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Erschienen in: Critical Care 1/2020

Open Access 01.12.2020 | COVID-19 | Research

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

verfasst von: Judith van Paassen, Jeroen S. Vos, Eva M. Hoekstra, Katinka M. I. Neumann, Pauline C. Boot, Sesmu M. Arbous

Erschienen in: Critical Care | Ausgabe 1/2020

Abstract

Background

In the current SARS-CoV-2 pandemic, there has been worldwide debate on the use of corticosteroids in COVID-19. In the recent RECOVERY trial, evaluating the effect of dexamethasone, a reduced 28-day mortality in patients requiring oxygen therapy or mechanical ventilation was shown. Their results have led to considering amendments in guidelines or actually already recommending corticosteroids in COVID-19. However, the effectiveness and safety of corticosteroids still remain uncertain, and reliable data to further shed light on the benefit and harm are needed.

Objectives

The aim of this systematic review and meta-analysis was to evaluate the effectiveness and safety of corticosteroids in COVID-19.

Methods

A systematic literature search of RCTS and observational studies on adult patients was performed across Medline/PubMed, Embase and Web of Science from December 1, 2019, until October 1, 2020, according to the PRISMA guidelines. Primary outcomes were short-term mortality and viral clearance (based on RT-PCR in respiratory specimens). Secondary outcomes were: need for mechanical ventilation, need for other oxygen therapy, length of hospital stay and secondary infections.

Results

Forty-four studies were included, covering 20.197 patients. In twenty-two studies, the effect of corticosteroid use on mortality was quantified. The overall pooled estimate (observational studies and RCTs) showed a significant reduced mortality in the corticosteroid group (OR 0.72 (95%CI 0.57–0.87). Furthermore, viral clearance time ranged from 10 to 29 days in the corticosteroid group and from 8 to 24 days in the standard of care group. Fourteen studies reported a positive effect of corticosteroids on need for and duration of mechanical ventilation. A trend toward more infections and antibiotic use was present.

Conclusions

Our findings from both observational studies and RCTs confirm a beneficial effect of corticosteroids on short-term mortality and a reduction in need for mechanical ventilation. And although data in the studies were too sparse to draw any firm conclusions, there might be a signal of delayed viral clearance and an increase in secondary infections.
Hinweise

Supplementary information

Supplementary information accompanies this paper at https://​doi.​org/​10.​1186/​s13054-020-03400-9.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Abkürzungen
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

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. A total of 40,559,736 cases have been reported, and 1,121,499 people have died as of October 19. [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, or even extracorporeal membrane oxygenation (ECMO) [4, 5]. Approximately 16–35% develop severe pneumonia, 2–17% need mechanical ventilation, of whom up to 15% need ECMO therapy, [68] and the case fatality rate is 1.4–15% [5, 9, 10]. 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 hyper inflammation and immunoparalysis [11]. A clinical presentation of massive vascular inflammation, disseminated coagulation, shock and ARDS is frequently triggered [911].
Though many therapies aiming at mitigation of the inflammatory response are being evaluated, strong evidence of benefit is lacking. Corticosteroids might have beneficial effects in overcoming both hyperinflammation and ARDS [4, 1517]. Furthermore, they could serve as an easily accessible and affordable treatment option. On the other hand, there are known adverse effects of corticosteroid use, such as delayed viral clearance, opportunistic infections and suppression of the hypothalamic-pituitary-adrenal axis [2, 18, 19]. Earlier studies done in MERS-CoV and SARS-CoV showed delayed viral clearance, opportunistic infections and hyperglycemia [2022]. Therefore, a high number of observational studies and randomized controlled trials (RCT) on corticosteroids for COVID-19 have been initiated and reported, and the signal is a beneficial effect. The RECOVERY trial was the first to report that the use of dexamethasone as opposed to usual care reduced 28-day mortality in patients requiring oxygen therapy or mechanical ventilation [23]. And a prospective meta-analysis of seven randomized clinical trials showed that administration of corticosteroids was associated with lower 28-day all-cause mortality [24]. And while initially the World Health Organization (WHO) recommended against corticosteroid treatment, as of September 2, 2020, the WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of patients with severe and critical COVID-19 [15, 25]. Also, the Surviving Sepsis Guideline on management of COVID-19 recommends administration of steroids in patients with severe COVID-19 on mechanical ventilation with ARDS and in patients with COVID-19 and refractory shock [26].
However, the effectiveness and safety of corticosteroids still remain uncertain, because of scarcity of RCTs and inconclusive observational studies, and reliable data to further shed light on the benefit and harm are needed. Therefore, the aim of this systematic review and meta-analysis of observational studies and RCTs was to evaluate the effectiveness and safety of corticosteroids in COVID-19.

