Impact of Corticosteroids in Coronavirus Disease 2019 Outcomes

Systematic Review and Meta-analysis
Published:October 28, 2020DOI:https://doi.org/10.1016/j.chest.2020.10.054

      Background

      Since its appearance in late 2019, infections caused by severe acute respiratory syndrome coronavirus 2 have created unprecedented challenges for health systems worldwide. Multiple therapeutic options have been explored, including corticosteroids. Preliminary results of corticosteroids in coronavirus disease 2019 (COVID-19) are encouraging; however, the role of corticosteroids remains controversial.

      Research Question

      What is the impact of corticosteroids in mortality, ICU admission, mechanical ventilation, and viral shedding in COVID-19 patients?

      Study Design and Methods

      We conducted a systematic review of literature on corticosteroids and COVID-19 in major databases (PubMed, MEDLINE, and EMBASE) of published literature through July 22, 2020, that report outcomes of interest in COVID-19 patients receiving corticosteroids with a comparative group.

      Results

      A total of 73 studies with 21,350 COVID-19 patients were identified. Corticosteroid use was reported widely in mechanically ventilated patients (35.3%), ICU patients (51.3%), and severe COVID-19 patients (40%). Corticosteroids showed mortality benefit in severelly ill COVID-19 patients (OR, 0.65; 95% CI, 0.51-0.83; P = .0006); however, no beneficial or harmful effects were noted among high-dose or low-dose corticosteroid regimens. Emerging evidence shows that low-dose corticosteroids do not have a significant impact in the duration of SARS-CoV-2 viral shedding. The analysis was limited by highly heterogeneous literature for high-dose and low-dose corticosteroids regimens.

      Interpretation

      Our results showed evidence of mortality benefit in severely ill COVID-19 patients treated with corticosteroids. Corticosteroids are used widely in COVID-19 patients worldwide, and a rapidly developing global pandemic warrants further high-quality clinical trials to define the most beneficial timing and dosing for corticosteroids.

      Key Words

      Abbreviations:

      COVID-19 (coronavirus disease 2019), MERS (Middle Eastern respiratory syndrome), SARS (severe acute respiratory syndrome), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), RR (relative risk)
      • Corticosteroids use is reported widely in COVID-19 patients worldwide, although their impact on clinically relevant outcomes in specific populations remains unclear.
      • Our study findings show mortality benefit for severely ill COVID-19 patients receiving corticosteroids.
      • Low-dose corticosteroids do not seem to have a significant impact in the duration of SARS-CoV-2 viral shedding.
      • Patients with severe COVID-19 may benefit from corticosteroids.
      In December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was linked to a cluster of cases of severe acute respiratory syndrome (SARS) in Wuhan, China.
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      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      By March 11, 2020, the outbreak had affected millions worldwide, and the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic.
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      Different interventions have been implemented based on previous experience with other coronavirus diseases, such as SARS caused by severe acute respiratory syndrome coronavirus 1, and Middle Eastern respiratory syndrome (MERS) caused by Middle Eastern respiratory syndrome coronavirus.
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      Emerging infectious diseases: focus on infection control issues for novel coronaviruses (severe acute respiratory syndrome-CoV and Middle East respiratory syndrome-CoV), hemorrhagic fever viruses (Lassa and Ebola), and highly pathogenic avian influenza viruses, A(H5N1) and A(H7N9).
      The literature is evolving rapidly, and newer findings position corticosteroids as a strong candidate for treatment. However, the role of corticosteroids in the management of COVID-19 remains a subject of controversy.
      The immune response is a key determinant of SARS-CoV-2 infection.
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      The first phase of illness is characterized by fever, cough, and high viral loads. The next stage, labeled the pulmonary phase, is characterized by persistent lung inflammation despite decreasing viral load, resulting in respiratory failure owing to ARDS (Fig 1). In the last stage, the uncontrolled hyper-inflammatory response results in a syndrome of multiorgan dysfunction with high mortality risk.
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      Figure thumbnail gr1
      Figure 1A, Diagram showing clinical phases of coronavirus disease 2019. B, Diagram showing immunomodulatory effects of glucocorticoid therapy in the nucleus driven by glucocorticoid response elements (GREs) resulting in increased expression of antiinflammatory molecules (annexin-1; nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α [IκBα]; secretory leukocyte protease inhibitor [SLPI], and IL-10) and decreased production of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and proinflammatory cytokines (IL-2, IL-6, and tumor necrosis factor α [TNFα]). CRP = c-reactive protein.
      In asymptomatic patients or those with mild disease, an effective immune response with neutralizing antibodies results in prompt viral clearance and a short-lived inflammatory response.
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      However, the immune response in patients with severe SARS-CoV-2 infection is ineffective and excessive, which often results in progressive pulmonary damage in the form of ARDS or hyper-inflammatory status and subsequent multiorgan dysfunction.
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      The trinity of COVID-19: immunity, inflammation and intervention.
      After the invasion of the host cells expressing angiotensin-converting enzyme 2 receptors, active viral replication results in pyroptosis and release of damage-associated molecular patterns, which are recognized by the neighboring cells, including alveolar macrophages. This triggers the release of an array of proinflammatory cytokines and chemokines (including IL-6, interferon γ-induced protein 10, macrophage inflammatory protein 1α, macrophage inflammatory protein 1β, andmonocyte chemoattractant protein 1). Further recruitment of monocytes, macrophages, and T cells to the site infection promotes more inflammation.
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      Multiple studies showed higher levels of proinflammatory cytokines in patients with severe SARS-CoV-2 compared with patients with mild to moderate illness, both in the serum and in the respiratory specimens. Given the significant role of the immune response in the pathogenesis of SARS-CoV-2, it became clear that immune modulation will be essential in its management. A targeted approach focusing on some of the cytokines involved in the pathogenesis of the hyperinflammatory, status like granulocyte-macrophage colony-stimulating factor, IL-6, or complement, is currently under investigation.
      Corticosteroids were the main immunomodulatory agent used for the clinical management of SARS; both benefits and poor outcomes have been reported as a result of their use. Some retrospective studies showed benefits in mortality outcomes.
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      Beyond mortality, a study of 107 patients treated with high-dose methylprednisolone (0.5–1 mg/kg prednisolone on day 3, followed by hydrocortisone 100 mg every 8 h plus methylprednisolone pulse 0.5 g intravenously for 3 additional days), 95 (89%) patients recovered from SARS.
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      Outcomes of COVID-19 patients treated with corticosteroids are starting to emerge mainly in the form of retrospective data. One of the earliest published meta-analyses reviewed 5,270 patients from 15 observational studies of coronavirus diseases caused by SARS-CoV-2, severe acute respiratory syndrome coronavirus 1, and Middle Eastern respiratory syndrome coronavirus with literature available up to March 15, 2020.
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      Of the 5,270 patients, only 179 (3.39%) were COVID-19 patients from two Chinese studies.
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      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      ,
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      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Overall, patients receiving corticosteroids with coronavirus diseases were more likely to be critically ill, had a longer length of hospital stay, had higher mortality, had more bacterial infections, and had higher rates of hypokalemia.
      A similar meta-analysis addressing the impact of corticosteroids in adults with coronavirus diseases (MERS, SARS, and COVID-19 literature up to March 20, 2020)
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      • Hu F.
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      Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis.
      included four studies available for COVID-19 and showed no mortality benefit or harm with corticosteroid use in coronavirus diseases, although data from three studies
      • Yang X.
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      • Xu J.
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      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      • Zhou F.
      • Yu T.
      • Du R.
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      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      • Wu C.
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      • Cai Y.
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      Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.
      were generated at the same institution (Jinyintan Hospital in Wuhan, China) without more information about possible overlapping cases.
      It is worth emphasizing that COVID-19, SARS, and MERS are phenotypically heterogeneous in terms of contagiousness, fatality rates, and severity, despite their close virus phylogeny,
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      and grouping these diseases to report outcomes may pose significant selection bias, hence the need for literature on COVID-19 specifically. A meta-analysis with mortality outcomes available in four studies for 495 COVID-19 patients (comprising literature up to May 7, 2020) showed no differences in mortality among patients with or without corticosteroid treatment (relative risk [RR], 1.38; 95% CI, 0.87-2.18; P = .17).

