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Effectiveness of Systemic Corticosteroids Therapy for Nonsevere Patients With COVID-19: A Multicenter, Retrospective, Longitudinal Cohort Study

  • Author Footnotes
    ∗ Zhenyuan Chen and Xiaoxv Yin contributed equally to this work.
    Zhenyuan Chen
    Footnotes
    ∗ Zhenyuan Chen and Xiaoxv Yin contributed equally to this work.
    Affiliations
    Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
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  • Author Footnotes
    ∗ Zhenyuan Chen and Xiaoxv Yin contributed equally to this work.
    Xiaoxv Yin
    Footnotes
    ∗ Zhenyuan Chen and Xiaoxv Yin contributed equally to this work.
    Affiliations
    Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
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  • Xiangping Tan
    Affiliations
    Lichuan Center for Disease Control and Prevention, Enshi Tujia and Miao Autonomous Prefecture, P. R. China
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  • Jing Wang
    Affiliations
    Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
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  • Nan Jiang
    Affiliations
    Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
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  • Mengge Tian
    Affiliations
    Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
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  • Hui Li
    Affiliations
    Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
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  • Zuxun Lu
    Affiliations
    Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
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  • Nian Xiong
    Affiliations
    Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
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  • Yanhong Gong
    Correspondence
    Correspondence: Yanhong Gong, PhD, Department of Social Medicine and Health Management, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.
    Affiliations
    Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
    Search for articles by this author
  • Author Footnotes
    ∗ Zhenyuan Chen and Xiaoxv Yin contributed equally to this work.
Published:February 24, 2022DOI:https://doi.org/10.1016/j.jval.2021.12.013

      Highlights

      • Glucocorticoids are used to treat patients with nonsevere COVID-19 in clinic, but the efficacy of such treatment is still a matter of intense debate.
      • In hospitalized patients with nonsevere COVID-19, systemic glucocorticoids treatment increased the risk of progression from nonsevere to severe, all-cause mortality, and prolonged length of stay, and dose-response relationships were present.
      • In nonsevere patients with COVID-19, we propose that systemic glucocorticoids be avoided unless absolutely essential, but more cautious treatment strategies and clinical adverse drug reaction monitoring should be undertaken if necessary.

      Abstract

      Objectives

      Corticosteroids were clinically used in the treatment of nonsevere patients with COVID-19, but the efficacy of such treatment lacked sufficient clinical evidence, and the impact of dose had never been studied. This study aimed to evaluate the effect of systemic corticosteroid use (SCU) in nonsevere patients with COVID-19.

      Methods

      We conducted a multicenter retrospective cohort study in Hubei Province. A total of 1726 patients admitted with nonsevere type COVID-19 were included. Mixed-effect Cox model, mixed-effect Cox model with time-varying exposure, multiple linear regression, and propensity score analysis (inverse probability of treatment weight and propensity score matching) were used to explore the association between SCU and progression into severe type, all-cause mortality, and length of stay.

      Results

      During the follow-up of 30 days, 29.8% of nonsevere patients with COVID-19 received treatment with systemic corticosteroids. The use of systemic corticosteroids was associated with higher probability of developing severe type (adjusted hazard ratio 1.81; 95% confidence interval 1.47-2.21), all-cause mortality (adjusted hazard ratio 2.92; 95% confidence interval 1.39-6.15) in time-varying Cox analysis, and prolonged hospitalization (β 4.14; P < .001) in multiple linear regression. Analysis with 2 propensity score cohorts displayed similar results. Besides, increased corticosteroid dose was significantly associated with elevated probability of developing severe type (P < .001) and prolonged hospitalization (P < .001).

      Conclusions

      Corticosteroid treatment against nonsevere patients with COVID-19 was significantly associated with worse clinical outcomes. The higher dose was significantly associated with elevated risk of poor disease progression. We recommend that SCU should be avoided unless necessary among nonsevere patients with COVID-19.

      Keywords

      Introduction

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      reported that treatment with corticosteroid was not significantly associated with increased in-hospital mortality in noncritically severe cases. Another 2 studies reported that corticosteroid therapy was associated with poor lung injury recovery and worse clinical outcomes in nonsevere patients with COVID-19.
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      The relatively small sample size and retrospective design limited the interpretation of these results. The UK-based Randomized Evaluation of COVID-19 Therapy study, a large-scale and well-designed randomized clinical trial, showed that no benefit of dexamethasone use was observed among those patients who did not require respiratory support.
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      In addition, none of these studies explored the relationship between corticosteroid dose and outcomes of patients with COVID-19. The therapeutic efficacy and adverse reactions of corticosteroids are strongly correlated with the dose, and it is not clear whether there is a safe low dose.
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      Hence, it is necessary to clarify the effect of corticosteroids on outcomes in patients with nonsevere patients with COVID-19.
      This study used a multicenter retrospective cohort design to analyze the effects of systemic corticosteroids on mortality rate, disease progression, and length of stay to provide clinical evidence for optimizing the therapy of nonsevere patients with COVID-19.