Methods

Data sources and search strategy

A systematic review according to the PRISMA guidelines was conducted [27]. The meta-analysis was retrospectively registered under number 38752 at ISRCTN.org. A comprehensive systematic search was conducted for published studies in Medline/PubMed, Embase and Web of Science from December 1, 2019, to October 1, 2020. The search strategy consisted of the components “COVID-19,” “intensive care” and “corticosteroids” (Additional file 1).

Eligibility

RCTs and observational 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, corticosteroids not restricted with respect to type, dose and duration. Studies concerning pregnant women or children, reviews, case series including less than 15 patients and articles that were not available in English were excluded [28].

Definition of primary and secondary outcomes

The primary outcomes were short-term mortality (i.e., short-term mortality as defined in the study, including 28-day, 30-day and hospital mortality) and viral clearance (i.e., as defined by the study, based on RT-PCR in respiratory specimens). Secondary outcomes were: mechanical ventilation (i.e., as defined by the study: need for invasive mechanical ventilation, duration of mechanical ventilation, ventilator-free days or other oxygen therapy), length of hospital stay (LOS-hospital) and secondary infections. For exact used definitions see Additional file 2.

Study selection

Suitable studies were selected in two stages. First, six independent reviewers screened all selected titles and abstracts (JvP, JV, EH, KN, PB, SA). 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 and included if both authors agreed. If needed, the article was discussed with the third reviewer until consensus was reached.

Data extraction and quality analysis

After selection, data were extracted by one and checked by a second investigator (JvP, JV, EH, KN, PB). 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 corticosteroids, median time before corticosteroid initiation, duration of administration, primary and secondary outcomes and adverse events at any time point after admission were extracted in a standardized data extraction form (Additional file 2).
For each individual study, the quality was assessed. For RCTs, the risk of bias was assessed on six domains (random sequence generation, concealment of allocation, blinding, selective outcome reporting, incomplete outcome data and other) [29, 30]. The Newcastle Ottawa Scale was used for validity assessment of observational studies [31, 32]. The NOS score ranges from 0 (low quality) to 9 (high quality) points.

Data analysis and reporting

For the effect of corticosteroids on mortality, a pooled estimate was calculated and graphically summarized in a forest plot. Data from observational studies were analyzed separately from the RCTs, and both the separate results and the overall combined outcomes were calculated and summarized in the plot. When available, the adjusted odds ratio (OR) or relative risk (RR) from the cohort studies were used for pooling to reduce confounding. Since the endpoint (mortality) occurred relative infrequently, the OR will be close to the RR and therefore we decided to pool both RR and OR estimates of the individual studies [33]. Furthermore, a pooled estimate was calculated and graphically summarized in a forest plot for need for mechanical ventilation.
To allow studies to have a different underlying effect, a random effects model was used. I2 statistics was used to quantify heterogeneity. Furthermore, for the pooled estimate of effect on mortality, tau2 was used to assess the variance of the true effects. The GRADE approach was used to assess the quality of the evidence for the effect of corticosteroids on mortality. STATA 16.0 was used to perform data analysis.