      Wang Y, Ao G, Qi X, Zeng J. The influence of corticosteroid on patients with COVID-19 infection: a meta-analysis [published online ahead of print June 23, 2020]. Am J Emerg Med. https://doi.org/10.1016/j.ajem.2020.06.040.

      Another meta-analysis with literature until April 25, 2020, showed no benefit of corticosteroids in COVID-19 based on two studies,
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      • Xu S.
      • Yu M.
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      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      ,
      • Lu X.
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      but again, the data were generated at the same hospital with overlapping timelines for both studies.
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      The impact of corticosteroids in COVID-19 outcomes remains unclear based on early literature mainly comprising retrospective studies with significant population overlap; however, as the pandemic evolves, corticosteroid use in COVID-19 is being reported worldwide. In this study, we sought to determine the mortality impact of corticosteroids vs standard of care in hospitalized COVID-19 patients. Secondary outcomes addressed for qualitative synthesis comprised disease severity, ICU admission, need for mechanical ventilation, viral clearance, and safety.

      Methods

      We conducted a systematic review and meta-analysis searching for corticosteroids (methylprednisolone, dexamethasone, prednisone, corticoids, and steroids) and COVID-19 cases in major databases (PubMed, MEDLINE, and EMBASE) for published literature until July 22, 2020. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and meta-analysis.
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      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      A detailed search strategy and the PRISMA checklist can be found in e-Appendix 1.

       PICO Question

      Population: Hospitalized patients with COVID-19.
      Intervention: Corticosteroids administered while hospitalized.
      Comparisons: Standard of care or investigational therapies.
      Outcomes: Mortality (quantitative analysis), severity of COVID-19, ICU admission, need for mechanical ventilation, viral clearance, and safety (qualitative analysis).

       Study Selection

      The inclusion criteria were (1) peer-reviewed publications on COVID-19 only, (2) retrospective or prospective studies with more than three cases, (3) reporting the outcomes of interest for adult patients receiving corticosteroids in (4) all languages available. We excluded studies (1) without a comparison group to characterize better the effect of corticosteroids, (2) of special populations such as pregnant or pediatric patients because COVID-19 presentation and management are different in these populations, and (3) of organ transplant recipients or inflammatory or rheumatologic patients who reported chronic corticosteroid use.
      A total of 945 studies were identified after removing duplicates; 774 were excluded after initial screening. Two investigators (E. J. C., C. C. C.) independently reviewed the identified abstracts and selected articles for full review. Discordances were resolved by a third investigator (X. F.). The excluded studies comprised reviews (n = 275), short communications or letters (n = 229), case reports with fewer than four patients (n = 134), literature on pregnant women or children (n = 49), guidelines or society recommendations (n = 47), studies not reporting outcomes on COVID-19 (n = 27), and preclinical data (n = 13). A total of 171 full-text studies were analyzed for eligibility and 73 peer-reviewed articles were included for qualitative and quantitative analysis (Fig 2).
      Figure thumbnail gr2
      Figure 2PRISMA flow diagram showing study selection.
      Data extracted for each study included study design; median or mean age, or both; country, region, or hospital to assess possible population overlap; sample size; patients receiving corticosteroids; corticosteroid dose and duration; other reported therapies; whether they reported outcomes on special populations; and outcomes of interest. Quantitative meta-analysis was performed for mortality outcomes, whereas other clinically relevant end points such as severity of COVID-19, ICU admission, need for mechanical ventilation, viral clearance, and other adverse events were summarized in a qualitative fashion. We labeled as low-dose corticosteroids any reported dose of methylprednisolone ≤ 200 mg daily or ≤ 2 mg/kg/d or equivalent in other corticosteroids.

       Risk of Bias Assessment

      Risk of bias was determined using the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool for nonrandomized studies
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      and version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB-2).
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      Studies from the same hospital or region were noted to perform sensitivity analysis in the likelihood of population overlap.

       Statistical Analysis

      Summary risk ratios also referred to as relative risk [RR] and their 95% CIs were calculated using the DerSimonian and Laird random-effects model and s fixed-effect model for specific populations as deemed appropriate.
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      Extending DerSimonian and Laird’s methodology to perform multivariate random effects meta-analyses.
      Heterogeneity was assessed with an I2 statistic, where 0% indicates no heterogeneity and 100% indicates the highest level of heterogeneity.
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      Sensitivity and subgroup analyses were performed to analyze sources of heterogeneity. Data analysis was performed using Review Manager (RevMan, version 5.4; The Cochrane Collaboration). This meta-analysis used de-identified publicly available published data and required no ethics committee approval.