      Methods

      Ethical Statement

      The Medical Ethics Committee of Tongji Medical College of Huazhong University of Science and Technology approved this study. The ethics committee abandoned the requirements of informed consent. Only the pseudonymized data that cannot be recognized were used for our analysis.

      Study Design and Patients

      This multicenter retrospective cohort study analyzed information on hospitalized patients with COVID-19 admitted to 4 hospitals in Hubei Province, China. A total of 2501 patients with COVID-19 were admitted during the period from December 31, 2019 to March 31, 2020.
      The diagnosis and clinical classification of COVID-19 followed the World Health Organization interim guidance and the Diagnosis and Treatment Protocol for COVID-19 Patients released by the National Health Commission of China.
      Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance. World Health Organization.
      ,
      Diagnosis and treatment protocol for COVID-19 patients (tentative 8th edition). National Health Commission of the People’s Republic of China.
      All confirmed patients with COVID-19 included in this study were diagnosed by physicians based on epidemiological history, clinical symptoms, laboratory examination, etiology and serology examination, and chest imaging. Based on the definition of the Diagnosis and Treatment Protocol for COVID-19 Patients, there were 4 clinical classifications of patients with COVID-19: (1) mild cases (those with mild clinical symptoms and no evidence of pneumonia in chest radiology), (2) moderate cases (those with fever and respiratory symptoms and the chest radiology suggestive of pneumonia), (3) severe cases (those who met any of the following criteria: respiratory rate of at least 30 breaths per minute, oxygen saturation of 93% or lower in a resting state, ratio of arterial partial pressure of oxygen and oxygen concentration ≤300 mm Hg, >50% lesion progression in lung imaging within 24-48 hours), and (4) critical cases (those who met any of the following criteria: respiratory failure and the mechanical ventilation is needed, other organ failure, shock, or death). Referring to this protocol and the published literature,
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      we defined the mild and moderate cases as nonsevere type of patients and the severe and critical cases as severe type of patients in this study.
      The inclusion criteria contained patients with COVID-19 who were admitted to the hospitals in Hubei, China, from December 31, 2019 to March 31, 2020. The exclusion criteria contained (1) age of <18 years, (2) pregnancy, (3) acquired immune deficiency syndrome, (4) autoimmune diseases (eg, systemic lupus erythematosus, myasthenia gravis), (5) severe cases within 48 hours of admission, (6) using systemic corticosteroids after progression into severe cases, and (7) the time of systemic corticosteroids initiation from admission was >30 days.
      The demographic information (age and sex), clinical symptoms (cough, fever, and anhelation), comorbidities (hypertension, malignancy, diabetes, chronic obstructive pulmonary disease [COPD], and coronary heart disease), treatments (antiviral drugs, nonsteroidal anti-inflammatory drugs [NSAIDs], and antibiotic drugs), and clinical outcomes were obtained from the electronical medical system. Laboratory data on admission (white blood cell count, albumin, and C-reaction protein) were collected from the laboratory information system. Prescription information of corticosteroids, including type, dose, initiation form admission, and duration, was also collected. We converted all preparations to hydrocortisone equivalent doses
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      and anonymized personally identifiable information, such as name and identity card number, and generated a new identification for each patient to protect their privacy.

      Exposure and Outcomes

      The exposure in this study was patients with nonsevere COVID-19 receiving systematic corticosteroids therapy for the first time. Patients in this group were classified as systemic corticosteroid use (SCU) group. Otherwise, patients were defined as the non-SCU (NSCU) group. To further explore the effect of dose on outcomes among patients with COVID-19, the total hydrocortisone equivalent dose since admission was classified as an ordinal categorical variable (grouped by every 500 mg increase). The study outcomes were (1) progressing from nonsevere type COVID-19 to severe type during 30 days of in-hospital follow-up, (2) all-cause death during 30 days of in-hospital follow-up, and (3) length of stay.

