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

doi:10.21203/rs.3.rs-52240/v1

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.

Critical Care & Emergency Medicine

Infectious Diseases

COVID-19

SARS-CoV-2

coronavirus

corticosteroids

mortality

viral clearance

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.

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]

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]

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.

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

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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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. J Med Virol. 2020 May 22. doi:10.1002/jmv.26052.
Liu J, Zheng X, Huang Y, Shan H, Huang J. Successful use of methylprednisolone for treating severe COVID-19. J Allergy Clin Immunol. 2020 May 29. doi:10.1016/j.jaci.2020.05.021.
Wang Y, Jiang W, He Q, Wang C, Wang B, Zhou P, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther. 2020 Apr 28;5(1):57.
Yang SS, Lipes J. Corticosteroids for critically ill COVID-19 patients with cytokine release syndrome: a limited case series. Can J Anaesth. 2020 May 11. doi:10.1007/s12630-020-01700-w.
Zhang G, Hu C, Luo L, Fang F, Chen Y, Li J, et al. Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China. Journal of Clinical Virology. 2020 June;127.
Zhou W, Liu Y, Tian D, Wang C, Wang S, Cheng J, et al. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia. Signal Transduct Target Ther. 2020 Feb 21;5(1):18.
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Fernández Cruz A, Ruiz-Antorán B, Muñoz Gómez A, Sancho López A, Mills Sánchez P, Centeno Soto GA, et al. Impact of glucocorticoid treatment in SARS-CoV-2 infection mortality: a retrospecitve controlled cohort study. Antimicrob Agents Chemother. 2020 Jun 22. doi:10.1128/aac.01168-20.
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Table 1: Descriptive characteristics of included studies of corticosteroids and COVID-19

Author

Country, region

Hospital

Publication date

Period of inclusion

Study type

Sample size

Follow-up (days)

Study population

Study groups

Mean/median age, in study groups (yr)

Males (%), in study groups

Critically ill patients: (%)

NOS

Cao et al.

China, Wuhan

Zhongnan Hospital

2 Apr 2020

3 Jan to 1 Feb, 2020

Retrospective observational

102

Followed up at discharge

Hospitalized COVID-19 patients

Non-survivors (17) vs. survivors (85)

72, 53

76.5, 47.1

Transfer to ICU: 17.6%

5¹

Chen et al.

China, Guangzhou

Eighth People’s Hospital, Guangzhou Medical University

26 Jun 2020

20 Jan to 15 Mar 2020

Retrospective observational

267

Not specified

Hospitalized COVID-19 patients

No group division

NR

Serious: 15.0%

Critical: 1.5%

8²

Chroboczek et al.

France

Centre Hospitalier Alpes Léman

16 Jun 2020

10 Mar to 9 Apr, 2020

Retrospective observational

70

Not specified

Hospitalized COVID-19 patients requiring more than 3L of oxygen

Steroid (21) vs non-steroid (49)

NR

5³

Fadel et al.

USA, Michigan

Five hospitals in southeast and south-central Michigan

19 May 2020

12 Mar to 27 Mar 2020

Quasi-experimental

213

≥14 days

Adult hospitalized patients with confirmed moderate to severe COVID-19

Standard of Care (81) vs early steroid group (132)

64, 61

50.6, 51.5

Admitted to ICU: 26.8%

8¹

Fang et al.

China, Anhui

Provincial Hospital

8 Apr 2020

22 Jan to 1 Mar, 2020

Retrospective observational

78

Until viral clearance

Hospitalized COVID-19 patients

General with steroid (9), general with non-steroid (46), severe with steroid (16), and severe with non-steroid (7)

40.2, 39.9

55.6, 47.8

Severe: 29.5%

6¹

Feng et al.

China, Wuhan, Shanghai, Anhui

Jinyintan Hospital, Shanghai Public Health Clinical Center, Tongling People's Hospital

10 Apr 2020

1 Jan to 15 Feb, 2020

Retrospective observational

476

Not specified

Hospitalized COVID-19 patients

Moderate (352), severe (54), critical (70)

51, 58, 61

54.0, 61.1

Severe: 9.5%

Critical: 14.7%

9¹

Fernandez Cruz et al.

