Corticosteroid use in COVID-19 patients: A systematic review and meta-analysis on clinical outcomes

Abstract

Background In the current SARS-CoV-2 pandemic, there has been worldwide debate on the use of corticosteroids in COVID-19. In a recent RCT (RECOVERY trial), a reduced 28-day mortality in patients requiring oxygen therapy or mechanical ventilation evaluating the effect of dexamethasone was shown. Their results have led to considering amendments in guidelines or actually already recommending corticosteroid use in COVID-19. However, the supposed effect of corticosteroids on mortality and viral clearance remains unclear and a clear evidence-based therapeutic strategy is still lacking.

Objectives The aim of this systematic review and meta-analysis was to evaluate the effect of corticosteroids on mortality, viral clearance and secondary outcomes in COVID-19 patients.

Data source, study eligibility, participants, interventions

A systematic literature search was performed across Medline/PubMed, Embase, and Web of Science from 1st of December 2019 until 10th of July 2020, according to the PRISMA guidelines. RCTs and cohort studies reporting in English, on ≥15 adult COVID-19 patients, treated with any type of corticosteroid therapy were included. Studies on pregnant women, reviews and with a NOS (Newcastle Ottawa Scale for validity assessment of observational studies) score of ≤4 were excluded.

Results Twenty-two articles were included, covering 9,760 patients. In eight studies, the effect of corticosteroid use was quantified. The pooled estimate of the observational studies supported the positive effect on mortality of corticosteroid therapy in COVID-19 as reported in the RECOVERY trial, in respiratory compromised COVID-19 patients, i.e. oxygen or mechanical ventilation dependent or with ARDS. The overall pooled estimate (observational studies and the RCT) showed reduced mortality in the corticosteroid group (relative risk 0.55 [95% CI 0.27-0.83]). Furthermore, mechanical ventilation rate seemed lower in corticosteroid treated COVID-19 patients, though no definite conclusions could be drawn because of a low number of studies. With regard to potential side effects of corticosteroids, the effect on viral clearance duration was ambiguous, i.e. prolonged in 4 of 9 and without effect in 5 of 9 studies.

Conclusions It appears safe with respect to viral clearance to administer corticosteroids in respiratory compromised COVID-19 patients with possible improvement in mortality and conflicting effects on viral clearance.  

Background

Since the start of the outbreak, Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS-CoV-2, has spread globally from Wuhan, China. 16,465,707 cases have been reported and 653,862 people have died as of July 28th.[1] Many countries have been affected, causing immense stress on healthcare systems worldwide. This is the third epidemic caused by a coronavirus, after Severe Acute Respiratory Syndrome (SARS) in 2002 and Middle East Respiratory Syndrome (MERS) in 2012.[2, 3] The clinical presentation ranges from asymptomatic or mild disease to severe pneumonia in which the most severe cases deteriorate with acute respiratory distress syndrome (ARDS) requiring prolonged mechanical ventilation.[4, 5] Approximately 16–35% develop severe pneumonia, 2–17% need mechanical ventilation and the case fatality rate is 1.4–15%.[5–7] In the pathophysiology of severe COVID-19, the host immune response plays a key role and it has become evident that COVID-19 pneumonia is associated with both hyperinflammation and immunoparalysis.[8] A clinical presentation of massive vascular inflammation, disseminated coagulation, shock, and ARDS is frequently triggered.[9–11]

Although much has been written on this topic in recent months, a clear evidence-based therapeutic strategy is still lacking.[8, 12] Several therapeutic interventions to mitigate the inflammatory response have been studied but none of them, among which corticosteroids, showed an irrefutable beneficial effect. Bearing the pathophysiology in mind, corticosteroids might have beneficial effects in overcoming both hyperinflammation and ARDS.[4, 13–15] Furthermore, they could serve as an easily accessible and affordable treatment option. The use of corticosteroids, however, is controversial because of known adverse effects such as delayed viral clearance, opportunistic infections and suppression of the hypothalamic-pituary-adrenal axis.[2, 16, 17] Earlier studies done in MERS-CoV and SARS-CoV showed delayed viral clearance, opportunistic infections and hyperglycemia.[18–20] Thus, until recently (June 25th 2020), both the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) did not recommend the routine use of systemic corticosteroids in COVID-19 patients.[13, 21] Additionally, the Surviving Sepsis Guideline on management of COVID-19 recommends administration of steroids only in patients with severe COVID-19 on mechanical ventilation with ARDS, and in patients with COVID-19 and refractory shock.[22] Furthermore, anticipating the actual evidence from randomized trials, in some national guidelines, e.g. in China, corticosteroids have already been adopted as a treatment in COVID-19 patients with severe disease progression.[11]