      Results

      A total of 73 peer-reviewed articles were included for qualitative (n = 55) and quantitative (n = 33) analysis. Variables extracted for each publication are listed in Table 1.
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      • Xu X.W.
      • Wu X.X.
      • Jiang X.G.
      • et al.
      Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.
      • Yan Y.
      • Yang Y.
      • Wang F.
      • et al.
      Clinical characteristics and outcomes of patients with severe covid-19 with diabetes.
      • Yang L.
      • Liu J.
      • Zhang R.
      • et al.
      Epidemiological and clinical features of 200 hospitalized patients with corona virus disease 2019 outside Wuhan, China: a descriptive study.
      • Yang Q.
      • Xie L.
      • Zhang W.
      • et al.
      Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019.
      • Yuan M.
      • Xu X.
      • Xia D.
      • et al.
      Effects of corticosteroid treatment for non-severe COVID-19 pneumonia: a propensity score-based analysis.
      • Zha L.
      • Li S.
      • Pan L.
      • et al.
      Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19).
      • Zhang G.
      • Hu C.
      • Luo L.
      • et al.
      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      • Zhang J.
      • Yu M.
      • Tong S.
      • Liu L.Y.
      • Tang L.V.
      Predictive factors for disease progression in hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      • Zhang Y.
      • Li H.
      • Zhang J.
      • et al.
      The clinical characteristics and outcomes of patients with diabetes and secondary hyperglycaemia with coronavirus disease 2019: a single-centre, retrospective, observational study in Wuhan.
      • Zhao J.
      • Gao H.Y.
      • Feng Z.Y.
      • Wu Q.J.
      A Retrospective analysis of the clinical and epidemiological characteristics of COVID-19 patients in Henan Provincial People’s Hospital, Zhengzhou, China.
      • Zhao X.Y.
      • Xu X.X.
      • Yin H.S.
      • et al.
      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      • Zheng C.
      • Wang J.
      • Guo H.
      • et al.
      Risk-adapted treatment strategy for COVID-19 patients.
      • Zheng Y.
      • Sun L.J.
      • Xu M.
      • et al.
      Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.
      All 73 studies included outcomes on COVID-19 patients receiving corticosteroids and a comparison group that did not receive corticosteroids. We were able to find four studies that reported outcomes of propensity score-matched populations
      • Lu X.
      • Chen T.
      • Wang Y.
      • Wang J.
      • Yan F.
      Adjuvant corticosteroid therapy for critically ill patients with COVID-19.
      ,
      • Chroboczek T.
      • Lacoste M.
      • Wackenheim C.
      • et al.
      Corticosteroids in patients with COVID-19: what about the control group?.
      ,
      • Fernandez-Cruz A.
      • Ruiz-Antoran B.
      • Munoz-Gomez A.
      • et al.
      A retrospective controlled cohort study of the impact of glucocorticoid treatment in SARS-CoV-2 infection mortality.
      ,
      • Yuan M.
      • Xu X.
      • Xia D.
      • et al.
      Effects of corticosteroid treatment for non-severe COVID-19 pneumonia: a propensity score-based analysis.
      and one randomized clinical trial.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • et al.
      Dexamethasone in hospitalized patients with Covid-19—preliminary report.
      The remaining studies had limited information about baseline characteristics of their population receiving corticosteroids.
      Table 1Summary of Evidence of Corticosteroid Use in COVID-19
      StudyDesignAge, yRegion, HospitalPossible Population OverlapSample SizePatients Receiving CorticosteroidsCorticosteroids DosageOther Therapies ReportedSpecial PopulationsOutcomes or Characteristics Reported
      a Outcomes: 1 = severity, ICU admission, or both; 2 = mechanical ventilation; 3 = mortality; 4 = viral clearance; and 5 = adverse events.
      Risk of Bias
      Almazeedi et al
      • Almazeedi S.
      • Al-Youha S.
      • Jamal M.H.
      • et al.
      Characteristics, risk factors and outcomes among the first consecutive 1096 patients diagnosed with COVID-19 in Kuwait.
      RCS41 (25-75)KuwaitNo1,09640 (3.64). . .ABX, AVR, HCQ. . .1,3Moderate
      Argenziano et al
      • Argenziano M.G.
      • Bruce S.L.
      • Slater C.L.
      • et al.
      Characterization and clinical course of 1000 patients with COVID-19 in New York: retrospective case series.
      RCS63 (50-75)United StatesNo850178 (20.9). . .ABX, AVR, IVIG, HCQ, TCZB. . .1Serious
      Ayerbe et al
      • Ayerbe L.
      • Risco C.
      • Ayis S.
      The association between treatment with heparin and survival in patients with Covid-19.
      Case series67.57 ± 15.52SpainNo2,075960 (46.2). . .ABX, AVR, HCQ, TCZB. . .3Moderate
      Blanco et al
      • Blanco J.L.
      • Ambrosioni J.
      • Garcia F.
      • et al.
      COVID-19 in patients with HIV: clinical case series.
      Case series40 (31-40)SpainNo51 (20). . .ABX, AVR, HCQ, TCZBHIV1Serious
      Callejas-Rubio et al
      • Callejas-Rubio J.L.
      • del Castillo J.D.L.
      • Fernandez J.D.
      • Arrabal E.G.
      • Ruiz M.C.
      • Centeno N.O.
      Effectiveness of corticoid pulses in patients with cytokine storm syndrome induced by SARS-CoV-2 infection.
      Case series63.9 ± 12.9SpainNo9283 (90.2)MP, 2 mg/kg/3 d, 250 mg/3 d, and 500 mg/3 dTCZB. . .2,3Moderate
      Cao et al
      • Cao J.
      • Tu W.J.
      • Cheng W.
      • et al.
      Clinical features and short-term outcomes of 102 patients with coronavirus disease 2019 in Wuhan, China.
      Case series54 (37-67)China, Zhongnan HospitalYes10251 (50). . .AVR, ABX, IVIG, CTM. . .3Moderate
      Cao et al
      • Cao Z.H.
      • Li T.Z.
      • Liang L.C.
      • et al.
      Clinical characteristics of coronavirus disease 2019 patients in Beijing, China.
      RCS53 ± 20China, Beijing YouAn HospitalYes8019 (23.7). . .AVR, ABX, CTM. . .1Serious
      Chen et al
      • Chen Q.
      • Quan B.
      • Li X.N.
      • et al.
      A report of clinical diagnosis and treatment of nine cases of coronavirus disease 2019.
      Case series50.5 (42.5-53.25)China, WuhanNo84 (50)MP, 40 mg/d for 6 dABX, AVR. . .3Serious (size)
      Chen et al
      • Chen T.
      • Dai Z.
      • Mo P.
      • et al.
      Clinical characteristics and outcomes of older patients with coronavirus disease 2019 (COVID-19) in Wuhan, China (2019): a single-centered, retrospective study.
      RCS54 (20-91)China, Zhongnan HospitalYes5534 (61.8)MP, 40-80 mg/d for 3-5 dABX, AVR, IVIGAge > 65 y3Moderate
      Chen et al
      • Chen X.
      • Zhu B.
      • Hong W.
      • et al.
      Associations of clinical characteristics and treatment regimens with the duration of viral RNA shedding in patients with COVID-19.
      Cohort study49 (34-62)China, Guangzhou 8th People’s HospitalNo26729 (10.8). . .ABX, AVR, HCQ. . .4Serious
      Chen et al
      • Chen Y.
      • Zhang K.
      • Zhu G.
      • et al.
      Clinical characteristics and treatment of critically ill patients with COVID-19 in Hebei.
      RCS58.9 ± 13.7China, Hebei (13 designated hospitals)No5146 (90.1)MP, 80 mg/d for 5-6 dABX, AVRCritically ill patients2,3Moderate
      Chroboczek et al
      • Chroboczek T.
      • Lacoste M.
      • Wackenheim C.
      • et al.
      Corticosteroids in patients with COVID-19: what about the control group?.
      Case series61 ± 12FranceNo7021 (30). . .ABX, AVR, HCQPSM2Low
      Dang et al
      • Dang J.Z.
      • Zhu G.Y.
      • Yang Y.J.
      • Zheng F.
      Clinical characteristics of coronavirus disease 2019 in patients aged 80 years and older.
      RCS88 (86.6-90)China, Renmin HospitalYes176 (35.2). . .ABX, AVR, IVIG, TCM. . .1Serious
      Deng et al
      • Deng Y.
      • Liu W.
      • Liu K.
      • et al.
      Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: a retrospective study.
      RCS69 (62-74) in deceased patients vs 40 (33-57) in survivorsChina, Tongji, Huazhong and Hankou branch of The Wuhan’s Central HospitalYes225152 (67.5). . .. . .. . .3Moderate
      Ding et al
      • Ding Q.
      • Lu P.P.
      • Fan Y.H.
      • Xia Y.J.
      • Liu M.
      The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and influenza virus in Wuhan, China.
      Case series49 (47-50)China, Tongji and Huazhong HospitalYes53 (60). . .ABX, AVRInfluenza coinfection1,2,3Critical (coinfection)
      Fadel et al
      • Fadel R.
      • Morrison A.R.
      • Vahia A.
      • et al.
      Early short course corticosteroids in hospitalized patients with COVID-19.
      Quasi-experimental prospective62 (51-62)United StatesNo213132 (61.9)MP, 0.5-1 mg/kg/d for 3 d. . .. . .1,2,3Low
      Fang et al
      • Fang X.W.
      • Mei Q.
      • Yang T.J.
      • et al.
      Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19.
      Case series40 ± 12.6China, Anhui Provincial HospitalYes7825 (32.0)MP hydrocortisone-equivalent dose, 237.5 mg/d for 7 d in general group, 250.0 mg/d for 4.5 d in severe groupAVR, TCZB. . .4Moderate
      Feng et al
      • Feng Y.
      • Ling Y.
      • Bai T.
      • et al.
      COVID-19 with different severities: a multicenter study of clinical features.
      RCS53 (40-64)China, Jinyintan Hospital, Shanghai Public Health Clinical Center, and Tongling People’s HospitalYes476127 (26.6). . .AVR, ABXCritical patients1,3Moderate
      Fernandez-Cruz et al
      • Fernandez-Cruz A.
      • Ruiz-Antoran B.
      • Munoz-Gomez A.
      • et al.
      A retrospective controlled cohort study of the impact of glucocorticoid treatment in SARS-CoV-2 infection mortality.
      RCS65.4 ± 12.9 in steroid treated, 68.1 ± 15.7 in steroid freeSpainNo463396 (85.5)Low dose: MP, 1 mg/kg/d for 3-5 d