      Statistical Analyses

      Continuous variables were expressed as median and interquartile range (IQR), and categorical variables were expressed as number and percent (%). Statistical differences between 2 groups were analyzed using the Student’s t test or Wilcoxon-Mann-Whitney U test for continuous variables, whereas categorical variables were compared using Pearson’s chi-square test or Fisher’s exact tests. We evaluated the association between SCU and disease progression and mortality rate using 2 approaches. First, the mixed-effect Cox regressions model with site as a random effect was conducted to examine the impact of systemic corticosteroids and dose groups on the clinical outcomes. Multivariable analyses were all adjusted for age, sex, clinical symptoms (cough, fever, and anhelation), comorbidities (hypertension, malignancy, diabetes, COPD, and coronary heart disease), treatments (antiviral drugs, NSAID, and antibiotic drugs), and laboratory data on admission (white blood cell count, albumin, and C-reaction protein). Second, in mixed-effect Cox regressions model, SCU was accounted as a time-varying exposure to mitigate immoral time bias. In time-varying analysis, data were reconstructed according to the time of SCU. The time from admission to time of SCU was classified as unexposed. The hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. The cumulative probability of progression to severe type COVID-19 was analyzed using the Kaplan-Meier method and compared by log-rank test. Multiple linear regression models were used to examine the influence of systemic corticosteroids and dose groups on length of stay. The covariates are the same as the adjusted variables of the mixed-effect Cox regressions model.
      To reduce the effect of systemic corticosteroid treatment selection bias and potential confounding in this observational study, we performed rigorous adjustment for differences in baseline characteristics by propensity score (PS)-matched (PSM) and inverse probability of treatment weight (IPTW) analysis, respectively.
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      ,
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      The PS was calculated using a logistic regression model in which all baseline characteristics were included and the treatment group (SCU vs NSCU) was the dependent variable within each imputed sample. In PSM, 2 cohorts were matched at a ratio of 1:1 with a caliper width of 0.2. In IPTW, for the SCU group, the weight was equal to 1/PS, whereas for the NSCU group, the weight was equal to 1/(1−PS). The balance among covariates was evaluated by estimating the standardized differences between SCU and NSCU groups in PSM and IPTW cohorts. Only those with absolute value <0.1 were considered as qualified.
      The interaction between the use of corticosteroids and age, sex, clinical symptoms (cough, fever, and anhelation), comorbidities (hypertension, malignancy, diabetes, COPD, and coronary heart disease), and treatments (antiviral drugs, NSAID, and antibiotic drugs) on developing severe type and all-cause mortality was explored using multivariable logistic regression in the PSM cohort. Data were analyzed in SAS 9.4 (by SAS Institute Inc, Cary, North Carolina) and R4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).

      Results

      This study cohort included 2501 patients with COVID-19 who were admitted to 4 hospitals in Hubei, China. After excluding 773 participants following our exclusion criteria, 1726 participants were included in the analysis. Among them, 514 (29.78%) patients received systemic corticosteroid treatment (SCU group), and the remaining 1212 (70.22%) did not receive systemic corticosteroid (NSCU group) (Fig. 1). Patients in the SCU group were more likely to be younger (51 [IQR 37-64] vs 56 [IQR 41-67] years; P < .001), be male (50.58% vs 43.40%; P = .006), and have a higher proportion of malignancy (7.78% vs 4.62%; P = .009). Of the COVID-19 symptoms, fever was more frequent in the SCU group than the NSCU group (74.32% vs 54.37%; P < .001), whereas anhelation was more frequent in the NSCU group than the SCU group (10.48% vs 7.20%; P = .034). Laboratory findings on admission showed that the median C-reaction protein was higher in the SCU group than in the NSCU group (14.65 [IQR 4.25-38.10] vs 2.60 [IQR 0.70-13.96] mg/liter; P < .001). Moreover, antivirus drugs (95.33% vs 85.48%; P < .001), NSAIDs (48.64% vs 19.06%; P < .001), and antibiotic drugs (95.14% vs 61.22%; P < .001) were more frequently used in the SCU group (Table 1).
      Figure thumbnail gr1
      Figure 1Flowchart of the patient enrollment.
      NSCU indicates nonsystemic corticosteroid use; PSM, propensity score matching; SCU, systemic corticosteroid use.
      Table 1Characteristics of 1726 nonsevere patients with COVID-19.
      ParametersTotal
      Categorical variables are presented as number (percent), and continuous variables are presented as median (interquartile range).
      (N = 1726)
      NSCU
      Categorical variables are presented as number (percent), and continuous variables are presented as median (interquartile range).
      (n = 1212)
      SCU
      Categorical variables are presented as number (percent), and continuous variables are presented as median (interquartile range).
      (n = 514)
      P value
      P values indicate differences between the NSCU and SCU groups.
      Baseline characteristics
       Age (years)55 (39-66)56 (41-67)51 (37-64)<.001
      Laboratory test
       White blood cell count (109/liter)5.30 (4.10-6.64)5.41 (4.28-6.64)4.95 (3.55-6.63).1642
       Albumin(g/liter)39.80 (36.50-42.90)39.90 (36.60-43.00)39.60 (36.20-42.70).3659
       C-reaction protein (mg/liter)4.60 (1.00-22.30)2.60 (0.70-13.96)14.65 (4.25-38.10)<.001
      Sex.006
       Female940 (54.46)686 (56.60)254 (49.42)
       Male786 (45.54)526 (43.40)260 (50.58)
      Symptom
       Cough799 (46.29)561 (46.29)238 (46.30).995
       Fever1041 (60.31)659 (54.37)382 (74.32)<.001
       Anhelation164 (9.50)127 (10.48)37 (7.20).034
      Comorbidity
       Hypertension539 (31.23)384 (31.68)155 (30.16).531
       Malignancy96 (5.56)56 (4.62)40 (7.78).009
       Diabetes258 (14.95)183 (15.10)75 (14.59).787
       COPD104 (6.03)74 (6.11)30 (5.84).830
       Coronary heart disease145 (8.40)99 (8.17)46 (8.95).593
      Treatment
       Antivirus drugs1526 (88.41)1036 (85.48)490 (95.33)<.001
       NSAID481 (27.87)231 (19.06)250 (48.64)<.001
       Antibiotic drugs1231 (71.32)742 (61.22)489 (95.14)<.001
      Outcomes
       Length of stay (days)16 (10-24)14 (9-20)22 (14-30)<.001
       Progression to severe type (30 days)509 (29.49)328 (27.06)181 (35.21)<.001
       All-cause death (30 days)43 (2.49)25 (2.06)18 (3.50).079
      COPD indicates chronic obstructive pulmonary disease; NSAID, nonsteroidal anti-inflammatory drug; NSCU, nonsystemic corticosteroid use; SCU, systemic corticosteroid use.
      Categorical variables are presented as number (percent), and continuous variables are presented as median (interquartile range).
      P values indicate differences between the NSCU and SCU groups.
      After PSM and IPTW (baseline shown in Appendix Tables 1 and 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.12.013), the baseline characteristics were balanced between NSCU and SCU groups with absolute value of standard mean differences < 0.1. In PSM data sets, 418 patients in the NSCU group were matched with 418 patients in the SCU group at a ratio of 1:1.