Results

Study selection

Our search yielded 1640 unique studies. After qualification of title and abstract, 101 studies were selected for full review. Based on exclusion criteria, 57 additional studies were excluded (references in Additional file 3). The remainder of 44 studies, comprising 20.197 patients, was included in this systematic review and meta-analysis. (Fig. 1).

Study characteristics (Table 1 and Additional file 4)

Table 1
Study characteristics
 
Author
Reference
Study type
Type—dose c corticosteroids
Sample size
CoVID—Study population
Reporting outcomea
Quality scoreδ (Risk of bias or NOS)
Main findings
M
V
H
R
O
I
1
Angus
34
REMAPt b
Hydrocortisone  < 1 mg/kg ED
403
ICU patients
x
 
x
x
  
Risk of biasd
Two hydorcoritsone dosing resulted high probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days, compared to standard of care
2
Bani-Sadr
39
Cohort with historical controls
Prednisolone or Methylprednisolone  ≥ 1 mg/kg ED
319
Hospitalized patients
x
   
x
x
4
Addition of corticosteroids to our institution’s COVID-19 treatment protocol was associated with a significant reduction in hospital mortality in the “after” period
3
Cao
80
Retrospective Observational
Unknown
102
Hospitalized patients
x
     
5
Patient characteristics seen more frequently in those who died were development of systemic complications following onset of the illness and the severity of disease requiring admission to the ICU
4
Chen Zu
 
Retrospective Observational
Unknown
267
Hospitalized patients
x
x
    
7
Corticosteroid treatment is associated with prolonged viral RNA shedding and should be used with caution
5
Chroboczek
72
Retrospective Observational
Unknown
70
Hospitalized patients
   
x
  
6
Corticosteroids therapy affected the risk of intubation with a risk difference of − 47.1% (95% CI − 71.8 to − 22.5)
6
Dequin
35
Randomized controlled trial
Methylprednisolone or hydrocortisone  < 1 mg/kg ED
149
ICU patients with respiratory failure
x
  
x
x
x
Risk of Biasd
Low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21 in critically ill patients
7
Fadel
38
Quasi experimental
Methylprednisolone  ≥ 1 mg/kg ED
213
Moderate-to-severe CoVID patients
x
 
x
x
  
6
An early short course of methylprednisolone in patients with moderate-to-severe COVID-19 reduced escalation of care and improved clinical outcomes
8
Fang Mei
40
Retrospective Observational
Methylprednisolone  < 1 mg/kg ED
78
Hospitalized patients
 
x
    
5
Low-dose corticosteroid therapy may not delay viral clearance in patients with COVID-19
9
Feng Ling
66
Retrospective Observational
Unknown
476
Hospitalized patients
x
 
x
   
5
Differences in AT II receptor inhibitors use were associated with different severities of disease. Multiple lung lobes involvement and pleural effusion were associated with the severity of COVID-19. Advanced age (> 75 yr) was a risk factor for mortality
10
Fernandez
41
Retrospective Observational
Methylprednisolone  ≥ 1 mg/kg ED
463
Patients with ARDS hyperinflammation
x
   
x
 
5
Glucocorticoid use is associated with increased survival and improved mortality rates in severe CoVID-19 patients
11
Gazzaruso
42
Retrospective Observational
Methylprednisolone or prednisone  < 1 mg/kg ED
219
Hospitalized patients
x
   
x
 
3
Antirheumatic drugs, probably steroids included, may modulate inflammation and avoid a hyperinflammation that leads to severe complications and death in subjects with COVID-19
12
Gong Guan
43
Retrospective Observational
Methylprednisolone  ≥ 1 mg/kg ED
34
Hospitalized Patients < 50 years
 
x
  
x
 
6
Corticosteroids therapy can effectively release COVID‐19 symptoms, improve oxygenation and prevent disease progression. However, it can prolong the negative conversion of nucleic acids
13
Horby
23
Randomized controlled trial
Dexamethasone  < 1 mg/kg ED
6425
Hospitalized patients
x
 
x
x
  
Risk of biasd
The use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support
15
Hu Wang
44
Retrospective Observational
Prednisolone or methylprednisolone  > 1 mg/kg ED
308
Hospitalized patients
x
x
    
