research Ethics Commission of General Hospital of Southern Theater Command of PLA (HE-2020–08) and the requirement for informed consent was waived by the Ethics Commission. Inclusion Criteria for all patients: (1) Adult aged >= 18 years old; (2) Laboratory (RT-PCR) confirmed SARS-COV-2 infection in throat swab and/or sputum and/or lower respiratory tract samples; or conformed plasma positive of specific antibody (IgM or/and IgG) against SARS-COV-2; (3) In-hospital treatment ≥72 h. The patients in who meet any one of the following criteria were enrolled in severe type group 4: (a) Respiratory rate >= 30/min; or (b) Rest SPO2 <= 90%; or (c) PaO2/FiO2 <= 300 mmHg. The patients in who meet any one of the following criteria were enrolled in critical type group 4: (a) Respiratory failure and needs mechanical ventilation; or (b) Shock occurs; or (c) Multiple organ failure and needs ICU monitoring. Exclusion Criteria: (1) Exist of other evidences that can explain pneumonia including but not limited to influenza A virus, influenza B virus, bacterial pneumonia, fungal pneumonia, noninfectious causes, etc.; (2) Women who are pregnant or breast-feeding. Data from 338 patients diagnosed as critical COVID-19 were collected in present study. According to whether methylprednisolone was employed during treatment, 164 in Non-MP group and 174 in MP group. For all cases, MP treatment did not show benefit in prognosis (Fig. 1). The effects of MP differed between different clinical classification and baseline lactate concentration. MP treatment on the critical type patients could decrease the 60-day fatality (HR: 0.409, 95% CI: 0.238–0.704, p-value: 0.001), while it has no influence on the fatality of severe type patients. In addition, patients with higher lactate concentration on baseline could get more benefit from MP treatment. For the patients with lactic acid concentration over 2 mmol/L, MP treatment could significantly decrease the 60-day fatality (HR: 0.150, 95% CI: 0.055–0.408, p-value: < 0.001). These results showed that MP treatment have more efficiency on the patients with serious condition. Glucocorticoid could suppress lung inflammation and but also inhibit immune responses. Therefore, balancing the risk and benefit is crucial during the treatment, that is, not all patients could benefit from GC therapy. Critical type COVID-19 patients showed excessive inflammatory responses and MP treatment could alleviate the cytokine storm by inhibiting the inflammatory cells activation 5Gregory Julia L. Pam Hall Michelle Leech Morand Eric F. Hickey Michael J. Independent roles of macrophage migration inhibitory factor and endogenous, but not exogenous glucocorticoids in regulating leukocyte trafficking.Microcirculation. 2009; 16: 735-748https://doi.org/10.3109/10739680903210421Crossref PubMed Scopus (20) Google Scholar. In addition, critical illness-related corticosteroid insufficiency occurs across a broad spectrum of critical illness due to the impairment of the hypothalamic pituitary axis 6Annane Djillali Stephen M. Pastores Bram Rochwerg Wiebke Arlt Robert A. Balk Albertus Beishuizen et al.Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.Intensive Care Med. 2017; 43: 1751-1763https://doi.org/10.1007/s00134-017-4919-5Crossref PubMed Scopus (192) Google Scholar. Inadequate endogenous glucocorticoid resulted in insufficient anti-inflammatory activity, and MP treatment could adverse this issue. Moreover, MP could improve the microcirculation in critical patients 7Nina Kumowski Tobias Hegelmaier Jonas Kolbenschlag Tina Mainka Beate Michel-Lauter Christoph Maier Short-term glucocorticoid treatment normalizes the microcirculatory response to remote ischemic conditioning in early complex regional pain syndrome.Pain Pract. 2019; 19: 168-175https://doi.org/10.1111/papr.12730Crossref PubMed Scopus (9) Google Scholar. That explained that our subgroup analysis results, which showed that MP treatment reduced the fatality of the patients with increased lactate. Few studies have discussed the application time, dosage and duration of MP, which were mostly based on the physician experience. To further clarify when and how to employ MP application on the critical type patients, the hazards ratios were analyzed in each group according to the starting time, dosage, and treatment duration (Fig. 2). In all 107 critical type patients, 33 of them were not received MP treatment, 59 of them received MP treatment in 7 days after admission to hospital and 12 of them were received after 7 days. 3 patients received MP treatment, but the starting time were missed, and they were not enrolled in analysis. Our results showed MP treatment in 7 days after admission could decrease the 60-day fatality (HR: 0.294, 95% CI: 0.159–0.543, p-value < 0.001), while MP treatment after 7 days has no effect on the fatality. Subgroup with different doses of MP (=< 80 mg/d or > 80 mg/d) were also analyzed. We found that small dose MP showed significant effect on the fatality (HR: 0.329, 95% CI: 0.178–0.605, pvalue < 0.001). In addition, most patients benefited from MP were received treatment no more than 7 days. MP long-term treatment might increase the death risk. Present multicenter retrospective cohort study showed that methylprednisolone therapy could decrease the 60-fatality for the COVID-19 patients diagnosed as critical type, that is, those occurred respiratory failure and needs mechanical ventilation, or shock, or multiple organ failure and needs ICU monitoring. Early (starting in 7 days after admission), low-dose (no more than 80 mg/d), and short-term (no more than 7 days) methylprednisolone therapy could significant decrease the 60-day fatality. This work was supported by grants from the National Natural Science Foundation of China (NO. 82,072,143), PLA Logistics Research Project of China (18CXZ030, 17CXZ008), Sanming Project of Medicine in Shenzhen (SZSM20162011) and Clinical Research Project of Shenzhen municipal health commission (SZLY2017007).