      Pulses: 2-4 MP pulses, < 250 mg/d (20.1%), 250 mg/d (62.5%), and 500 mg/d (17.1%)
      ABX, AVR, HCQ, TCZB, OIMPSM1,3Moderate
      Giacobbe et al
      • Giacobbe D.R.
      • Battaglini D.
      • Ball L.
      • et al.
      Bloodstream infections in critically ill patients with COVID-19.
      Case series66 (57-70)ItalyNo7824 (30.7)MP, 1 mg/kg/dABX, TCZB. . .5Moderate
      Gong et al
      • Gong Y.
      • Guan L.
      • Jin Z.
      • Chen S.
      • Xiang G.
      • Gao B.
      Effects of methylprednisolone use on viral genomic nucleic acid negative conversion and CT imaging lesion absorption in COVID-19 patients under 50 years old.
      RCS38 ± 8.9China, First Clinical Medical College of Three Gorges UniversityNo3418 (52.9)MP, 1-2 mg/kg/d gradually halved every 3 d for a total of 5-10 d. . .. . .4Moderate
      Guan et al
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      RCS47 (35-58)China, Jin Yin-tan HospitalYes1,099204 (18.5). . .ABX, AVR, IVIG. . .1,2,3Moderate
      Hong et al
      • Hong K.S.
      • Lee K.H.
      • Chung J.H.
      • et al.
      Clinical features and outcomes of 98 patients hospitalized with SARS-CoV-2 infection in Daegu, South Korea: a brief descriptive study.
      RCS55.4 ± 17.1South KoreaNo9818 (18.3). . .ABX, AVR, HCQ. . .1Serious
      Horby et al
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • et al.
      Dexamethasone in hospitalized patients with Covid-19—preliminary report.
      Randomized clinical trial66.1 ± 15.7United KingdomNo6,4252,104 (32.7)Dexamethasone 6 mg/d up to 10 dABX, AVR, HQC, TCM. . .2,3Low
      Hu et al
      • Hu Z.L.
      • Lv Y.L.
      • Xu C.J.
      • et al.
      Clinical use of short-course and low-dose corticosteroids in patients with non-severe COVID-19 during pneumonia progression.
      RCS46 (33-57)China, Second Hospital of NanjingNo7228 (38.8)MP 140 mg/d for 4.54 daysABX, AVR, IVIG. . .3,4Moderate
      Huang et al
      • Huang C.
      • Wang Y.
      • Li X.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      RCS49 (41-58)China, Jin Yin-tan HospitalYes419 (21.9)MP 40–120 mg/dABX, AVR. . .1,3,5Moderate
      Huang et al
      • Huang Y.X.
      • Cai C.L.
      • Zang J.L.
      • et al.
      Treatment strategies of hospitalized patients with coronavirus disease-19.
      Case series45 (34-59)China, First Hospital of Changsha cityNo23876 (31.9). . .AVR, HCQ. . .1Serious
      Jacobs et al
      • Jacobs J.P.
      • Stammers A.H.
      • St Louis J.
      • et al.
      Extracorporeal membrane oxygenation in the treatment of severe pulmonary and cardiac compromise in coronavirus disease 2019: experience with 32 patients.
      Case series52.4 ± 12.5United StatesNo325 (15.6). . .AVR, HCQ, OIMICU, ECMO3Moderate
      Jiang et al
      • Jiang Y.
      • He S.
      • Zhang C.
      • et al.
      Clinical characteristics of 60 discharged cases of 2019 novel coronavirus-infected pneumonia in Taizhou, China.
      RCS41 (12-74)China, Taizhou Enze Medical CenterNo609 (15). . .ABX, AVR, IVIG. . .1Serious
      Kato et al
      • Kato H.
      • Shimizu H.
      • Shibue Y.
      • et al.
      Clinical course of 2019 novel coronavirus disease (COVID-19) in individuals present during the outbreak on the Diamond Princess cruise ship.
      Case series67 (62-71)JapanNo702 (2.85)Steroid pulse therapyABX, AVR. . .2Serious
      Khamis et al
      • Khamis F.
      • Al-Zakwani I.
      • Al Naamani H.
      • et al.
      Clinical characteristics and outcomes of the first 63 adult patients hospitalized with COVID-19: an experience from Oman.
      Case series48 ± 16OmanNo6315 (23.8). . .ABX, AVR, HCQ, OIM, CPT. . .1Serious
      Li et al
      • Li K.
      • Chen D.
      • Chen S.
      • et al.
      Predictors of fatality including radiographic findings in adults with COVID-19.
      RCS57 (45-70)China, Tongji HospitalYes12852 (40.6). . .ABX, AVR, TCM, IVIG. . .3Moderate
      Li et al
      • Li S.
      • Hu Z.
      • Song X.
      High-dose but not low-dose corticosteroids potentially delay viral shedding of patients with COVID-19.
      RCS. . .China, Yichang Central People’s

      Hospital
      Yes206NAUnspecified corticosteroids 40-80 mg/d. . .. . .4Critical
      Li et al

      Li TZ, Cao ZH, Chen Y, et al. Duration of SARS-CoV-2 RNA shedding and factors associated with prolonged viral shedding in patients with COVID-19 [published online ahead of print July 9, 2020]. J Med Virol. https://doi.org/10.1002/jmv.26280.

