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.
Corticosteroids use is reported widely in COVID-19 patients worldwide, although their impact on clinically relevant outcomes in specific populations remains unclear.
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Our study findings show mortality benefit for severely ill COVID-19 patients receiving corticosteroids.
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Low-dose corticosteroids do not seem to have a significant impact in the duration of SARS-CoV-2 viral shedding.
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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.
By March 11, 2020, the outbreak had affected millions worldwide, and the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)
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
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
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,
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.
Efficacy and safety of corticosteroids in COVID-19 based on evidence for COVID-19, other coronavirus infections, influenza, community-acquired pneumonia and acute respiratory distress syndrome: a systematic review and meta-analysis.
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.
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 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
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.
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.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
Clinical characteristics and outcomes of older patients with coronavirus disease 2019 (COVID-19) in Wuhan, China (2019): a single-centered, retrospective study.
Effects of methylprednisolone use on viral genomic nucleic acid negative conversion and CT imaging lesion absorption in COVID-19 patients under 50 years old.
Extracorporeal membrane oxygenation in the treatment of severe pulmonary and cardiac compromise in coronavirus disease 2019: experience with 32 patients.
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.
Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression.
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.
The clinical value of two combination regimens in the management of patients suffering from Covid-19 pneumonia: a single centered, retrospective, observational study.
The clinical characteristics and outcomes of patients with diabetes and secondary hyperglycaemia with coronavirus disease 2019: a single-centre, retrospective, observational study in Wuhan.
A Retrospective analysis of the clinical and epidemiological characteristics of COVID-19 patients in Henan Provincial People’s Hospital, Zhengzhou, 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
Clinical characteristics and outcomes of older patients with coronavirus disease 2019 (COVID-19) in Wuhan, China (2019): a single-centered, retrospective study.
Effects of methylprednisolone use on viral genomic nucleic acid negative conversion and CT imaging lesion absorption in COVID-19 patients under 50 years old.
Extracorporeal membrane oxygenation in the treatment of severe pulmonary and cardiac compromise in coronavirus disease 2019: experience with 32 patients.
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.
Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression.
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.
The clinical value of two combination regimens in the management of patients suffering from Covid-19 pneumonia: a single centered, retrospective, observational study.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
The clinical characteristics and outcomes of patients with diabetes and secondary hyperglycaemia with coronavirus disease 2019: a single-centre, retrospective, observational study in Wuhan.
A Retrospective analysis of the clinical and epidemiological characteristics of COVID-19 patients in Henan Provincial People’s Hospital, Zhengzhou, China.
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.
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),
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.
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
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
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
Study
Age, y
Region, Hospital
Patients Receiving Corticosteroids
Corticosteroid Dosage
Viral Clearance in Corticosteroids vs No Corticosteroids
MP hydrocortisone-equivalent dose, 237.5 mg/d for 7 d in general group, 250.0 mg/d for 4.5 d in severe group
Mean 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)
Effects of methylprednisolone use on viral genomic nucleic acid negative conversion and CT imaging lesion absorption in COVID-19 patients under 50 years old.
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
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
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
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
) 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 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 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 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 6Forest plot showing mortality outcomes in coronavirus disease 2019 patients receiving low-dose corticosteroids vs those not receiving corticosteroids.
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.
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.
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.
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.
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.
Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS.
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.
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.
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,
Updated guidance on the management of COVID-19: from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020).
Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America website.
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.
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).
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
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.
Efficacy and safety of corticosteroids in COVID-19 based on evidence for COVID-19, other coronavirus infections, influenza, community-acquired pneumonia and acute respiratory distress syndrome: a systematic review and meta-analysis.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
Clinical characteristics and outcomes of older patients with coronavirus disease 2019 (COVID-19) in Wuhan, China (2019): a single-centered, retrospective study.
Effects of methylprednisolone use on viral genomic nucleic acid negative conversion and CT imaging lesion absorption in COVID-19 patients under 50 years old.
Extracorporeal membrane oxygenation in the treatment of severe pulmonary and cardiac compromise in coronavirus disease 2019: experience with 32 patients.
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.
Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression.
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.
The clinical value of two combination regimens in the management of patients suffering from Covid-19 pneumonia: a single centered, retrospective, observational study.
The clinical characteristics and outcomes of patients with diabetes and secondary hyperglycaemia with coronavirus disease 2019: a single-centre, retrospective, observational study in Wuhan.
A Retrospective analysis of the clinical and epidemiological characteristics of COVID-19 patients in Henan Provincial People’s Hospital, Zhengzhou, China.
Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS.
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.
Updated guidance on the management of COVID-19: from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020).
Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America website.
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