Spain, Madrid

Hospital Puerta de Hierro-Majadahonda

22 Jun, 2020

4 Mar to 7 Apr, 2020

Retrospective observational

463

Not specified

Adult patients with COVID-19 pneumonia complicated with ARDS and/or an hyperinflammatory syndrome

Steroids (396) vs controls (67)

65.4, 68.1

69.7, 61.2

Severe ARDS

Steroids: 7.1

Controls: 0

9¹

Gong et al.

China, Hubei

Yi Chang Central People's Hospital

22 May 2020

30 Jan to 20 Feb, 2020

Retrospective observational

34

Not specified

Hospitalized COVID-19 patients under 50 years old

Steroid (18) vs non-steroid (16)

38.22, 33.75

61.1, 68.8

47.1% severe patients

5²

Horby et al.

United Kingdom

179 NHS hospitals

22 June 2020

19 Mar to 8 Jun, 2020

Randomized controlled trial

6425

28 days

Hospitalized COVID-19 patients

Steroid (2104) vs usual care (4321)

66.9, 65.8

64, 64

Invasive mechanical ventilation: 15.6%

NA

Ling et al.

China, Shanghai

Shanghai Public Health Clinical Center

28 Feb 2020

20 Jan to 10 Feb, 2020

Retrospective observational

66

Until viral clearance

Recovered hospitalized COVID-19 patients with two successive negative RT-PCR tests

Steroid (5) vs. non-steroid(61)

51, 41

20.0, 42.2

NR

6²

Liu et al.

China, Zhuhai

Fifth Affiliated Hospital of Sun Yat-sen University

29 May 2020

22 Jan to 2 Mar, 2020

Retrospective observational

101

Not specified

Consecutive hospitalized COVID-19 patients

Non-severe with steroid (0), non-severe with non-steroid (75), severe with steroid (15) vs severe with non-steroid (9)

44.0, 56.8

38.7, 57.7

25.7% severe and critical patients

6²

Lu et al.

China, Wuhan

Tongji Hospital

19 May 2020

25 Jan to 25 Feb, 2020

Retrospective observational and case-control analysis

244

Not specified

Hospitalized adult COVID-19 patients

Steroid (151) vs non-steroid (93)

Case control: steroid (31) vs non-steroid (31)

64, 59

55, 48

All patients were critically ill

9¹

Mo et al.

China, Wuhan

Zhongnan Hospital

16 Mar 2020

1 Jan to 5 Feb, 2020

Retrospective observational

155

Not specified

Consecutive hospitalized COVID-19 patients

General (70) and refractory⁺ (85)

46, 61

44.3, 64.7

Serious: 35.5%

Critical: 23.9%

6³

Shen et al.

China, Shanghai

Shanghai Public Health Clinical Center

23 Jun 2020

20 Jan to 29 Feb, 2020

Retrospective observational

325

28 days

Hospitalized COVID-19 patients

Glucocorticoids (27) vs no glucocorticoids (272)

51 (in total cohort)

51.7 (in total cohort)

Severe: 3.1

Critical: 4.9

6²

Shi et al.

China, Zhejiang

First Affiliated Hospital of Zhejiang University

2 Jul 2020

19 Jan to 17 Feb, 2020

Retrospective observational

99

28 days

Hospitalized COVID-19 patients

Virus negative (61) and virus positive (38)

50, 61.5

57.4, 68.4

NR

8²

Wang et al.

China, Wuhan

Union Hospital of Huazhong University of Science and Technology

28 Apr 2020

20 Jan to 25 Feb, 2020

Retrospective observational

46

Until discharge/death

Severe patients with COVID-19 pneumonia at the isolation ward

Steroid (26) vs. non-steroid (20)

54, 53

62, 50

All patients were severely ill

5¹

Wu et al.

China, Wuhan

Jinyintan Hospital

13 Mar 2020

25 Dec 2019 to 6 Jan, 2020

Retrospective observational

201

18 - 50

Hospitalized COVID-19 patients

ARDS (84) vs. non-ARDS (117) and ARDS survivors (27) vs. ARDS non-survivors (23)

58.8, 48.0

71.4, 58.1

Patients with ARDS according to WHO guidelines: 41.8%

9¹

Xu et al.