      RCS47.5 (36-63.5)China, Beijing YouAn HospitalYes6617 (25.7)MP, low-dose group: ≤ 300 mg; high-dose group, > 300 mgABX, AVR, TCM. . .4Moderate
      Li et al
      • Li X.
      • Xu S.
      • Yu M.
      • et al.
      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      Case series56 (44-66)China, Tongji HospitalYes5486 (1.1)Prednisone medium cumulative dose 200 mg for 4 dABX, AVR, IVIG. . .1Moderate
      Ling et al
      • Ling Y.
      • Xu S.B.
      • Lin Y.X.
      • et al.
      Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients.
      RCS44 (34-62)China, Shanghai Public Health Clinical CenterYes665 (7.6). . .. . .. . .4Serious
      Liu et al
      • Liu F.
      • Xu A.F.
      • Zhang Y.
      • et al.
      Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression.
      Case series42 (34-50)China, Xixi HospitalNo103 (30)MP, 80 mg/dABX, AVR, IVIG. . .1,2Serious
      Liu et al
      • Liu J.
      • Zheng X.
      • Huang Y.
      • Shan H.
      • Huang J.
      Successful use of methylprednisolone for treating severe COVID-19.
      Case series45 (30-62)China, Fifth Affiliated Hospital of Sun Yat-sen UniversityNo10115 (14.8)MP, 2-8 mg/kg/d; maximum 500 mg/dABX, AVR1,2Moderate
      Liu et al
      • Liu J.
      • Li S.
      • Liu J.
      • et al.
      Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients.
      Case series48 (30-62)China, Wuhan Union HospitalYes408 (20)MP, 40 mg/dABX, AVR1Moderate
      Liu et al
      • Liu L.
      • Lei X.
      • Xiao X.
      • et al.
      Epidemiological and clinical characteristics of patients with coronavirus disease-2019 in Shiyan City, China.
      Case series38 (28-47)China, Renmin HospitalYes5312 (22.6). . .ABX, AVR, IVIG3Moderate
      Lu et al
      • Lu X.
      • Chen T.
      • Wang Y.
      • Wang J.
      • Yan F.
      Adjuvant corticosteroid therapy for critically ill patients with COVID-19.
      Case series62 (50-71)China, Tongji HospitalYes6231 (50)Median hydrocortisone-equivalent dosage, 200 mg/d (range, 100-800 mg/d) for 4-12 dABX, IVIGICU, PSM2,3Moderate
      Luo et al
      • Luo P.
      • Liu Y.
      • Qiu L.
      • Liu X.
      • Liu D.
      • Li J.
      Tocilizumab treatment in COVID-19: a single center experience.
      Case series73 (62-80)China, Tongji HospitalYes158 (53.3)MP, 40-160 mg/dTCZB. . .1,3Moderate
      Montastruc et al
      • Montastruc F.
      • Romano C.
      • Montastruc J.L.
      • et al.
      Pharmacological characteristics of patients infected with SARS-Cov-2 admitted to intensive care unit in south of France.
      Case series63.4 (20-89)FranceNo9613 (13.5). . .. . .ICU1,2Moderate
      Okoh et al
      • Okoh A.K.
      • Sossou C.
      • Dangayach N.S.
      • et al.
      Coronavirus disease 19 in minority populations of Newark, New Jersey.
      RCS62 (49-74)United StatesNo25135 (13.9). . .ABX, AVR, HCQ, TCZB. . .3Moderate
      Shahriarirad et al
      • Shahriarirad R.
      • Khodamoradi Z.
      • Erfani A.
      • et al.
      Epidemiological and clinical features of 2019 novel coronavirus diseases (COVID-19) in the South of Iran.
      RCS53.8 ± 16.6IranNo1135 (4.4). . .. . .. . .3Moderate
      Shen et al
      • Shen Y.
      • Zheng F.
      • Sun D.
      • et al.
      Epidemiology and clinical course of COVID-19 in Shanghai, China.
      RCS51 (36-64)China, Shanghai Public Health Clinical CenterYes32550 (15.3). . .ABX, AVR, CPT. . .4Critical
      Shi et al
      • Shi D.
      • Wu W.
      • Wang Q.
      • et al.
      Clinical characteristics and factors associated with long-term viral excretion in patients with severe acute respiratory syndrome coronavirus 2 infection: a single-center 28-day study.
      RCS54 (39-64)China, First Affiliated Hospital of Zhejiang UniversityYes9977 (77.7)Unspeficied corticosteroids 60 mg/dABX, AVR, IVIG. . .4Moderate
      Sun et al
      • Sun L.
      • Shen L.
      • Fan J.
      • et al.
      Clinical features of patients with coronavirus disease 2019 from a designated hospital in Beijing, China.
      RCS44 (34-56)China, Beijing 302 HospitalNo5525 (45.4)Unspecified corticosteroid 40-80 mg/d for 3-5 dAVR, IVIG. . .1Serious
      Vahedi et al
      • Vahedi E.
      • Ghanei M.
      • Ghazvini A.
      • et al.
      The clinical value of two combination regimens in the management of patients suffering from Covid-19 pneumonia: a single centered, retrospective, observational study.
      RCS58.39 ± 13.57IranNo6030 (50)Prednisolone 25 mg/dABX, AVR. . .3Moderate
      Wan et al
      • Wan S.
      • Xiang Y.
      • Fang W.
      • et al.
      Clinical features and treatment of COVID-19 patients in northeast Chongqing.
      Case series47 (36-55)China, Chongqing Three Gorges Central HospitalNo13536 (26.6). . .ABX, AVR, TCM. . .1Moderate
      Wang et al
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      RCS56 (42-68)China, Zhongnan HospitalYes13862 (44.9). . .ABX, AVR. . .1Low
      Wang et al
      • Wang D.
      • Yin Y.
      • Hu C.
      • et al.
      Clinical course and outcome of 107 patients infected with the novel coronavirus, SARS-CoV-2, discharged from two hospitals in Wuhan, China.
      RCS51 (36-65)China, Zhongnan HospitalYes10762 (57.9). . .ABX, AVR. . .3Moderate
      Wang et al
      • Wang F.
      • Hou H.
      • Wang T.
      • et al.
      Establishing a model for predicting the outcome of COVID-19 based on combination of laboratory tests.
      Case series71 ± 10.6China, Tongji HospitalYes10855 (50.9)MP 40-80 mg/d for 3-5 dABX, AVR, IVIG. . .3Moderate
      Wang et al
      • Wang J.
      • Yang Q.
      • Zhang P.
      • Sheng J.
      • Zhou J.
      • Qu T.
      Clinical characteristics of invasive pulmonary aspergillosis in patients with COVID-19 in Zhejiang, China: a retrospective case series.
      RCS63 ± 14China, First Affiliated Hospital of Zhejiang UniversityYes10463 (60.5)MP 40-80 mg/dABX, AVR. . .5Moderate
      Wang et al
      • Wang Y.
      • Jiang W.
      • He Q.
      • et al.
      A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia.
      RCS54 (48-64)China, Union Hospital of Huazhong University of Science and TechnologyYes4626 (56.5)MP, 1-2 mg/kg/d for 5-7 dABV, AVRSevere disease2,3Moderate
      Wu et al
      • 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.
      RCS58.5 (50-69)China, Jin Yin-tan HospitalYes8450 (59.5). . .ABX, AVRARDS3Serious (ARDS)
      Wu et al
      • Wu J.
      • Huang J.
      • Zhu G.
      • et al.
      Elevation of blood glucose level predicts worse outcomes in hospitalized patients with COVID-19: a retrospective cohort study.
      RCS61 (50-69)China, Wuhan Hankou Hospital and No. Six Hospital of WuhanNo2,0411,026 (50.2). . .ABX, AVR. . .1Serious
      Xu et al
      • Xu K.
      • Chen Y.
      • Yuan J.
      • et al.
      Factors associated with prolonged viral RNA shedding in patients with coronavirus disease 2019 (COVID-19).
      Case series52 (43-63)China, First Affiliated Hospital and the Shenzhen Third People’s HospitalNo11364 (56.6)MP, < 1.5 mg/kg/dAVR. . .4Serious
      Xu et al
      • Xu X.W.
      • Wu X.X.
      • Jiang X.G.
      • et al.
      Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.
      Case series41 (32-52)China, multicenter including Wenzhou Central HospitalYes6216 (25.8)Unspecified corticosteroid 40-80 mg/dAVR. . .3Moderate
      Yan et al
      • Yan Y.
      • Yang Y.
      • Wang F.
      • et al.
      Clinical characteristics and outcomes of patients with severe covid-19 with diabetes.
      RCS64 (49-73)China, Tongji HospitalYes193136 (70.4). . .ABX, AVRDiabetes3Serious (diabetes)
      Yang et al
      • Yang L.
      • Liu J.
      • Zhang R.
      • et al.
      Epidemiological and clinical features of 200 hospitalized patients with corona virus disease 2019 outside Wuhan, China: a descriptive study.
      Case series55 ± 17.1China, Yichang Central People’s HospitalYes200112 (56). . .ABX, AVR. . .1Serious
      Yang et al
      • Yang Q.
      • Xie L.
      • Zhang W.
      • et al.
      Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019.
      Case series56 (44-64)China, Wuhan Third HospitalNo13655 (40.4)MP, 40 mg/dABX, AVR, CTM. . .1Moderate
      Yang et al
      • Yang X.
      • Yu Y.
      • Xu J.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      RCS59.7 ± 13.3China, Jin Yin-tan HospitalYes5230 (57.6). . .ABX, AVR, IVIGICU3Moderate
      Yuan et al
      • Yuan M.
      • Xu X.
      • Xia D.
      • et al.
      Effects of corticosteroid treatment for non-severe COVID-19 pneumonia: a propensity score-based analysis.
      RCS48.1 (33-64)China, Central Hospital of WuhanNo7035 (50)MP, median dose, 44.6 mg/dABXNonsevere cases, PSM1,4,5Moderate
      Zha et al
      • Zha L.
      • Li S.
      • Pan L.
      • et al.
      Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19).
      RCS39 (32-54)China, Anhui Provincial HospitalYes3111 (35.4)MP 40 mg once or twice daily for 5 dABX, AVR. . .3,4Moderate
      Zhang et al
      • Zhang G.
      • Hu C.
      • Luo L.
      • et al.
      Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China.
      Case series55 (39-66)China, Zhongnan HospitalYes221115 (52)MP 1-2 mg/kg/dABX, AVR. . .1Moderate
      Zhang et al
      • Zhang J.
      • Yu M.
      • Tong S.
      • Liu L.Y.
      • Tang L.V.
      Predictive factors for disease progression in hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      Case series38 (32-57)China, Union Hospital of Huazhong University of Science and TechnologyYes11130 (27.0). . .ABX, AVR, IVIG. . .1,2Moderate
      Zhang et al
      • Zhang Y.
      • Li H.
      • Zhang J.
      • et al.
      The clinical characteristics and outcomes of patients with diabetes and secondary hyperglycaemia with coronavirus disease 2019: a single-centre, retrospective, observational study in Wuhan.
      RCS62 ± 14.2China, Tongji HospitalYes16638 (22.8)MP, 1-2 mg/kg/d for 3-7 d; critically ill patients received MP 240-500 mg pulses/d for 3 dABX, AVR, IVIG, TCZBDiabetes5Serious
      Zhao et al
      • Zhao J.
      • Gao H.Y.
      • Feng Z.Y.
      • Wu Q.J.
      A Retrospective analysis of the clinical and epidemiological characteristics of COVID-19 patients in Henan Provincial People’s Hospital, Zhengzhou, China.
      RCS56.0 (31.5-66)China, Henan Provincial People’s HospitalNo2913 (44.8). . .ABX, AVR, IVIG, TCM. . .1Serious
      Zhao et al
      • Zhao X.Y.
      • Xu X.X.
      • Yin H.S.
      • et al.
      Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.
      RCS46China, Jingzhou Central HospitalNo9179 (86.8). . .ABX, AVR, IVIG. . .1Moderate
      Zheng et al
      • Zheng C.
      • Wang J.
      • Guo H.
      • et al.
      Risk-adapted treatment strategy for COVID-19 patients.
      Case series59-62 (range)China, Wuhan Union HospitalYes5521 (38.1)MP 0.5-1 mg/kg/d for 5 dABX, AVR. . .1,2Moderate
      Zheng et al
      • Zheng Y.
      • Sun L.J.
      • Xu M.
      • et al.
      Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.
      RCS66 (58-76)China, Hangzhou 12 Wenzhou Central HospitalNo3433 (97.0). . .ABX, AVR, IVIGICU1,2Moderate
      Zhou et alRCS56 (46-67)China, Jin Yin-tan HospitalYes19157 (29.8). . .ABX, AVR, IVIG. . .3Moderate
      Data are presented as No. (%), mean ± SD, or median (interquartile range), unless otherwise indicated. ABX = antibiotics; AVR = antivirals; COVID-19 = coronavirus disease 2019; CPT = convalescent plasma transfusion; CS = corticosteroids; HCQ = hydroxychloroquine; IVIG = IV immunoglobulin; MP = methylprednisolone; OIM = other immunomodulators; PSM = propensity score matching; RCS = retrospective cohort study; TCM = traditional Chinese medicine; TCZB = tocilizumab.
      a Outcomes: 1 = severity, ICU admission, or both; 2 = mechanical ventilation; 3 = mortality; 4 = viral clearance; and 5 = adverse events.