      Corticosteroid Use

      Among the 514 patients, the most commonly used systemic corticosteroids in clinical treatment was methylprednisolone (93.00%), followed by prednisone (10.31%) and dexamethasone (9.34%), with the least use of hydrocortisone (0.19%). Systemic corticosteroids were initiated within a median of 2 days (IQR 1-4) of hospital admission. The median duration of systemic corticosteroid treatment was 8 days (IQR 4-13), and the median dose was 200 mg (IQR 158.33-227.27) per day of hydrocortisone equivalent (Table 2).
      Table 2Description of corticosteroid used in the SCU group (N = 514).
      Medication variablesMedian [IQR] or n (%)
      Systemic corticosteroids prescribed
       Methylprednisolone478/514 (93.00)
       Dexamethasone48/514 (9.34)
       Prednisone53/514 (10.31)
       Prednisolone14/514 (2.72)
       Hydrocortisone1/514 (0.19)
      Duration of systemic corticosteroids, days8 [4, 13]
      Systemic corticosteroids initiation from admission, days2 [1, 4]
      Dose, hydrocortisone equivalents per day (mg)200.00 [158.33-227.27]
      IQR indicates interquartile range; SCU, systemic corticosteroid use.

      Progression to Severe Type COVID-19

      During the follow-up of 30 days, 509 patients progressed into severe type. The proportion of patients progressed into severe type COVID-19 in the SCU group was significantly higher than that in the NSCU group (35.21% [181 of 514] vs 27.06% [328 of 1212]; P < .001). In the mixed-effect Cox model treating site as a random effect, SCU was independently associated with higher probability of developing severe type (adjusted HR 1.27; 95% CI 1.04-1.55). The mixed-effect Cox regressions model with time-varying exposure showed similar results that the SCU group had higher risk of turning into severe type than the NSCU group (adjusted HR 1.81; 95% CI 1.47-2.21) (Tables 1 and 3).
      Table 3Association of systemic corticosteroid use and outcomes in nonsevere patients with COVID-19.
      Progression to severe typeAll-cause death (30 days)Length of stay
      CoxTime-varying CoxCoxTime-varying Cox
      Adjusted HR (95% CI)P valueAdjusted HR (95% CI)P valueAdjusted HR (95% CI)P valueAdjusted HR (95% CI)P valueβ (SD)P value
      SCU and NSCU
       Unmatched1.27 (1.04-1.55).02121.81 (1.47-2.21)<.00011.93 (0.94-3.97).07242.92 (1.39-6.15).00494.14 (0.43)<.0001
       PSM (1:1)
      PSM and IPTW were conducted to adjust for basic demographic characteristics (age and sex), symptoms (cough, fever, and anhelation), comorbidities (hypertension, diabetes, malignancy, COPD, and coronary heart disease), treatments (antiviral drugs, NSAID, and antibiotic drugs), and laboratory data on admission (white blood cell count, albumin, and C-reaction protein).
      1.19 (0.94-1.49).14761.78 (1.41-2.25)<.00012.41 (1.01-5.73).04704.16 (1.67-10.34).00224.27 (0.52)<.0001
       IPTW
      PSM and IPTW were conducted to adjust for basic demographic characteristics (age and sex), symptoms (cough, fever, and anhelation), comorbidities (hypertension, diabetes, malignancy, COPD, and coronary heart disease), treatments (antiviral drugs, NSAID, and antibiotic drugs), and laboratory data on admission (white blood cell count, albumin, and C-reaction protein).
      1.36 (1.21-1.54)<.00012.22 (1.96-2.52)<.00011.65 (1.01-2.68).04462.66 (1.61-4.40).00014.52 (0.37)<.0001
      Corticosteroid dose group
      Corticosteroid dose group: grouped by increasing hydrocortisone equivalent dose per 500 mg.
       Unmatched1.06 (1.04-1.08)<.00011.08 (1.06-1.09)<.00011.06 (1.00-1.13).04271.07 (1.01-1.13).02380.72 (0.06)<.0001
       PSM (1:1)
      PSM and IPTW were conducted to adjust for basic demographic characteristics (age and sex), symptoms (cough, fever, and anhelation), comorbidities (hypertension, diabetes, malignancy, COPD, and coronary heart disease), treatments (antiviral drugs, NSAID, and antibiotic drugs), and laboratory data on admission (white blood cell count, albumin, and C-reaction protein).
      1.06 (1.04-1.08)<.00011.07 (1.05-1.09)<.00011.05 (0.98-1.14).17411.06 (0.99-1.14).10180.72 (0.07)<.0001
       IPTW
      PSM and IPTW were conducted to adjust for basic demographic characteristics (age and sex), symptoms (cough, fever, and anhelation), comorbidities (hypertension, diabetes, malignancy, COPD, and coronary heart disease), treatments (antiviral drugs, NSAID, and antibiotic drugs), and laboratory data on admission (white blood cell count, albumin, and C-reaction protein).
      1.09 (1.08-1.10)<.00011.10 (1.09-1.11)<.00011.05 (1.00-1.10).04911.06 (1.01-1.10).01450.92 (0.05)<.0001
      CI indicates confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; IPTW, inverse probability of treatment weight; NSAID, nonsteroidal anti-inflammatory drug; NSCU, nonsystemic corticosteroid use; PSM, propensity score matching; SCU, systemic corticosteroid use; β, regression coefficient.
      PSM and IPTW were conducted to adjust for basic demographic characteristics (age and sex), symptoms (cough, fever, and anhelation), comorbidities (hypertension, diabetes, malignancy, COPD, and coronary heart disease), treatments (antiviral drugs, NSAID, and antibiotic drugs), and laboratory data on admission (white blood cell count, albumin, and C-reaction protein).
      Corticosteroid dose group: grouped by increasing hydrocortisone equivalent dose per 500 mg.
      Further analysis was done with PSM and IPTW data sets to balance measured baseline characteristics across treatment groups. In the mixed-effect Cox regressions model with time-varying exposure, SCU was also independently associated with a higher probability of developing severe type after both PS analyses (adjusted HR 1.78; 95% CI 1.41-2.25 in PSM; adjusted HR 2.22; 95% CI 1.96-2.52 in IPTW) (Table 3). Kaplan-Meier curves after PSM and IPTW are shown in Figure 2A,B. Furthermore, there was a statistically significant interaction between the SCU and NSAID use with the respect to risk of developing severe type (adjusted OR = 2.544; P = .0045 for interaction). There was no significant interaction between the effect of systemic corticosteroids and other covariates on developing severe type (P > .05 for interaction) (Appendix Table 3 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.12.013).
      Figure thumbnail gr2
      Figure 2Kaplan-Meier curves for cumulative probability of progression to severe type COVID-19 during 30-day follow-up duration in SCU/NSCU groups in (A) PSM and (B) IPTW cohorts.
      CI indicates confidence interval; HR, hazard ratio; IPTW, inverse probability of treatment weight; NSCU, nonsystemic corticosteroid use; PSM, propensity score matching; SCU, systemic corticosteroid use.
      In addition, all of these mixed-effect Cox models showed that increased corticosteroid dose was significantly associated with elevated probability of developing severe type. The adjusted HR of corticosteroid dose group indicated that every 500-mg increase in dose was associated with an additional 8% risk of progression to severe type (adjusted HR 1.08; 95% CI 1.06-1.09) in the mixed-effect Cox model with time-varying exposure (Table 3).