Recently, Horby et al. found a significantly reduced 28-day mortality in patients requiring oxygen therapy or mechanical ventilation in a pre-published randomized controlled trial evaluating the effect of dexamethasone.[23] Their results have led to considering amendments or actually recommending corticosteroid use by infection control regulatory bodies worldwide.[24, 25] However, the supposed effect of corticosteroids on viral clearance and optimal timing, dose, and type of corticosteroid administration remains unclear. As COVID-19 knowledge is rapidly expanding and literature on this topic is updated every day, this calls for a state-of-the-art analysis of current literature. Therefore the aim of this systematic review is to provide an overview of studies conducted until July 10th, 2020 on the effectiveness of corticosteroids in COVID-19 on mortality, viral clearance and secondary outcomes.

Methods

Data sources and search strategy

A systematic review according to the PRISMA guidelines was conducted.[26] A comprehensive systematic search was conducted for published studies in Medline/PubMed, Embase, and Web of Science from December 1^st 2019 to July 10^th 2020. The search strategy consisted of the components “COVID-19”, “intensive care”, and “corticosteroids” (Appendix I). 

Eligibility

RCTs and cohort studies assessing the effect of corticosteroids in COVID-19 were eligible if they met the following inclusion criteria: adult patients (age ≥ 18 years), COVID-19 patients diagnosed by reverse transcriptase polymerase chain reaction (RT-PCR), reporting on outcome measures in relation to corticosteroid treatment. Studies concerning pregnant women or children, reviews, case series including less than 15 patients and articles that were not available in English were excluded.[27] 

Study selection

Suitable studies were selected in two stages. First, three independent reviewers screened all selected titles and abstracts (EH, KN, PB). If there was consensus that a study was unsuitable for inclusion, it was excluded. Next, the full-text articles were screened independently by two authors (EH, KN, or PB) and included if both authors agreed. If needed, the article was discussed with the third reviewer until consensus was reached. After screening full-text articles, the Newcastle Ottawa Scale was used for validity assessment of observational studies.[28,29] The NOS score ranges from 0 (low quality) to 9 (high quality) points. Studies scoring four points or less on the NOS score were excluded. 

Data extraction and quality analysis

After selection, data were extracted by one and checked by a second investigator (EH, KN, PB). Quality analysis on each study in the pooled data analysis was described: risk of bias was assessed on six domains (random sequence generation, concealment of allocation, blinding, selective outcome reporting, incomplete outcome data and other).[30,31]

For each study, the author, journal, country, city and hospital in which the study was conducted, date of start of inclusion, study population, study groups, type, dose, route of administration of corticosteroid, median time before corticosteroid initiation, duration of administration, primary and secondary outcomes and adverse events were extracted.

Primary outcomes were mortality and viral clearance. Secondary outcomes were change in oxygenation (either descriptive or actual change in PaO₂/FiO₂), duration of mechanical ventilation and length of hospital stay. 

Data analysis and reporting

For the effect of corticosteroids on mortality, a pooled estimate was calculated and graphically summarized in a forest plot, separately for observational studies, the randomized trial and their combined effects. When available, the adjusted odds ratio (OR) or hazard ratio (HR) from the cohort studies were used for pooling to reduce confounding. To allow studies to have a different underlying effect, a random effects model was used. I² statistics was used to quantify heterogeneity. STATA 16.0 was used to perform data analysis.[32]

Results

Our search yielded 788 unique studies (Figure 1). During the conceptualization of this manuscript, the preliminary results of the RECOVERY trial in the United Kingdom were published,[23] which led to amendments in CDC guidelines and to consideration of amendments by WHO on corticosteroid therapy. Therefore, this trial was judged to be so relevant that it was included after the original database search. After qualification of title and abstract, 30 studies were selected for full review. After exclusion based on low NOS score or the inability to extract risk estimates, 22 studies, studying 9,760 subjects, were included (Table 1, 2). 

Study characteristics (Table 1)

Seventeen of the 22 studies originated from China. The inclusion period of patients ranged from late December 2019 until June 2020.

