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Xinyu Jia, Yuan Ma, Zhenzhen Wu, Ningfei Ji, Mao Huang. The prognosis and short-term efficacy of corticosteroid therapy for COVID-19 patients[J]. The Journal of Biomedical Research. doi: 10.7555/JBR.34.20200079
Citation: Xinyu Jia, Yuan Ma, Zhenzhen Wu, Ningfei Ji, Mao Huang. The prognosis and short-term efficacy of corticosteroid therapy for COVID-19 patients[J]. The Journal of Biomedical Research. doi: 10.7555/JBR.34.20200079

The prognosis and short-term efficacy of corticosteroid therapy for COVID-19 patients

doi: 10.7555/JBR.34.20200079
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  • Received: 31 May 2020
  • Revised: 17 June 2020
  • Accepted: 19 June 2020
  • Published: 21 August 2020
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  • [1] Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome[J]. Am J Respir Crit Care Med, 2018, 197(6): 757–767. doi:  10.1164/rccm.201706-1172OC
    [2] Ni YN, Chen G, Sun JK, et al. The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis[J]. Crit Care, 2019, 23(1): 99. doi:  10.1186/s13054-019-2395-8
    [3] Auyeung TW, Lee JSW, Lai WK, et al. The use of corticosteroid as treatment in SARS was associated with adverse outcomes: a retrospective cohort study[J]. J Infect, 2005, 51(2): 98–102. doi:  10.1016/j.jinf.2004.09.008
    [4] Siemieniuk RAC, Meade MO, Alonso-Coello P, et al. Corticosteroid Therapy for Patients Hospitalized With Community-Acquired Pneumonia: A Systematic Review and Meta-analysis[J]. Ann Intern Med, 2015, 163(7): 519–528. doi:  10.7326/M15-0715
    [5] Zhao JP, Hu Y, Du RH, et al. Expert consensus on the use of corticosteroid in patients with 2019-nCoV pneumonia[J]. Chin J Tubercul Respirat Dis (in Chinese), 2020, 43(3): 183–184.
    [6] Du ZW, Wang L, Cauchemez S, et al. Risk for Transportation of Coronavirus Disease from Wuhan to Other Cities in China[J]. Emerg Infect Dis, 2020, 26(5): 1049–1052. doi:  10.3201/eid2605.200146
    [7] Huang CL, Wang YM, Li XW, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[J]. Lancet, 2020, 395(10223): 497–506. doi:  10.1016/S0140-6736(20)30183-5
    [8] Ruan QR, Yang K, Wang WX, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China[J]. Intensive Care Med, 2020, 46(5): 846–848. doi:  10.1007/s00134-020-05991-x
    [9] Wang DW, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China[J]. Jama, 2020, 323(11): 1061–1069. doi:  10.1001/jama.2020.1585
    [10] Yang XB, Yu Y, Xu JQ, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study[J]. Lancet Respir Med, 2020, 8(5): 475–481. doi:  10.1016/S2213-2600(20)30079-5
    [11] Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China[J]. N Engl J Med, 2020, 382(18): 1708–1720. doi:  10.1056/NEJMoa2002032
    [12] Liu W, Tao ZW, Lei W, et al. Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease[J]. Chin Med J (Engl), 2020, 133(9): 1032–1038. doi:  10.1097/CM9.0000000000000775
    [13] Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses[J]. Eur J Epidemiol, 2010, 25(9): 603–605. doi:  10.1007/s10654-010-9491-z
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The prognosis and short-term efficacy of corticosteroid therapy for COVID-19 patients

doi: 10.7555/JBR.34.20200079
Xinyu Jia, Yuan Ma, Zhenzhen Wu, Ningfei Ji, Mao Huang. The prognosis and short-term efficacy of corticosteroid therapy for COVID-19 patients[J]. The Journal of Biomedical Research. doi: 10.7555/JBR.34.20200079
Citation: Xinyu Jia, Yuan Ma, Zhenzhen Wu, Ningfei Ji, Mao Huang. The prognosis and short-term efficacy of corticosteroid therapy for COVID-19 patients[J]. The Journal of Biomedical Research. doi: 10.7555/JBR.34.20200079
  • Dear Editor:

    Corticosteroids are widely used in the treatment of critically ill patients for active anti-inflammatory and immunosuppressive effects. However, the therapeutic effects of corticosteroid treatment are still disputable. Some studies have shown that corticosteroids can delay coronavirus RNA clearance[1], increase mortality[2] and cause adverse events[3]. Conversely, other studies have confirmed the clinical value of corticosteroids in shortening hospital stays and decreasing the need for mechanical ventilation[4]. Similarly, the use of corticosteroids in COVID-19 patients is controversial. Expert consensus in China has indicated that corticosteroids can be used as appropriate in critical patients[5]. However, World Health Organization interim guidance opposes the routine use of corticosteroids in treatment[6]. Therefore, we herein discussed the therapeutic effects of corticosteroids in COVID-19 patients based on the experience of front-line physicians and a meta-analysis.