      All-Cause Mortality During 30 Days of In-Hospital Follow-Up

      During a 30-day follow-up period, 43 died of the 1726 patients with COVID-19 admitted with nonsevere type. There was no significant difference between NSCU and SCU groups (2.06% [25 of 1212] vs 3.50% [18 of 514]; P = .079) in the risk of all-cause mortality during 30 days of in-hospital follow-up. In the mixed-effect Cox model with time-varying exposure, the SCU was associated with a higher probability of all-cause mortality (adjusted HR 2.92; 95% CI 1.39-6.15). In 2 PS cohorts, the SCU group had a higher 30-day all-cause mortality risk in the time-varying exposure model (adjusted HR 4.16; 95% CI 1.67-10.34 in PSM; adjusted HR 2.66; 95% CI 1.61-4.40 in IPTW) (Kaplan-Meier curves after PSM and IPTW are shown in Appendix Figure 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.12.013). Furthermore, there was no significant interaction between the effect of systemic corticosteroids and other covariates on all-cause mortality (P > .05 for interaction) (Appendix Table 3 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.12.013). In the mixed-effect Cox models grouped by corticosteroid dose, the result showed a tendency toward the association between corticosteroid dose and 30-day mortality. Nevertheless, some of those showed no statistical significance (Tables 1 and 3).

      Length of Stay

      The median length of stay was 14 days (IQR 9-20) in the NSCU group and 22 days (IQR 14-30) in the SCU group (P < .001). Multiple linear regression showed that, compared with the NSCU group, the SCU group increased the average length of hospital stay by 4.14 days (P < .001). Analysis with PSM and IPTW cohorts displayed similar results (β 4.27; P < .001 in PSM; β 4.52; P < .001 in IPTW). In addition, all of these cohorts showed that corticosteroid dose was significantly associated with length of stay. For every 500-mg increase in corticosteroid dose, the length of stay increased by 0.72 (P < .001) days in the PSM cohort and 0.92 (P < .001) days in the IPTW cohort (Tables 1 and 3).