Most studies (20/22) were retrospective observational studies, except for Fadel et al., who conducted a quasi-experimental study with a historical control group[33] and Horby et al., who performed a large randomized controlled trial (RCT).[23] The study populations varied from hospitalized patients (19/22) to patients admitted to the Intensive Care Unit (ICU) (2/22), and one study included discharged patients for viral clearance assessment. The median age of patients ranged from 34 to 72 years. The severity of illness was generally assessed through the guideline of the National Health Commission of the People's Republic of China and ranged from mild to critically ill.[34,35] The median NOS score of the included studies was 6 (5-8) points. The risk of bias table is depicted in Figure 2. All observational studies were prone for selection bias (e.g. indication bias)  and in three studies follow up time was too short to allow all patients to have reached their endpoint with 6.5% to 75.6% of patients remaining hospitalized.[33,37,42] 

Corticosteroid therapy (see also Table 2)

In the 22 included studies, corticosteroid regimen was very diverse with respect to type, dose, duration, and median time of initiation of corticosteroid therapy after admission. In all studies, except two,[23,33] more severely ill patients were more likely to receive corticosteroids.
The indication for corticosteroids was reported in 7/22 studies and varied: most frequently it comprised (a combination of) worsening oxygenation, severe radiological findings, ICU admission, or persistence of inflammatory symptoms.[33,38-43] The median time of initiation after admission was reported in 8/22 studies and varied from 24 hours after hospital admission,[44] immediately after ICU admission [43] to approximately eight to fourteen days after onset of symptoms.[23,41,42,45-47] One study compared early (average 2 days after hospital admission) to late corticosteroid administration (average 5 days after hospital admission).[33]

Methylprednisolone was the most frequently used corticosteroid (13/22 studies).[33,37-40,42-44,46,48-51] In two studies methylprednisolone, hydrocortisone, or dexamethasone was used.[36,41] Ling et al. used prednisolone or dexamethasone,[52] and Horby et al. reported on dexamethasone use.[23] The type of steroid was not reported in the remaining five studies.[45,47,53-55]. In most studies a low dose methylprednisolone was administered, ranging from 0.5 to 2 mg/kg body weight per 24 hours.[33,38,40,42,43,51] Horby et al. administered 6 mg dexamethasone per 24 hours (equivalent of 30 mg methylprednisolone per 24 hours).[23] Only Liu et al. reported a single high dose up to 500 mg methylprednisolone.[39] The duration of corticosteroid therapy varied from 3 to 10 days except for Liu et al., who administered a single pulse dose. 

Mortality (see also Table 2)

Fourteen studies reported mortality, including in-hospital and 28-day mortality. In four of these, mortality was only described in the overall study population and not specified for steroid or non-steroid study groups.[41,51,54,55] Two studies reported that corticosteroid treatment did not significantly affect mortality, without the possibility to quantify the effect.[42,43]

In the remaining eight studies, the risk of corticosteroid use was quantified, and these were included to calculate the pooled estimate.[23,33,36,37,40,46,48,50] The overall pooled estimate (observational studies and the RCT) showed a favorable outcome in the corticosteroid group (relative risks RR 0.55, 95% CI 0.27-0.83, random effects) (Figure 2). 

In four of these eight studies, a beneficial effect on mortality was demonstrated.[23,33,37,46] Horby et al. demonstrated in a RCT of 6,425 patients that dexamethasone reduced mortality among patients receiving oxygen or invasive mechanical ventilation at allocation of treatment: dexamethasone reduced mortality by one-third in patients who received invasive mechanical ventilation (RR 0.64, 95% CI 0.51 to 0.81) and by one-fifth in patients receiving oxygen (RR 0.82, 95% CI 0.72 to 0.94). No positive effect was found in patients who did not receive respiratory support.[23] Wu et al. found in a study of 201 patients with ARDS that administration of methylprednisolone (dose and duration not reported) reduced the risk of death (HR 0.38, 95%CI 0.20-0.72).[37] Patients developing ARDS were more likely to receive methylprednisolone compared to patients who did not develop ARDS (59.5% vs. 10.3%). Fadel et al. studied 213 patients with moderate to severe COVID-19 and found that early corticosteroid treatment, consisting of three days of systemic methylprednisolone 0.5-1 mg/kg/day, reduced mortality from 26.3% to 13.6% when compared to standard of care in moderate to severe patients (p=0.024).[33] Fernandez-Cruz et al. reported lower mortality in patients with COVID-19 pneumonia complicated with ARDS and/or a hyperinflammatory syndrome treated with corticosteroids (HR 0.36, 95% CI 0.14 to 0.93, p=0.04).[46] 