    We analyzed the data of 67 difficult and complicated cases from 28 hospitals in 13 regions of Jiangsu Province, including 1 mild, 13 typical, 45 severe, and 8 critical patients. The severity of illness was defined by the expert consensus in China[5]. All patients were divided into two groups according to whether they used corticosteroids or not. The clinical characteristics, laboratory findings, and treatments are shown in Table 1. Data are presented as numbers (%) or median (IQR). P values were calculated by chi-square test, Fisher's exact test, or Mann-Whitney U test. Multidisciplinary experts guided the therapy by remote consultation through tracking vital signs and examination results and observing the dynamic changes in the patients' conditions. The results showed that the conditions of 18 corticosteroid users were improved or stable and that no patients died. We further analyzed the oxygen and blood indexes of 12 patients with complete data (≥4 consultations, follow-up time ≥10 days). The average course of corticosteroid treatment was 8 days. It was determined that short-term treatment with corticosteroids improved oxygen saturation (SaO2) and the ratio of arterial oxygen tension (PaO2) to inspiratory oxygen fraction (FiO2), and promoted the absorption of pulmonary lesions (Table 2). All statistical analyses were conducted by SPSS software (version 13.0). The results indicated that corticosteroids played a positive role in improving the short-term oxygenation of COVID-19 patients. To include more cases to test the hypothesis, we decided to carry out a meta-analysis.

    CharacteristicsTotal (n=67)Corticosteroids (n=38)No corticosteroids (n=29)P-value
     Gender (n, male/female) 44/23 26/12 18/11 0.587
     Age (years)a 59.0 (50.0, 70.0) 60.0 (51.5, 70.3) 58.0 (46.0, 70.5) 0.864
     BMIa 25.1 (22.9, 28.4) 24.8 (22.5, 28.4) 25.3 (23.5, 28.2) 0.354
     Wuhan exposureb 31 (46.3) 17 (44.7) 14 (48.3) 0.773
    Severity of illnessb
     Mild 1 (1.5) 0 (0.0) 1 (3.4) 0.056
     Typical 13 (19.4) 6 (15.8) 7 (24.1)
     Severe 45 (67.2) 25 (65.8) 20 (69.0)
     Critical 8 (11.9) 7 (18.4) 1 (3.4)
    Comorbidityb
     Hypertension 23 (34.3) 13 (34.2) 10 (34.5) 0.981
     Diabetes 15 (22.4) 9 (23.7) 6 (20.7) 0.771
     Cardiovascular disease 4 (6.0) 2 (5.3) 2 (6.9) 1.000
     Cerebral infarction 8 (11.9) 4 (10.5) 4 (13.8) 0.977
    Oxygen supportb
     None 12 (17.9) 3 (7.9) 9 (31.0) 0.025*
     Low flow oxygen 13 (19.4) 8 (21.1) 5 (17.2)
     High flow oxygen 15 (22.4) 8 (21.1) 7 (24.1)
     Non-invasive ventilation 27 (40.3) 19 (50.0) 8 (27.6)
    Laboratory findingsa
     PaO2/FiO2 187.5 (133.7, 296.5) 167.5 (123.2, 291.4) 207.5 (136.0, 306.9) 0.312
     SaO2 (%) 96.0 (94.0, 98.0) 95.2 (94.0, 98.0) 96.2 (94.5, 98.0) 0.427
     Lactic acid (mg/dL) 1.8 (1.4, 2.5) 1.8 (1.5, 2.5) 1.8 (1.3, 2.5) 0.686
     WBC (×109/L) 6.0 (4.2, 8.8) 6.6 (4.8, 9.5) 5.14 (3.8, 6.7) 0.048*
     RBC (×109/L) 4.3 (3.9, 4.7) 4.4 (4.1, 4.7) 4.3 (3.8, 4.8) 0.348
     Lymphocyte (×109/L) 0.7 (0.5, 1.0) 0.6 (0.4, 0.8) 0.9 (0.6, 1.4) 0.006*
     Platelet count (×109/L) 169.0 (137.5, 204.5) 164 (130.5, 199.5) 188.5 (139.3, 238.8) 0.129
    Treatmentb
     Antiviral therapy 57 (85.1) 34 (89.5) 23 (79.3) 0.264
     Antibiotic therapy 63 (94.0) 35 (92.1) 28 (96.6) 1.000
     Improvement/stabilizationb 34 (50.7) 18 (47.4) 16 (55.2) 0.527
    PaO2/FiO2: the ratio of arterial oxygen tension to inspiratory oxygen fraction; SaO2: oxygen saturation; WBC: white blood cell; RBC: red blood cell. Data were presented as median (interquartile range)a or number (%)b; P-values were calculated by chi-square test, Fisher's exact test, or Mann-Whitney U test. *P<0.05 was statistically significant.