China, Hangzhou and Shenzhen

School of Medicine, Zhejiang University, and the Shenzhen Third People’s Hospital

9 Apr 2020

13 Jan to 19 Feb, 2020

Retrospective observational

113

21

Hospitalized patients with 1 of 3 criteria: (1) disease duration over 21 days without viral RNA

clearance, (2) viral RNA clearance occurred within 21 days, or

(3) death occurred within 21 days.

Viral shedding duration < 15 days vs. viral shedding duration > 15 days

48.0, 54.4

40.5, 67.1

Critical illness^a during hospitalization: 20.4%

9²

Yang et al.

Canada, Montreal

Jewish General Hospital

11 May 2020

Not specified

Retrospective observational

15

Not specified

COVID-19 patients admitted to ICU who received corticosteroids in the context of cytokine release syndrome

No group division

72

60

All patients were critically ill

5¹

Zha et al.

China, Anhui

Second People’s

Hospital of Wuhu and Yijishan Hospital in Wuhu,

8 Apr 2020

24 Jan to 24 Feb, 2020

Retrospective observational

31

Not specified

Hospitalized COVID-19 patients

Steroid (11) vs. non-steroid (20)

53, 37

73, 60

NR

6²

Zhang et al.

China, Wuhan

Zhongnan Hospital

9 Apr 2020

2 Jan 2020 to 10 Feb, 2020

Retrospective observational

221

Up to Feb 15, 2020

Hospitalized COVID-19 patients

Severe^b (55) vs. non-severe (166) and

ICU-to ward transfer (23) vs. ICU-death (9)

62.0, 51.0

63.6, 44.0

Severe: 24.9%

5¹

Zhou et al.

China, Wuhan

Pulmonary Hospital

21 Feb 2020

1 Jan to 29 Jan, 2020

Retrospective observational

15

Up to Feb 9, 2020

Critical COVID-19 patients admitted to the ICU

Survivors (8) vs. non-survivors (7)