In the other four studies, no significant difference in mortality rates between steroid and non-steroid groups,[36,40,48] or even an increased risk in the group that received corticosteroids was demonstrated.[50] However, Lu et al. did note that every increase of 10 mg in hydrocortisone equivalent dosage was associated with a 4% elevation of the mortality risk (HR 1.04, 95% CI 1.01-1.07).[36] 

Viral clearance

Nine of 22 studies reported the effect of corticosteroids on viral RNA clearance. In 5/22 studies, time to viral clearance was not influenced by methylprednisolone treatment: Xu et al. (adjusted OR 1.38, 95% CI 0.52-3.65, p=0.519), Fang et al. (18.8 ± 5.3 vs. 18.3 ± 4.2 days, p=0.84), Shi et al. (adjusted HR 1.00 (0.53-1.89), p=0.990), Liu et al. (10.0 ± 5.3 days vs. 10.0 ± 7.9 days, p>0.05), and Zha et al. (15 (14-16) days vs. 14 (11-17) days, p=0.87).[39,44,47,49,51]

Four studies found that corticosteroids delayed viral clearance, i.e. Ling et al. (15 days vs. 8.0 days in pharyngeal swab, p= 0.013), Gong et al. (29.11 ± 6.61 days vs. 24.44 ± 5.21 days, p=0.03), Chen et al. (adjusted HR 0.60 (0.39-0.94), p=0.024), and Shen et al. (18 days vs. 13 days, p=0.003), although Shen et al. only observed delay in blood samples, not in oropharyngeal swabs.[38,50,52,53] Three did not adjust for confounders.[38,50,52]

The additional information possibly affecting viral clearance, i.e. timing, dose, and duration of corticosteroid therapy, and study population, was not consistently reported nor did show a consistent trend (Table 1 and 2). 

Secondary outcomes (see also table 2)

The most frequently reported secondary outcomes were oxygenation (n=7 studies), use of mechanical ventilation (n=6 studies), and length of hospital stay (n=7 studies).

Concerning oxygenation, large heterogeneity between study results was observed. Oxygenation was described as SpO2, SaO2, or SpO2/FiO2 ratio, and different associations of corticosteroid use and oxygenation were reported, without providing exact numbers.[39-41,43] Lu et al. and Fernandez-Cruz et al. reported significant favorable effects of corticosteroid therapy on oxygenation.[36,46]

In four of six studies, positive effects of corticosteroids on the need for mechanical ventilation were reported. Horby et al. described that need for invasive mechanical ventilation was reduced from 7.8% to 5.7% (RR 0.77, 95% CI 0.62-0.95) by dexamethasone treatment.[23] Wang et al. described that patients who had received corticosteroids less often required mechanical ventilation (11.5% of patients with methylprednisolone vs. 35% of patients without methylprednisolone, p=0.05).[40] Similarly, Fadel et al. described that the development of respiratory failure requiring mechanical ventilation decreased from 36.6% in the standard care group to 21.7% in the early corticosteroid group (p=0.025).[33] Chroboczek et al. reported a risk reduction of 47.1% (95% CI -71.8 to -22.5) of intubation after unspecified corticosteroid therapy in a cohort of 70 patients.[45]

Regarding hospital length of stay (LOS), various effects of corticosteroids were reported. Fadel et al. found a significant decrease in the early corticosteroids group compared to standard of care (5 (3-7) vs. 8 (5-14) days, p<0.001).[33] Horby et al. described that the chance of  discharge from hospital within 28 days was higher in the dexamethasone group, RR 1.10, 96% CI 1.03-1.17.[23]     In contrast, Feng et al. reported that patients who received corticosteroids generally had a longer hospital stay. However, severe and critically ill patients were treated with corticosteroids significantly more frequently (moderate 13.4% vs. severe 51.9% vs. critical 74.3%, p<0.001).[54] Zha et al. found no significant difference in hospital LOS between groups (p=0.14).[44]

Discussion

In this systematic review and meta-analysis on use of corticosteroids in COVID-19 patients, the pooled estimate of the observational studies supported the positive effect on mortality of corticosteroid therapy in COVID-19 disease as reported in the RECOVERY trial, in already respiratory compromised COVID-19 patients, i.e. oxygen or mechanical ventilation dependent or with ARDS. Furthermore, mechanical ventilation rate seemed lower in corticosteroid treated COVID-19 patients, though no definite conclusions can be drawn. The effect on viral clearance time was ambiguous, i.e. prolonged in four of nine and without effect in five of nine studies. Thus, it appears safe to administer corticosteroids with possible improvement in mortality and uncertain effects on viral clearance.