      Discussion

      In our study, 29.8% of nonsevere patients with COVID-19 received systemic corticosteroids. To assess the potential impact of corticosteroids on nonsevere patients, we adjusted for time factors and baseline differences that might affect the disease severity. We found that systemic corticosteroid treatment was associated with the risk of progression to severe type, all-cause mortality, and prolonged hospitalization in nonsevere patients with COVID-19. Besides, with the increase in corticosteroid dose, patients with COVID-19 had an increased risk of progression from nonsevere to severe and prolonged length of stay.
      Although the anti-inflammatory effects of corticosteroids may benefit patients with severe COVID-19, the risks of immunosuppression and delayed virus clearance in nonsevere patients with COVID-19 cannot be ignored.
      • Fadel R.
      • Morrison A.R.
      • Vahia A.
      • et al.
      Early short-course corticosteroids in hospitalized patients with COVID-19.
      ,
      • Shang L.
      • Zhao J.
      • Hu Y.
      • Du R.
      • Cao B.
      On the use of corticosteroids for 2019-nCoV pneumonia.
      ,
      • Mohammed El Tabaa M.
      • Mohammed El Tabaa M.
      Targeting neprilysin (NEP) pathways: a potential new hope to defeat COVID-19 ghost [published correction appears in Biochem Pharmacol. 2020;182:114249].
      Some evidence suggested that adverse effects might offset the benefits of corticosteroid treatment. Once the virus attacks the body, the immune system is activated to produce a series of immune responses. Corticosteroids are believed to reduce concentrations of proinflammatory cytokines and upregulate anti-inflammatory mediators by inhibiting the transcriptional effect of nuclear factor kappa B.
      • Adcock I.M.
      Corticosteroids: limitations and future prospects for treatment of severe inflammatory disease.
      Meanwhile, corticosteroids could prevent the migration of inflammatory cells from the circulation to issues by suppressing the synthesis of chemokines and cytokines and inhibiting immune responses mediated by T cells and B cells.
      • Annane D.
      Pro: the illegitimate crusade against corticosteroids for severe H1N1 pneumonia.
      ,
      • Ni Y.N.
      • Chen G.
      • Sun J.
      • Liang B.M.
      • Liang Z.A.
      The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis [published correction appears in Crit Care. 2020;24(1):376].
      Therefore, the alterations in immune reactions caused by corticosteroids might lead to reactivation of latent viruses and delay viral clearance, ultimately increasing the risk of mortality.
      • Adcock I.M.
      Corticosteroids: limitations and future prospects for treatment of severe inflammatory disease.
      In addition, the results showed a significant interaction between the effect of systemic corticosteroids and NSAID on developing severe type, suggesting that the combination use of systemic corticosteroids and NSAID had a higher risk of developing severe type than the use of corticosteroids alone. This may be due to the fact that NSAID could suppress hyperinflammatory responses and increase the activity of angiotensin-converting enzyme-2, promoting the progression of the disease.
      • Sodhi M.
      • Etminan M.
      Safety of ibuprofen in patients with COVID-19: causal or confounded?.
      ,
      • Bhaskar S.
      • Sinha A.
      • Banach M.
      • et al.
      Cytokine storm in COVID-19-immunopathological mechanisms, clinical considerations, and therapeutic approaches: the REPROGRAM consortium position paper.
      Although some studies have suggested that low-dose corticosteroid therapy appeared to have a beneficial role in managing patients with COVID-19, the results have been controversial.
      • Crisan Dabija R.
      • Antohe I.
      • Trofor A.
      • Antoniu S.A.
      Corticosteroids in SARS-COV2 infection: certainties and uncertainties in clinical practice.
      ,
      • Fang X.
      • Mei Q.
      • Yang T.
      • et al.
      Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19.
      It is now widely believed that low-dose corticosteroids effectively reduced the risk of mortality, respiratory failure, and delayed viral clearance of patients with severe COVID-19.
      • Horby P.
      • Lim W.S.
      • et al.
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with Covid-19.
      ,
      • Li S.
      • Hu Z.
      • Song X.
      High-dose but not low-dose corticosteroids potentially delay viral shedding of patients with COVID-19.
      ,
      • Cano E.J.
      • Fonseca Fuentes X.
      • Corsini Campioli C.
      • et al.
      Impact of corticosteroids in coronavirus disease 2019 outcomes: systematic review and meta-analysis.
      In a study evaluating the effects of low dose of corticosteroids, it was found that, in patients with severe COVID-19, the use of corticosteroids was associated with less likelihood of mortality and care escalation and significantly shorter hospitalizations.
      • Fadel R.
      • Morrison A.R.
      • Vahia A.
      • et al.
      Early short-course corticosteroids in hospitalized patients with COVID-19.
      Nevertheless, the researches evaluating the efficacy of low-dose corticosteroids in nonsevere patients with COVID-19 remain relatively insufficient, and the results are controversial. In a prospective cohort study of nonsevere patients with COVID-19, early, low-dose, and short-term corticosteroid therapy was associated with progression to severe disease, a longer virus clearance time, and a longer hospital stay.