    Table 1.  The clinical characteristics, laboratory findings, and treatment of COVID-19 patients

    ParametersDay 1Day 4Day 7Day 10P-value vs. Day 1
    Day 4Day 7Day 10
    PaO2/FiO2a 139.6 (110.4, 154.3) 140.6 (120.0, 184.0) 148.9 (102.5, 197.2) 175.0* (125.3, 241.5) 0.418 0.373 0.048
    SaO2 (%)a 91.6 (89.6, 96.0) 95.6 (94.0, 97.6) 95.6* (93.0, 98.5) 97.0* (94.3, 98.9) 0.053 0.028 0.006
    Lactic acid (mg/dL)a 1.8 (1.3, 3.5) 2.3 (1.4, 2.8) 1.6 (1.3, 2.1) 1.6 (1.2, 2.3) 0.921 0.373 0.338
    WBC (×109/L)a 6.9 (4.0, 9.0) 6.8 (5.4, 10.7) 8.1 (6.5, 13.6) 8.7 (5.3, 11.5) 0.453 0.166 0.356
    Lymphocyte (×109/L)a 0.46 (0.32, 0.61) 0.40 (0.28, 0.51) 0.45 (0.21, 0.50) 0.51 (0.33, 1.00) 0.225 0.355 0.419
    Chest X-ray or CTb 0   0   4 (33.3%) 11 (91.7%)
    The data were presented as median (interquartile range)a and frequency (%)b. SaO2: oxygen saturation; PaO2/FiO2: the ratio of arterial oxygen tension to inspiratory oxygen fraction; WBC: white blood cell. All comparisons were compared with Day 1 group. *P<0.05 was statistically significant.

    Table 2.  The effect of corticosteroid therapy on severe and critical patients of COVID-19 patients

    We carried out a systematic literature search on the PubMed, EMBASE, and Web of Science databases for relevant studies on COVID-19. We used the following keywords in our search: "2019-nCoV", "COVID-19", and "SARS-CoV-2". To avoid literature omission, we did not use "corticosteroids" or other keywords related to treatment. Articles dated up to March 15, 2020 were searched without language limit. Inclusion criteria were as follows: (1) the definite diagnosis of COVID-19; (2) two groups of corticosteroid use and non-corticosteroid use; (3) the clinical data available to extract. Exclusion criteria were as follows: (1) repeated publication; (2) failure to get the full text or detailed abstract; (3) the articles of editorials, reviews, or expert consensus; (4) difficulty in extracting the necessary data. Two researchers independently selected articles and extracted the data by reading the titles, abstracts, and full texts of the articles. The binary data analysis was conducted by Stata software (version 14.1).

    A total of 2431 articles were preliminarily retrieved. After deduplication and assessment of titles, abstracts, and full texts, six articles were chosen for study[7-12] (Fig. 1). We used the Newcastle-Ottawa scale to evaluate the quality of the study[13] (Table 3). We also included our research data, in which 38 patients used corticosteroids including 32 patients with severe conditions. The conditions of 18 users were improved or stable, while 16 of the non-users achieved the same result. The conditions of the remaining patients were aggravated or even deteriorated. Characteristics of studies included are shown in Table 3.

    Figure 1.  Flowchart for study selection.