Compared to other systematic reviews on corticosteroids and COVID-19, ours was able to include the largest number of studies so far, studying corticosteroid therapy specifically for COVID-19 patients, including the large RECOVERY trial. In the reported systematic reviews, some just extrapolated knowledge on SARS-CoV or MERS-CoV[19] or on non-viral ARDS,[4] others combined studies on corticosteroids and SARS-CoV, MERS-COV and SARS-CoV-2.[2, 16, 56] Although important for understanding and hypothesis generation, COVID − 19 has proven to be an unique entity of viral pneumonia causing ARDS, and knowledge particularly pertaining to SARS-CoV-2 is paramount. Furthermore, with the high publication rate of COVID-19 studies in the past months, it is important to include peer reviewed studies from which it is also possible to quantify a potential effect of corticosteroids and this was not the case in some earlier reviews.[16, 17] Our conclusions are also different as research into other serious coronavirus infections (SARS-CoV and MERS) discouraged the administration of steroids because of unconvincing survival improvement and side effects such as hyperglycemia, higher bacterial infection rate, delayed viral clearance.[2, 18, 19, 56]

Our review has several limitations. Most of the included studies were retrospective cohort studies with increased risk of bias and lower level of evidence. Besides that, large heterogeneity in the studies was present (i.e. study population, type, dose, initiation and duration of corticosteroids, outcome measures). In many studies confounding by indication was evidently present: two studies described that corticosteroid administration was “at the discretion of the treating physician”[46, 49] and seven reported that severe patients were more likely to receive corticosteroid treatment.[37, 39, 42, 49, 52, 54, 55] Full details on indication and administration of corticosteroid treatment are summarized in Table 2. Many studies had incomplete follow-up and a considerable amount of patients did not reach definite endpoints. However, our conscious exclusion of non-peer-reviewed and low-valid studies, the focus on a measurable and quantifiable endpoint, and, if possible, inclusion of risk estimates corrected for confounders and propensity matched, increased the validity of the retrospective evidence supporting the RECOVERY trial. Furthermore, from the 22 included studies, 17 originated in China, with the majority from the same region and some even from the same hospitals with similar inclusion periods. Overlap in patients can therefore not be ruled out and generalizability might by impaired. On the other hand, 75.5% of the study population were included from outside China. Therefore it remains debatable whether our results can be instantly applied to other regions but the direction of the results cannot be ignored. Moreover, in terms of generalizability, the median age from the included patients in this review ranged from 34 to 72 years. However, data from the CDC state that 42.9% of hospitalized patients in the United States are > 65 years and European numbers from the European Centre for Disease Prevention and Control (ECDC) show that 54.2% hospitalized patients are > 65 years with great variation between countries.[57, 58] Also, the fact that the included studies studied severe patients means that conclusions for mild or moderate cases of COVID-19 pneumonia cannot be drawn.

Severe COVID-19 patients are faced with a twofold problem. On the one hand, there is the hyperinflammatory response, resulting in pulmonary thrombosis, extravasation of cell debris, and acute lung injury or even ARDS.[59] On the other hand there is a need to clear the viral infection itself. This primary phenomenon suggests a possible target for corticosteroids.[15] Thus, the confirmation that there is predominantly a beneficial effect of corticosteroids on mortality is congruent with pathophysiological reasoning and prior knowledge. The fact that we found an inconsistent result on viral clearance is partly caused by large heterogeneity and unspecified interventions. Since this meta-analysis found a beneficial effect on mortality, it might also imply that the possible delay in viral clearance of SARS-CoV-2 after corticosteroid use does not affect mortality. Furthermore, it remains unclear whether the delayed viral clearance is an effect of the corticosteroid treatment or of confounding factors such as severity of disease. Hence, the suggestion of delayed viral clearance should not be presented as the key argument to avoid corticosteroid treatment in COVID-19 patients. What is lacking is knowledge on the optimal start of corticosteroid administration after start of clinical illness, specific subpopulations and type, dose and duration. Horby et al. reported a strongly beneficial effect on mortality but did not investigate optimal timing and indication of corticosteroid administration.[23] Therefore, future research should focus on which patient characteristics, laboratory and radiological markers can be used to guide indication and timing of corticosteroid treatment.