       Overall Corticosteroid Use in COVID-19

      A total of 21,350 COVID-19 patients were included in the 73 studies; 4,618 (21.6%) patients received corticosteroids. The median or mean age of patients in these studies ranged from 39 years (interquartile range, 32-54 years) to 88 years (interquartile range, 86.6-90 years). The use of corticosteroids across studies was highly variable and ranged from 1% to 97%, with a median corticosteroid use of 35.5% across studies. Most studies were generated in China (n = 55 [75.3%]), followed by the United States (n = 4 [5.4%]) and Spain (n = 4 [5.4%]). The Chinese studies totaled 43% of patients (n = 9,200) included in the meta-analysis, with 2,450 (26.6%) receiving corticosteroids. We identified at least 37 studies from China that shared institutions, locations, and time of chart review that potentially could represent overlapping patients for which sensitivity analysis was performed in the quantitative synthesis. A total of 5,655 patients shared reported institutions or regions; 1,780 (31.4%) of these received corticosteroids.

       Dose and Timing of Corticosteroid Use

      Thirty-five of 73 studies (47.9%) reported the dose or timing of corticosteroids. From these 35 studies, 26 studies (74.2%) reported using low-dose corticosteroids, four studies reported high-dose or pulse corticosteroid only, two studies (5.6%) reported mixed high-dose and low-dose regimens, and three studies (8.3%) reported a dose of unspecified corticosteroid; thus, we were unable to classify the latter group to either the low-dose or high-dose group. Seventeen studies (47.2%) reported duration of treatment, ranging from 3 to 12 days. Methylprednisolone was the most common corticosteroid reported in 26 studies (35.6%).
      Adjunctive therapies reported concomitantly with corticosteroids are reported in Table 1 and include antibiotics, antivirals, tocilizumab, immunomodulators, traditional Chinese medicine, IV immunoglobulin, and convalescent plasma. Limited information was available on medication overlap for most studies, and qualitative synthesis was not performed.

       Corticosteroid Use in Severe COVID-19

      Nineteen studies (26%) reported corticosteroid use with significant variability ranging from 1% to 100% across studies. Corticosteroid use was reported in 396 of 987 severe COVID-19 patients (40%). These numbers were interpreted as baseline characteristics rather than outcomes because of the lack of information of baseline characteristics across studies (e-Table 1).

       Corticosteroid Use in ICU-Admitted Patients

      Eighteen studies reported corticosteroid use in 807 of 1,571 COVID-19 patients admitted to the ICU (51.3%). The rate of corticosteroid use in ICU patients ranged from 13.9% to 100% across studies (e-Table 2). Two studies limited their population to patients admitted to the ICU only.
      • Montastruc F.
      • Romano C.
      • Montastruc J.L.
      • et al.
      Pharmacological characteristics of patients infected with SARS-Cov-2 admitted to intensive care unit in south of France.
      ,
      • Zheng Y.
      • Sun L.J.
      • Xu M.
      • et al.
      Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.
      Four studies from China shared similar institutions and were labeled as possible overlapping populations.

       Corticosteroid Use in Mechanically Ventilated Patients

      Twelve studies reported corticosteroid use in 230 of 652 mechanically ventilated COVID-19 patients (35.3%), with highly variable corticosteroid use reported (8.5%-100%) across studies (e-Table 3). Two studies from China had possibly overlapping populations (n = 10 and n = 18, respectively),
      • Wang Y.
      • Jiang W.
      • He Q.
      • et al.
      A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia.
      ,
      • Zhang J.
      • Yu M.
      • Tong S.
      • Liu L.Y.
      • Tang L.V.
      Predictive factors for disease progression in hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      but represented a small fraction of mechanically ventilated patients.

       SARS-CoV-2 Shedding in Corticosteroid Use

      Thirteen studies reported viral clearance in 1,482 COVID-19 patients receiving corticosteroids vs no corticosteroids. The nucleic acid test results and timing were not standardized, and the method of reporting viral clearance varied significantly among studies. Three studies that did not report corticosteroid dose concluded that patients treated with corticosteroids might have prolonged viral shedding.
      • Chen X.
      • Zhu B.
      • Hong W.
      • et al.
      Associations of clinical characteristics and treatment regimens with the duration of viral RNA shedding in patients with COVID-19.
      ,
      • Ling Y.
      • Xu S.B.
      • Lin Y.X.
      • et al.
      Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients.
      ,
      • Shen Y.
      • Zheng F.
      • Sun D.
      • et al.
      Epidemiology and clinical course of COVID-19 in Shanghai, China.
      Seven studies reported low-dose corticosteroids and viral clearance in 604 COVID-19 patients. Findings are summarized in Table 2. Five studies comprising 457 patients showed no evidence for prolonged SARS-CoV-2 viral shedding in low-dose corticosteroid administration. Xu et al
      • Xu K.
      • Chen Y.
      • Yuan J.
      • et al.
      Factors associated with prolonged viral RNA shedding in patients with coronavirus disease 2019 (COVID-19).
      reported a higher proportion of COVID-19 patients with prolonged viral shedding receiving low-dose corticosteroids; however, the duration of shedding was not reported by corticosteroids use. Only the study of Gong et al
      • Gong Y.
      • Guan L.
      • Jin Z.
      • Chen S.
      • Xiang G.
      • Gao B.
      Effects of methylprednisolone use on viral genomic nucleic acid negative conversion and CT imaging lesion absorption in COVID-19 patients under 50 years old.
      showed a significant delay in viral clearance by an average of 5 days in patients receiving low-dose corticosteroids (29.11 ± 6.61 days vs 24.44 ± 5.21; P < .05).
      Table 2Studies Reporting Viral Clearance in COVID-19 Patients Receiving Corticosteroids
      StudyAge, yRegion, HospitalPatients Receiving CorticosteroidsCorticosteroid DosageViral Clearance in Corticosteroids vs No Corticosteroids
      Fang et al
      • Fang X.W.
      • Mei Q.
      • Yang T.J.
      • et al.
      Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19.
      40 ± 12.6China, Anhui Provincial Hospital25/78 (32)MP hydrocortisone-equivalent dose, 237.5 mg/d for 7 d in general group, 250.0 mg/d for 4.5 d in severe groupMean viral clearance in nonsevere patients: corticosteroids 17.6 ± 4.9 d vs no corticosteroids 18.7 ± 7.7 d (P = .667)