    AuthorYearCountryRegionMulticenterSample
    (n)
    Gender
    (n, M/F)
    Age*Evaluation criteriaStudy designDurationDoseOutcomes measuredNOS score
    Huang et al[7] 2020 China Wuhan N 41 11/30 49.0 (41.0, 58.0) 1. ICU/non-ICU
    2. ARDS/non-ARDS
    3. The use of corticosteroids
    Retrospective study December 16, 2019–January 2, 2020 NA 1. The use of corticosteroids
    2. Mortality
    3. Discharge
    7
    Ruan et al[8] 2020 China Wuhan Y 150 102/48 NA The use of corticosteroids Retrospective study NA NA 1. Mortality
    2. Discharge
    7
    Wang et al[9] 2020 China Wuhan N 138 75/63 56 (42, 68) ICU/non-ICU Retrospective study January 1, 2020–January 2, 2020 NA The use of corticosteroids 7
    Yang et al[10] 2020 China Wuhan N 52 35/17 59.7 (13.3) The use of corticosteroids Retrospective study December 2019–January 26, 2020 NA Mortality 7
    Guan et al[11] 2020 China 31 provinces/
    provincial municipalities
    Y 1099 640/459 47.0 (35.0, 58.0) 1. Severe/non-severe
    2. The use of corticosteroids
    Retrospective study –January 29, 2020 The median of maximal daily dose was 1.5 (0.7-40.0) mg/kg 1. The use of corticosteroids
    2. Composite endpoint (the admission to ICU, or mechanical ventilation, or death)
    8
    Liu et al[12] 2020 China Wuhan N 78 39/39 38 (33, 57) The use of corticosteroids Retrospective study December 30, 2019–January 15, 2020 The median dose was
    40 (20, 40)* mg intravenously (iv) every day (qd)
    Improvement/
    stabilization
    7
    Huang et al 2020 China Jiangsu province Y 67 44/23 59.0 (50.0, 70.0) 1. Severe/non-severe
    2. The use of corticosteroids
    Retrospective study January 29, 2020–March 12, 2020 The median dose was 40 (20, 80) mg intravenously (iv) every day (qd) 1. The use of corticosteroids
    2. Improvement/
    stabilization
    8
    *Data were presented as median (interquartile range); NOS: Newcastle-Ottawa Scale; ICU: intensive care unit; ARDS: acute respiratory distress syndrome; NA: not available; Y: yes; N: no.

    Table 3.  Characteristics of included studies

    Finally, a total of 1625 subjects, including 441 corticosteroid users and 1184 non-users, were included from these 7 articles. The forest plot of critical and non-critical patients (Fig. 2A) showed critical patients are more likely to use corticosteroids (OR, 4.82; 95% CI, 3.55–6.54). The result of corticosteroid use (Fig. 2B and C) showed the improvement rate of the corticosteroid group was lower than that of the noncorticosteroid group (OR, 0.54; 95% CI, 0.33–0.88), but corticosteroid use was not associated with mortality of COVID-19 patients (OR, 2.64; 95% CI, 0.86–2.08). Due to the small number of articles, we did not conduct heterogeneity analysis.

    Figure 2.  Forest plot of corticosteroid therapy on COVID-19 patients.

    Some related meta-analyses of corticosteroid therapy for lung diseases used mortality, need for intensive care unit (ICU) admission or mechanical ventilation as prognostic indicators. In this meta-analysis, we selected only mortality. Because we thought the need for ICU or mechanical ventilation was the evaluation criteria for critical patients who need to use corticosteroids according to the experts consensus. It could not be used as a prognostic indicator simply. However, although the composite endpoints included admission to the ICU, mechanical ventilation, or death, a study by Weijie G et al[11] was included after discussion due to the large number of subjects and extra subgroups of non-severe and severe patients.

  • Currently, evidence for the use of corticosteroid therapy for COVID-19 patients is mostly empirical. This meta-analysis provided the first preliminary systematic review showing the prognosis and short-term efficacy of corticosteroid use for COVID-19. Obviously, our analysis has some limitations. First, the effect of mechanical ventilation on patients' oxygenation status was not considered. Moreover, due to the limited data, the changes of indicators in the noncorticosteroid group were not discussed. Second, the studies included in the meta-analysis were mostly retrospective studies rather than high-quality randomized controlled trial (RCT) studies. Third, due to the small number of included articles, we included two that used discharge as an evaluation of improvement/stabilization, which was not consistent with other included studies. Fourth, the included studies were all Chinese studies. More studies from other different countries and regions need to be considered to carry out RCT studies and subgroup analysis.

    We believed, based on the front-line COVID-19 treatment experience, that the use of corticosteroids might have a positive effect on improving the short-term oxygenation of critically ill patients. However, there is no evidence-based support for this claim. Some researchers have indicated that corticosteroids should be applied when the body's inflammatory response is over activated (i.e. inflammatory cytokine storm). It is necessary to make a comprehensive evaluation based on the patient's vital signs, oxygenation status, and dynamic changes in inflammatory indicators and imaging examinations. We hope that through our first-line experience and preliminary meta-analysis, new thoughts could be inspired for future researchers. Strictly following the indications of corticosteroid use, avoiding the occurrence of adverse events, and applying a more standardized and reasonable regimen of corticosteroids need not only to be proved by scientific evidence but also to be tested by the practical experience of front-line experts of multiple disciplines.

  • This work was supported by the Jiangsu Provincial Key Research and Development Program (BE2020616), and the National Natural Science Foundation of China (No. 81770031 and No. 81700028).

    Yours Sincerely,Xinyu Jia, Hengrui Zhang, Yuan Ma, Zhenzhen Wu, Ningfei Ji, Mao HuangDepartment of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.These authors contribute equally to this work.Corresponding author: Mao Huang, Tel/Fax: +86-25-68136269/+86-25-83673567, E-mail: huangmao6114@126.com.

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