      • Li Q.
      • Li W.
      • Jin Y.
      • et al.
      Efficacy evaluation of early, low-dose, short-term corticosteroids in adults hospitalized with non-severe COVID-19 pneumonia: a retrospective cohort study.
      A randomized clinical trial study by Tang et al
      • Tang X.
      • Feng Y.M.
      • Ni J.X.
      • et al.
      Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-intensive care unit patients with COVID-19 pneumonia: a multicenter, single-blind, randomized control trial.
      also found that the patients with nonsevere COVID-19 may not obtain any clinical benefits from low-dose methylprednisolone treatment, which even prolonged the virus clearance. On the contrary, some studies showed that low-dose corticosteroid therapy is associated with better clinical outcomes in nonsevere patients with COVID-19. In a retrospective cohort study with nonsevere COVID-19, the overall mortality, C-reactive protein value, and length of stay in the corticosteroids group were significantly lower than the noncorticosteroid group.
      • Almas T.
      • Ehtesham M.
      • Khan A.W.
      • et al.
      Safety and efficacy of low-dose corticosteroids in patients with non-severe coronavirus Disease 2019: a retrospective cohort study.
      Another study demonstrated that low-dose corticosteroids could benefit patients with mild COVID-19 without affecting the final clearance of viral nucleic acid.
      • Fu H.Y.
      • Luo Y.
      • Gao J.P.
      • et al.
      Effects of short-term low-dose glucocorticoids for patients with mild COVID-19.
      Moreover, in some studies, low-dose corticosteroid therapy showed no effect on in-hospital mortality, mechanical ventilation, and viral clearance in patients with nonsevere COVID-19.
      • Ikeda S.
      • Misumi T.
      • Izumi S.
      • et al.
      Corticosteroids for hospitalized patients with mild to critically-ill COVID-19: a multicenter, retrospective, propensity score-matched study.
      • Liu Z.
      • Li X.
      • Fan G.
      • et al.
      Low-to-moderate dose corticosteroids treatment in hospitalized adults with COVID-19.
      • Xu K.
      • Chen Y.
      • Yuan J.
      • et al.
      Factors associated with prolonged viral RNA shedding in patients with coronavirus disease 2019 (COVID-19).
      Thus, clinicians should carefully consider the risk versus benefit ratio and optimal dose of corticosteroid use for nonsevere patients with COVID-19.
      In addition, the risks of developing secondary bacterial infections, invasive fungal infections, and critical illness are increased in corticosteroid-treated patients because of the immunosuppressive effects of corticosteroids.
      • Qin Y.Y.
      • Zhou Y.H.
      • Lu Y.Q.
      • et al.
      Effectiveness of glucocorticoid therapy in patients with severe coronavirus disease 2019: protocol of a randomized controlled trial.
      Previous research had shown that corticosteroid treatment was significantly associated with more superinfections in critically ill patients with influenza A/H1N1.
      • Kim S.H.
      • Hong S.B.
      • Yun S.C.
      • et al.
      Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores.
      In fact, the adverse effects of corticosteroids therapy are related to the dose. Our study also confirmed that increased corticosteroid dose was significantly associated with elevated probability of developing severe type and increasing length of stay in patients with nonsevere COVID-19. Zhou et al
      • Zhou W.
      • Liu Y.
      • Tian D.
      • et al.
      Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia.
      reported that >240 mg of hydrocortisone equivalent dose or an excessive cumulative dose was considered to be able to generate some side effects, including hyperglycemia, psychosis, secondary infection, and avascular necrosis. One study found that every 10-mg increase in dose was associated with an additional 4% mortality risk in critically ill patients with COVID-19.
      • Lu X.
      • Chen T.
      • Wang Y.
      • Wang J.
      • Yan F.
      Adjuvant corticosteroid therapy for critically ill patients with COVID-19.
      What’s more, the average duration of corticosteroid treatment reported in our study was 8 days, which was much higher than the recommended duration of corticosteroid use (3∼5 days) by the guideline of Diagnosis and Treatment Protocol for COVID-19 Patients.
      Diagnosis and treatment protocol for COVID-19 patients (tentative 8th edition). National Health Commission of the People’s Republic of China.
      Thus, the abovementioned mechanisms may contribute to explaining why corticosteroids therapy could increase the risk of poor outcomes in nonsevere patients with COVID-19.
      This study evaluated the use of systemic corticosteroids among nonsevere patients with COVID-19 with multiple statistical methods and provided evidence-based support for optimizing SCU guidelines in patients with COVID-19. The study also has some limitations. First, because of the intrinsic defects of retrospective study, the confounding factors could not be addressed completely. Although we attempted to minimize the selection bias for corticosteroid use among different groups with PS analysis, we could only adjust for known and measurable confounding factors. Second, we cannot assess the effect of corticosteroids on viral clearance because of the lack of continuous observational data on viral RNA.