      Mean viral clearance in severe patients: corticosteroids 18.8 ± 5.3 d vs no corticosteroids 18.3 ± 4.2 d (P = .84)
      Gong et al
      • Gong Y.
      • Guan L.
      • Jin Z.
      • Chen S.
      • Xiang G.
      • Gao B.
      Effects of methylprednisolone use on viral genomic nucleic acid negative conversion and CT imaging lesion absorption in COVID-19 patients under 50 years old.
      38 ± 8.9China, First Clinical Medical College of Three Gorges University18/34 (52.9)MP, 1-2 mg/kg/d gradually halved every 3 d for a total of 5-10 dMean time to negative nucleic acid: corticosteroids 29.11 ± 6.61 d vs no corticosteroids 24.44 ± 5.21 d (P < .05)
      Hu et al
      • Hu Z.L.
      • Lv Y.L.
      • Xu C.J.
      • et al.
      Clinical use of short-course and low-dose corticosteroids in patients with non-severe COVID-19 during pneumonia progression.
      46 (33-57)China, Second Hospital of Nanjing28/72 (38.8)MP, 140 mg/d for 4.54 dMedian viral clearance: corticosteroids 18 d (IQR, 14.3-23.5 d) vs no corticosteroids 17 d (IQR,12-20 d; P = .252)
      Li et al
      • Li S.
      • Hu Z.
      • Song X.
      High-dose but not low-dose corticosteroids potentially delay viral shedding of patients with COVID-19.
      . . .China, Yichang Central People’s HospitalNA/206Unspecified corticosteroids 40-80 mg/dHigh-dose corticosteroids (80 mg/d) delayed viral clearance (aHR, 0.67; 95% CI, 0.46-0.96; P = .031), but low-dose corticosteroids (40 mg/d) did not (aHR, 0.72; 95% CI, 0.48-1.08; P = .11)
      Xu et al
      • Xu K.
      • Chen Y.
      • Yuan J.
      • et al.
      Factors associated with prolonged viral RNA shedding in patients with coronavirus disease 2019 (COVID-19).
      52 (43-63)China, First Affiliated Hospital and the Shenzhen Third People’s Hospital64/113 (56.6)MP, < 1.5 mg/kg/dViral shedding > 15 d was seen more frequently in patients receiving corticosteroids, 64.5% vs 40.5% (P = .025)
      Yuan et al
      • Yuan M.
      • Xu X.
      • Xia D.
      • et al.
      Effects of corticosteroid treatment for non-severe COVID-19 pneumonia: a propensity score-based analysis.
      48.1 (33-64)China, Central Hospital of Wuhan35/70 (50)MP, median dose 44.6 mg/dMedian viral clearance: corticosteroids 20.3 d (IQR, 15.2-24.8 d) vs no corticosteroids 19.4 d (IQR, 11.5-28.3 d; P = .669)
      Zha et al
      • Zha L.
      • Li S.
      • Pan L.
      • et al.
      Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19).
      39 (32-54)China, Anhui Provincial Hospital11/31 (35.4)MP, 40 mg once or twice daily for 5 dMedian viral clearance: corticosteroids 15 d (IQR, 14-16 d) vs no corticosteroids 14 d (IQR, 11-17; P = .87)
      Data are presented as No./Total No. (%), mean ± SD, or median (IQR), unless otherwise indicated. aHR = adjusted hazard ratio; COVID-19 = coronavirus disease 2019; IQR = interquartile range; MP = methylprednisolone.

       Corticosteroid Safety and Adverse Events

      Five studies reported adverse events related to corticosteroid therapy in COVID-19 patients. Unfortunately, details on severity, predisposing risk factors, or other details were not available in these studies. Giacobbe et al
      • Giacobbe D.R.
      • Battaglini D.
      • Ball L.
      • et al.
      Bloodstream infections in critically ill patients with COVID-19.
      reported bloodstream infection in 19 of 24 patients receiving corticosteroids or corticosteroids with tocilizumab vs in 26 of 54 patients who did not receive corticosteroids (P = .002). Huang et al
      • Huang C.
      • Wang Y.
      • Li X.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      reported secondary infection in three of nine patients receiving corticosteroids vs 1 of 32 patients not receiving corticosteroids. Wang et al
      • Wang J.
      • Yang Q.
      • Zhang P.
      • Sheng J.
      • Zhou J.
      • Qu T.
      Clinical characteristics of invasive pulmonary aspergillosis in patients with COVID-19 in Zhejiang, China: a retrospective case series.
      reported COVID-19-associated pulmonary aspergillosis in 6 of 63 patients (9.5%) receiving corticosteroids vs 2 of 41 patients (4.8%) not receiving corticosteroids. Yuan et al
      • Yuan M.
      • Xu X.
      • Xia D.
      • et al.
      Effects of corticosteroid treatment for non-severe COVID-19 pneumonia: a propensity score-based analysis.
      reported no infections in either the group receiving corticosteroids or the group receiving no corticosteroids. Zhang et al
      • Zhang Y.
      • Li H.
      • Zhang J.
      • et al.
      The clinical characteristics and outcomes of patients with diabetes and secondary hyperglycaemia with coronavirus disease 2019: a single-centre, retrospective, observational study in Wuhan.
      reported hyperglycemia in 23 of 38 patients (60%) receiving corticosteroids vs 59 of 128 patients (46%) not receiving corticosteroids.

       Quantitative Analysis

      Thirty-three of 73 studies reported mortality outcomes in patients receiving corticosteroids with a comparison group not receiving corticosteroids. One study was excluded (Ding et al
      • Ding Q.
      • Lu P.P.
      • Fan Y.H.
      • Xia Y.J.
      • Liu M.
      The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and influenza virus in Wuhan, China.
      ) owing to a critical risk of bias because it described outcomes in patients with COVID-19 and influenza coinfection.
      We identified 32 studies comparing glucocorticoids with not administering glucocorticoids in COVID-19 patients (Fig 3). Heterogeneity was too high (I2 = 90%) to combine meaningfully for meta-analysis in this set with statistically significant heterogeneity (P < .00001; e-Fig 1), with an overall detrimental effect of corticosteroids in mortality of (OR, 2.30; 95% CI, 1.45-3.63; P = .0004).
      Figure thumbnail gr3
      Figure 3Forest plot showing mortality outcomes in coronavirus disease 2019 patients receiving corticosteroids vs those not receiving corticosteroids.
      We identified eight studies reporting mortality outcomes exclusively in severely ill COVID-19 patients (ARDS, mechanically ventilated, or critically ill) receiving corticosteroids vs those who did not (Fig 4). Low heterogeneity (I2 = 29%; heterogeneity P = .19; e-Fig 2) was found, with favorable odds of mortality (fixed-effect model) among those receiving corticosteroids, achieving statistical significance (OR, 0.65; 95% CI, 0.51-0.83; P = .0006).
      Figure thumbnail gr4
      Figure 4Forest plot showing mortality outcomes in severely ill coronavirus disease 2019 patients receiving corticosteroids vs those not receiving corticosteroids.
      We also identified two studies that used high-dose corticosteroid protocols and 15 studies specifying low-dose regimens. Among those studies reporting higher doses (Fig 5), low heterogeneity was found (I2 = 0%; e-Fig 3), but the odds of mortality (random-effects model) among those receiving high-dose corticosteroids did not achieve statistical significance (OR, 0.57; 95% CI, 0.27-1.23; P = .16).
      Figure thumbnail gr5
      Figure 5Forest plot showing mortality outcomes in coronavirus disease 2019 patients receiving high-dose corticosteroids vs those not receiving corticosteroids.
      Low-dose corticosteroids were assorted with moderate heterogeneity (I2 = 60%; e-Fig 4) and also with a nonsignificant odds (random-effects model) for mortality (OR, 1.13; 95% CI, 0.71-1.8; P = .61) (Fig 6). Because of concern of possible overlap of some study populations, several iterations of sensitivity analyses were performed, serially removing studies in which the same patient may have been reported more than once. None of these resulted in a meaningful change in heterogeneity metrics, nor in the odds of benefit or harm reaching statistical significance.
      Figure thumbnail gr6
      Figure 6Forest plot showing mortality outcomes in coronavirus disease 2019 patients receiving low-dose corticosteroids vs those not receiving corticosteroids.