In conclusion, the evidence on the effect of corticosteroid treatment in COVID-19 patients is expanding. Recent findings in both observational studies and the RECOVERY trial point towards beneficial effects of corticosteroids on mortality, without clinically relevant delay of viral clearance. Optimal timing, dose and duration remain subject for further investigation. Since corticosteroids are affordable and easily accessible in healthcare systems quavering under the pressure of the global outbreak of this rapidly spreading coronavirus, this field of research should be a universal priority.

List Of Abbreviations

ARDS: acute respiratory distress syndrome

CDC: Centers for Disease Control and Prevention

CI: confidence interval

COVID-19: coronavirus disease 2019

CT: computed tomography

ECDC: European Centre for Disease Prevention and Control

FiO2: inspiratory oxygen fraction

HR: hazard ratio

ICU: Intensive care Unit

IQR: interquartile range

LOS: length of stay

MERS-CoV: Middle east respiratory syndrome coronavirus OR: Odds ratio

NOS: Newcastle Ottawa Scale

NR: not reported

OR: odds ratio

PaO2: arterial oxygen tension

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RNA: ribonucleic acid

RR: rate ratio

RT-PCR: reverse transcription polymerase chain reaction

SARS-CoV: severe acute respiratory syndrome coronavirus

SD: standard deviation

Steroids: glucocorticoids or corticoids

SpO2: plasma oxygen saturation

WHO: World Health Organization

Declarations

Ethics approval and consent to participate

Not applicable 

Consent for publication

Not applicable 

Availability of data and materials

Not applicable 

Conflicts of interest

All persons who meet authorship criteria are listed as authors. The manuscript has been seen and approved by all authors. On behalf of all authors, the corresponding author states that there is no conflict of interest. 

Funding

Not applicable 

Author contributions

SA created the study project. PB, EH, KN, JvP and SA analysed the data. JvP and SA performed the statistical analyses with the aid of OD (in acknowledgements). PB, EH, KN, JvP and SA wrote the draft and all co-authors critically revised the manuscript and approved the final version for publication. 

Acknowledgements

We would like to express our gratitude to C. Pees, librarian, for her efforts in designing the search strategies used in collecting data. We would also like to express our gratitude to Olaf M. Dekkers for his aid in the statistical analysis, i.e. calculating pooled estimate and constructing the forest plot.

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Tables

Table 1: Descriptive characteristics of included studies of corticosteroids and COVID-19 

Footnotes: unless otherwise specified, severity was defined according to National Health Commission of the People's Republic of China guidelines, meaning that severe cases were defined as either respiratory distress (≥30 breaths/ min), oxygen saturation ≤93% in rest, or arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ≤300 mmHg (1 mmHg=0.133kPa). Critical cases were defined as either respiratory failure and requiring mechanical ventilation, shock, or with other organ failure that required ICU care. a) defined according to WHO guidelines. b) according to guidelines of the American Thoracic Society and Infectious Disease Society of America.
Unless otherwise specified, time to viral clearance and viral shedding duration are defined as time to negative RT-PCR. 

+) defined as not meeting the following criteria: (i) obvious alleviation of respiratory symptoms (eg. cough, chest distress and breath shortness) after treatment; (ii) maintenance of normal body temperature for ≥3 days without the use of corticosteroid or antipyretics; (iii) improvement in radiological abnormalities on chest CT or X-ray after treatment; (iv) a hospital stay of ≤10 days.

NOS score was based on 1) mortality, 2) viral clearance, or 3) secondary outcomes.

Table 2: Descriptives of corticosteroid intervention and outcomes in COVID-19 patients 

Footnotes Table 2: unless otherwise specified, severity was defined according to National Health Commission of the People's Republic of China guidelines, meaning that severe cases were defined as either respiratory distress (≧30 breaths/ min), oxygen saturation ≤93% in rest, or arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2)≦300 mmHg (1 mmHg=0.133kPa). Critical cases were defined as either respiratory failure and requiring mechanical ventilation, shock, or with other organ failure that required ICU care. a = severity defined according to WHO guidelines. + = defined as not meeting the following criteria: (i) obvious alleviation of respiratory symptoms (eg. cough, chest distress and breath shortness) after treatment; (ii) maintenance of normal body temperature for ≥3 days without the use of corticosteroid or antipyretics; (iii) improvement in radiological abnormalities on chest CT or X-ray after treatment; (iv) a hospital stay of ≤10 days.