      Conclusions

      This study found that systemic corticosteroid treatment against nonsevere patients with COVID-19 was significantly associated with the higher risk of progression from nonsevere to severe, all-cause mortality, and prolonged length of stay. Furthermore, increased systemic corticosteroid dose was significantly associated with elevated risk of poor disease progression. Given the abovementioned effects of corticosteroid use, we recommend that SCU should be avoided unless absolutely necessary among nonsevere patients with COVID-19, but more cautious treatment strategies and clinical adverse drug reaction monitoring are considered if necessary.

      Article and Author Information

      Author Contributions: Concept and design: Chen, Gong
      Acquisition of data: Tan, Li, Gong
      Analysis and interpretation of data: Chen, Wang, Jiang, Tian, Li, Gong
      Drafting of the manuscript: Chen, Yin, Wang, Jiang
      Critical revision of the paper for important intellectual content: Yin, Tian
      Statistical analysis: Tan, Wang, Jiang, Tian, Li
      Provision of study materials or patients: Tan, Lu, Xiong
      Obtaining funding: Yin
      Administrative, technical, or logistic support: Lu, Xiong
      Supervision: Lu, Xiong
      Conflict of Interest Disclosures: Dr Yin reported receiving funding from Huazhong University of Science and Technology. No other disclosures were reported.
      Funding/Support: This work was supported by grants 2020kfyXGYJ073 from the Fundamental Research Funds for the Central Universities, Huazhong University of Science and Technology.
      Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

      Acknowledgment

      The authors thank all patients and their families involved in the study and all healthcare workers who are working against COVID-19.

      Supplemental Materials

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      Linked Article

      • COVID-19 Health Economics: Looking Back and Scoping the Future
        Value in HealthVol. 25Issue 5
        • Preview
          As of March 2022, nearly 6 million people have died of COVID-19 globally.1 The COVID-19 pandemic has already gone through several distinct stages during the first 2 years, with noticeable health and health economics impact at each stage. The initial emergency stage resulted in lockdowns that incurred enormous societal costs, concerning gross domestic product reductions as well as (mental) health damages. Diagnostic tests were implemented on a never-before-seen scale in many healthcare systems, without health economics justification,2,3 as exemplified in a systematic review in this themed section.
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