      Discussion

      In this systematic review and meta-analysis, we identified 73 comparative studies describing the experience of corticosteroids in COVID-19, which represents a considerable number of publications for a relatively new disease. Also, significant potential population overlap exists in studies generated in China that should be considered in future syntheses.
      Overall, 21.6% of COVID-19 patients received corticosteroids in our analysis, highlighting the wide use of corticosteroids, despite the lack of well-established indications or high-quality studied in favor or against corticosteroids. Almost half of studies reported dose or timing of corticosteroids, with low-dose methylprednisolone being the most common approach. Corticosteroids were used widely in mechanically ventilated patients (35.3%), ICU patients (51.3%), and severe COVID-19 patients (40%), which potentially could reflect a general practice, rather than the impact of corticosteroids in severity of disease, pending high-quality studies. Also, evidence emerged in our synthesis showing that low-dose corticosteroids do not have significant impact in duration of SARS-CoV-2 viral shedding, in contrast with data from SARS and MERS.
      • Li H.
      • Chen C.
      • Hu F.
      • et al.
      Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis.
      Severely ill COVID-19 patients showed a statistically significant mortality benefit from corticosteroids (OR, 0.65; 95% CI, 0.51-0.83; P = .0006) in our analysis. No beneficial or harmful effect was noted among high-dose or low-dose corticosteroids recipients. Overall mortality of COVID-19 patients receiving corticosteroids was higher than in patients not receiving corticosteroids, with the caveat that the population studied was too heterogeneous, possibly because of selection bias among studies, with corticosteroids administered to patients with grave prognosis at baseline. The vast majority of studies did not report baseline characteristics of the group receiving corticosteroids.
      Side effects in COVID-19 patients receiving corticosteroids included superinfection, COVID-19-associated pulmonary aspergillosis, and hyperglycemia; however, the literature on side effects is lacking. Well-known corticosteroid side effects such as hyperglycemia and superimposed infections have been reported in coronavirus diseases.
      • Russell C.D.
      • Millar J.E.
      • Kenneth Baillie J.
      Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.
      ,
      • Stockman L.J.
      • Bellamy R.
      • Garner P.
      SARS: systematic review of treatment effects.
      However, the largest meta-analysis on low-dose corticosteroid use in patients with sepsis did not show an increased risk of superinfection (n = 5,356; RR, 1.06; 95% CI, 0.95-1.19; P = .27) or gastroduodenal bleeding (n = 5,171; RR, 1.07; 95% CI, 0.85-1.35; P = .55), although an increased risk of hyperglycemia (RR, 1.20; 95% CI, 1.10-1.31; P < .0001), hypernatremia (RR, 1.66; 95% CI, 1.34-2.06; P < .0001), and muscle weakness (RR, 1.21; 95% CI, 1.01-1.44; P = .04) was found.
      • Annane D.
      • Bellissant E.
      • Bollaert P.E.
      • et al.
      Corticosteroids for treating sepsis in children and adults.
      Although the role of corticosteroids in COVID-19 remains unclear, evidence suggests benefits of corticosteroids in ARDS. A meta-analysis published in 2018 in patients with ARDS receiving corticosteroids (n = 494 for hydrocortisone and n = 272 for methylprednisolone) showed reduced time to extubation, duration of hospitalization, and mortality, with an increase in ventilation-free days and ICU-free days.
      • Hashimoto S.
      • Sanui M.
      • Egi M.
      • et al.
      The clinical practice guideline for the management of ARDS in Japan.
      The proposed doses for methylprednisolone in this setting are 1 to 2 mg/kg bolus followed by the same daily dose at an infusion rate of 10 mL/h daily with a gradual taper.
      • Meduri GU
      • Siemieniuk R.A.C.
      • Ness R.A.
      • Seyler S.J.
      Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS.
      ,
      • Villar J.
      • Ferrando C.
      • Martínez D.
      • et al.
      Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.
      Based on similar information, the Society of Critical Care Medicine/the European Society of Intensive Care Medicine guidelines also recommended the early use of corticosteroids in moderate to severe ARDS.
      • Annane D.
      • Pastores S.M.
      • Rochwerg B.
      • 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.
      However, the quality of evidence supporting these findings has been questioned.
      • Griffiths M.J.D.
      • McAuley D.F.
      • Perkins G.D.
      • et al.
      Guidelines on the management of acute respiratory distress syndrome.

       Study Limitations

      Our qualitative synthesis was limited by the detail of reported patients’ characteristics among studies. Also, a lack of details in dosing, indication, and timing of corticosteroids was found across studies. Potential for population overlap also was noted in most studies generated in China. Although this was mitigated by sensitivity analysis in the quantitative synthesis, it is difficult to assess the impact of the overlap in the qualitative synthesis. Our qualitative synthesis was limited by the heterogeneity of studies included in high-dose and low-dose corticosteroids.

       International Recommendations for Corticosteroids in COVID-19

      The international recommendations for corticosteroid use in COVID-19 are summarized in Table 3. The Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment published by the Chinese National Health Committee set the initial recommendations for methylprednisolone in patients with progressive clinical deterioration.
      National Health Commission of the People’s Republic of China
      Chinese COVID-19 guidelines. National Health Commission of the People’s Republic of China website.
      Other international societies and organizations are incorporating recommendations for corticosteroids in COVID-19 based on disease severity, including the American Thoracic Society,
      • Bai C.
      • Chotirmall S.H.
      • Rello J.
      • et al.
      Updated guidance on the management of COVID-19: from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020).
      the Infectious Disease Society of America,
      • Bhimraj A.
      • Morgan R.L.
      • Shumaker A.H.
      • et al.
      Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America website.
      the National Institutes of Health of the United States,
      National Institutes of Health
      COVID-19 treatment guidelines, corticosteroids. National Institutes of Health website.
      the Surviving Sepsis Campaign,
      • Alhazzani W.
      • Møller M.H.
      • Arabi Y.M.
      • et al.
      Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19).
      and the World Health Organization.
      World Health Organization
      Corticosteroids for COVID-19. World Health Organization website.
      Table 3Summary of International Recommendations of Corticosteroid Use in COVID-19
      OrganizationDateCOVID-19 PopulationRecommended DoseLevel of EvidenceCorticosteroid Use Recommendation
      Chinese National Health Committee (7th version)3/4/2020Progressive deterioration of oxygenation indicators, rapid radiographic progression, and excessive activation of inflammatory responseMP, 1-2 mg/kg/d for 3-5 dExpert consensusFavors corticosteroids
      The Surviving Sepsis Campaign: Society of Critical Care Medicine/European Respiratory Society3/28/2020Patients on mechanical ventilation and ARDSHydrocortisone 200 mg/dWeak recommendation, low-quality evidenceFavors corticosteroids
      Infectious Disease Society of America9/25/2020Critically ill patients with severe disease, ie, SpO2 ≤ 94% on room air, those who require supplemental oxygen, mechanical ventilation, or ECMODexamethasone 6 mg for 10 d (or until discharge if earlier) or equivalent corticosteroids doseStrong (critically ill)/conditional (severe disease) recommendation, moderate certainty of evidenceFavors corticosteroids
      Patients without hypoxemia, not requiring supplemental oxygen. . .Conditional recommendation, low certainty of evidenceAgainst corticosteroids
      National Institutes of Health8/27/2020Patient on mechanical ventilation or requiring oxygen supplementationDexamethasone 6 mg/d (or alternative corticosteroids) for up to 10 d or until hospital dischargeAI
      a Grade A, level 1: strong recommendation, high-quality evidence.
      (mechanically ventilated patients), BI
      b Grade B, level 1: strong recommendation, moderate-quality evidence.
      (requiring oxygen)
      Favors corticosteroids
      Patients not requiring oxygen supplementation. . .AI
      a Grade A, level 1: strong recommendation, high-quality evidence.
      Against corticosteroids
      World Health Organization
      c World Health Organization is in the process of updating treatment guidelines to include dexamethasone or other corticosteroids.
      9/2/2020Patients with severe disease and critically illDexamethasone 6 mg/d or hydrocortisone 50 mg every 8 h for 7-10 dStrong recommendation, moderate certainty evidenceFavors corticosteroids
      American Thoracic Society4/3/2020No suggestion. . .Expert consensusAgainst corticosteroids
      ECMO = extracorporeal membrane oxygenation; MP = methylprednisolone; SpO2 = oxygen saturation.
      a Grade A, level 1: strong recommendation, high-quality evidence.
      b Grade B, level 1: strong recommendation, moderate-quality evidence.
      c World Health Organization is in the process of updating treatment guidelines to include dexamethasone or other corticosteroids.

      Interpretation

      The current evidence does not support indiscriminate corticosteroid administration in patients with COVID-19. However, severely ill COVID-19 patients may benefit from corticosteroids based on our findings. The potential role for corticosteroids as an immunomodulatory agent in COVID-19 needs to be explored further in clinical trials. This is particularly important in resource-limited settings where targeted immunomodulators may not be readily available or affordable.

      Acknowledgments

      Author contributions: All the authors assume responsibility for all content of the manuscript. All the authors contributed significantly to the conceptualization, drafting, and final editing of the manuscript.
      Financial/nonfinancial disclosures: None declared.
      Additional information: The e-Appendix, e-Figures, and e-Tables can be found in the Supplemental Materials section of the online article.

      Supplementary Data

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