56.3, 68.0

75, 57.1

All ICU patients with moderate or severe ARDS

5¹

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

Author	Type of steroid	Patients treated (number, %)	Indication	Dose	Initiation of treatment (days)	Duration of treatment (days)	Mortality (%)	Viral clearance (days)	Length of hospital stay (days)	Use of mechanical ventilation (%)	Oxygenation
Cao et al.	Methylprednisolone	Survivors: 47.1 Non-survivors: 64.7 p=0.184	NR	NR	NR	NR	Overall mortality: 16.7 No differences in mortality among those who did or did not receive steroids.	NR	NR	NR	NR
Chen et al.	Not specified	29/267 (10.9)	NR	NR	NR	NR	NR	Corticosteroids (yes vs. no): Multivariable analysis: HR 0.60 (95% CI 0.39-0.94), p=0.024 Stepwise analysis: HR 0.55 (95% CI 0.36-0.84), p=0.005	NR	NR	NR
Chroboczek et al.	Not specified	21/70 (30)	NR	NR	From symptom onset, mean: 13.0±4.2 days	NR	NR	NR	NR	Corticosteroid therapy affected the risk of intubation with a risk difference (ATE) of -47.1% (95% CI -71.8 to -22.5)	NR
Fadel et al.	Methylprednisolone	Overall: 136 (63.89) Standard of care: 46 (56.8) Early steroid: 90 (68.2) p=0.094	Requiring ≥4 liters of oxygen per minute on admission, escalating oxygen requirements from baseline, or ICU-admission	0.5-1 mg/kg/day in 2 divided doses	Median time from admission: Standard of care: 5 (3-7) Early steroid: 2 (1-3) p<0.001	3 to 5 days For patients who required ICU admission: 3 to 7 days	Standard of care: 26.3 Early steroid: 13.6 OR 0.45 (95% CI 0.22-0.91) p=0.024	NR	Standard of Care: 8 (5-14) Early steroid: 5 (3-7) p<0.001	Overall: Standard of Care: 36 (44.4) Early steroid: 38 (28.8) p=0.020 Respiratory failure requiring mechanical ventilation: Standard of Care: 26 (36.6) Early steroid: 26 (21.7) p=0.025	NR
Fang et al.	Severe patients: IV methylprednisolone	General group: (9/55) 16.36 Severe patients: (16/23) 69.57	According to severity and the individual opinion of clinicians.	Severe: 40 mg/day	NR	Severe: 4.5 (3.0, 5.8)	NR	Severe patients: Steroid: 18.8±5.3 Non-steroid: 18.3±4.2	NR	NR	NR
Feng et al.	Not specified	Overall: 127/476 (26.7) Moderate: 47/352 (13.4) Severe: 28/54 (51.9) Critical: 52/70 (74.3) p<0.001	NR	NR	NR	NR	Overall mortality 8.0	NR	Steroids: 22 (17-32) Non-steroid: 15 (11-22) p<0.001	NR	NR
Fernandez-Cruz et al.	Methylprednisolone	Overall: 396/463 (85.5)	At the discretion of the treating physician	1 mg/kg/day (or equivalent) or pulses	Median time from symptom onset: 10 (8-13)	NR Patients treated with pulses received a median of 3 pulses (2-4)	Steroids: 13.9 Controls: 23.9 HR 0.36 (95% CI 0.14-0.93) p=0.035	NR	NR	NR	PaO2/FiO2 Steroids: 263 (112.1) Controls: 267 (78.9) p=0.878 SatO2/FiO2 Steroids: 286 (123.0) Controls: 244 (91.9) p=0.021
Gong et al.	Methylprednisolone	52.9	Persistent high fever (body temperature> 39°) for three consecutive days, or progress in CT imaging within 2 days, or with hypoxia and difficulty breathing	1-2 mg/kg/d gradually halved every 3 days	NR	5 to 10 days	No deaths reported	Steroid: 29.11±6.61, Non-steroid: 24.44±5.21 p<0.05	NR	NR	NR
Horby et al.	Dexamethasone	Steroids: 95% Usual care: 7%	Randomization	6 mg once daily	Median time from symptom onset to corticosteroid treatment allocation: 8 (5-13)	For up to 10 days or until discharge if sooner	Dexamethasone: 21.6 Usual care: 24.6 p<0.001	NR	Dexamethasone: 12 days Usual care: 13 days	Progression of disease leading to receipt of invasive mechanical ventilation: Dexamethasone: 5.2 Usual care: 7.1 p=0.021	NR
Ling et al.	Prednisolone or dexamethasone	7.6. Glucocorticoid treatment group had more severe disease	NR	NR	NR	NR	NR	Steroid: 15 days (9.8-16.0) Non-steroid: 8.0 days (6.0-11.0) p=0.013	NR	NR	NR
Liu et al.	Methylprednisolone	Severe patients: 57.7 Non-severe: 0 Total population: 14.9%	One of the following: (1) PaO2/FiO2 ratio ≤ 150 mmHg, (2) persistent respiratory distress after high flow nasal oxygen therapy (duration ≥ 2 hours, gas flow ≥ 50L/min, FiO2 ≥ 0.6), or (3) multi-lobar infiltrates involving both lungs and an increase by ≥ 50% within 24-48 hours.	2-8 mg/kg per day in general, no more than 500mg per day	NR	Pulse single-dosage: if patients met administration criteria again, the pulse was repeated	No deaths reported	Steroid: 10.0 ± 5.3 days Non-steroid: 10.0 ± 7.9 days p>0.05	NR	NR	Improved significantly, no numbers reported
Lu et al.	Methylprednisolone, hydrocortisone or dexamethasone	61.9	NR	Median hydrocortisone-equivalent dosage 200 (100–800) mg/day	NR	Median: 8 (4-12)	Steroid: 52.3 Non-steroid: 5.4 (adjusted OR 1.05; 95% CI 0.15–7.46) p>0.3 Every 10-mg increase in dosage was associated with additional 4% mortality risk (adjusted HR 1.04, 95% CI 1.01–1.07) p=0.003	NR	NR	NR	SpO2/FiO2: Steroid: 259 (121-303) Non-steroid: 297 (279-388) p<0.01 Case-control: SpO2/FiO2: Steroid: 291 (212–452) Non-steroid: 294 (246–396) p=0.57
Mo et al.	Not specified	Total: 51.0 General: 34.3 Refractory: 64.7	NR	NR	NR	NR	Overall mortality: 14.2	NR	Association with refractory COVID-19 pneumonia⁺: OR 2.232 (95% CI 1.030-4.838) p=0.042	NR	NR
Shen et al.	Methylprednisolone	Total: 15.4	NR	NR	NR	NR	Severe patients: Glucocorticoids: 13.04 No glucocorticoids: 0 p=0.681	Mild patients, blood sample Glucocorticoid: 18 days (11-22) No glucocorticoid: 13 days (9-16) p=0.003 Mild patients, pharyngeal swab Glucocorticoid: 8 (6-11) No glucocorticoid: 8 (5-11) p=0.436 Severe-critical patients, blood sample: Glucocorticoid: 22.5±8.7 No glucocorticoid: 25.7±7.5 p=0.502 Severe-critical patients, pharyngeal swab: Glucocorticoid: 15.4±7.24 No glucocorticoid: 8.3±0.58 p=0.170	Median in total cohort: 15 days	In total cohort 7.1%	NR
Shi et al.	Not specified	Virus positive: 78.9 Virus negative: 77	NR	Median initial dosage: Virus positive: 60 mg/d (40-80) Virus negative: 40 mg/d (40-80) p=0.47	Median time from symptom onset: Virus positive:7.5 (5-10) Virus negative: 8 (6-10) p=0.35	NR	NR	Unadjusted HR 0.85 (95% CI 0.46-1.57) P = 0.599 Adjusted HR 1.00 (95% CI 0.53-1.89) p=0.990	ICU length of stay Virus positive: 8.5 (6.3-11) Virus negative: 4 (3-5.8) p=0.000	Virus positive: 26.3 Virus negative: 3.3 p=0.000
Wang et al.	Methylprednisolone	56.5	Severe COVID-19 pneumonia	1-2 mg/kg/d	Early administration, but not specified	5-7 days	Steroid: 2 (7.8) Non-steroid: 0 (0) p=0.714	NR	NR	Steroid: 11.5% Non-steroid: 35% p=0.05	Steroid use resulted in faster improvement of SpO2, no numbers reported
Wu et al.	Methylprednisolone	Without ARDS: 10.3 With ARDS: 59.5 p<0.001	NR	NR	NR	NR	Among patients with ARDS, steroids decreased the risk of death compared to non-steroids (HR, 0.38; 95% CI 0.20-0.72).	NR	NR	NR	NR
Xu et al.	Methylprednisolone	56.6	NR	0.5-1 mg/kg body weight	NR	NR	Overall mortality: 1.8	After multivariate analysis steroids were not identified as an independent risk factor: OR 1.38 (95% CI 0.52-3.65), p=0.519	NR	NR	NR
Yang et al.	Methylprednisolone (9), hydrocortisone (4), dexamethasone (2)	100	Hypoxic respiratory failure, vasoplegic shock on multiple vasopressors or both respiratory and cardiovascular failure.	Median methylprednisolone equivalent dose over 24h: 160 (83-160) mg.	Median time from symptom onset: 14 (12–15)	NR	Overall mortality: 20	NR	NR	NR	Average increase in P/F ratio of 44
Zha et al.	Methylprednisolone	35.5	NR	40 mg once or twice a day	Within 24 hours of hospital admission	Median: 5 (4.5-5.0)	No deaths reported	Steroid: 15 (14-16) Non-steroid: 14 (11-17) p=0.87	Steroid: 20 (18-21) Non-steroid: 17 (15.5-19.5) p=0.14	NR	NR
Zhang et al.	Methylprednisolone	Severe^b: 72.2 Non-severe: 45.2 p<0.001	Refractory high fever, exacerbation of wheezing symptoms, increased interstitial exudation based on chest radiology, and high levels of inflammatory mediators	1-2 mg/kg/day	Median time from symptom onset: ICU-to-ward: 9.5 (7.0–11.5) ICU-death: 11.0 (8.5–15.5) p=0.206	ICU-to ward: 6.5 (4.0-12.0) ICU-death: 8.0 (2.5-12.0) p=0.776	No effect of steroids on mortality	NR	NR	NR	NR
Zhou et al.	Methylprednisolone	100	ICU-admission	<1-2 mg per kg body weight per day. Median hydrocortisone- equivalent dose of 400.0 mg/day	Instantly after ICU admission	Average of 9.5 days, range not reported	No effect of steroids on mortality	NR	NR	NR	Steroids in the first 3−5 days could enhance oxygen saturation (SaO2) and arterial oxygen tension (PaO2)/inspiratory oxygen fraction (FiO2), no numbers reported

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.

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

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Abstract

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Background

Methods

Results

Discussion

List Of Abbreviations

Declarations

References

Tables

Supplementary Files

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