4
Glucocorticoid therapy did not significantly influence the outcomes nor the adverse events of COVID-19 pneumonia
16
Huang Song
45
Retrospective Observational
Methylprednisolone 2 study groups: High: ≥ 1 mg/kg ED Low: < 1 mg/kg ED
64
Hospitalized patients
x
     
4
There were no significant differences in the duration of severe illness or the number of days on high level respiratory support between low-dose and high-dose methylprednisolone group. The mean number of days in the hospital was higher in the high-dose group
14
Huang Yang
81
Retrospective Observational
Unknown
60
Severe CoVID patients
     
x
5
There were no statistically significant differences in immunoglobulin therapy and GCs therapy between the improvement and deterioration subgroups
17
Jeronimo
36
Randomized controlled trial
Methylprednisolone  < 1 mg/kg ED
393
Hospitalized patients
x
 
x
x
 
x
Risk of biasd
Results showed no overall reduction in mortality in 28 days. Patients over 60 years presented a lower mortality in a subgroup analysis
18
Keller
73
Retrospective Observational
Unknown
1806
Early hospitalized patients
x
  
x
  
6
In high CRP group, glucocorticoids show significantly reduced risk of mortality or mechanical ventilation (odds ratio, 0.23; 95% CI, 0.08–0.70). In low CRP group, glucocorticoids were associated with significantly increased risk of mortality or mechanical ventilation (OR, 2.64; 95% CI,1.39–5.03)
19
Li Hu
46
Retrospective Observational
Methylprednisolone high and low ED
203
Hospitalized patients
 
x
    
5
A dose response relation is suggested for corticosteroids on viral shedding. In addition, high-dose but not low-dose corticosteroids were found to potentially increase mortality in severe patients
20
Li Li
47
Retrospective Observational
Methylprednisolone or prednisone  < 1 mg/kg ED
475
Non-severe CoVID patients
x
x
x
  
x
5
Early, low-dose, and short-term corticosteroids therapy was associated with worse clinical outcomes
21
Li Zhou
48
Retrospective Observational
Methylprednisolone  > 1 mg/kg ED
187
Radiologically progressive CoVID patients
   
x
x
 
6
Short-term, low-to-moderate-dose corticosteroids benefits patients with LDH levels of less than two times the ULN, who may be in the early phase of excessive inflammation
22
Lui Fang
49
Retrospective Observational
Methylprednisolone ≥ 1 mg/kg ED
101
Hospitalized patients
x
     
3
The majority of patients present primarily with fever and typical manifestations on chest imaging. Middle-aged and elderly patients with underlying comorbidities are susceptible to respiratory failure and may have a poorer prognosis
23
Liu Zhang
81
Retrospective Observational
Unknown
1190
Hospitalized patients
x
     
5
Treatment with glucocorticoids increased the risk of progression from not severe to severe disease (OR 3.79, 95% CI 2.39–6.01)
24
Liu Zheng
50
Retrospective Observational
Methylprednisolone ≥ 1 mg/kg ED
101
Hospitalized patients
 
x
  
x
 
5
Timely and appropriate application of methylprednisolone in severe and critical patients may improve outcomes and lung function without negative impacts on specific SARS-CoV-2 IgG production
25
Lu Chen
51
Retrospective Observational
Methylprednisolone, hydrocortisone or dexamethasone  > 1 mg/kg ED
244
Hospitalized patients
x
   
x
 
7
Limited effect of corticosteroid therapy could pose to overall survival of critically ill patients with COVID-19. Given the adverse effects, corticosteroid therapy must be commenced with caution, and prudent dosage should be promoted under certain circumstances
26
Ma Qi
52
Retrospective Observational
Methylprednisolone 2 study groups:
High: ≥ 1 mg/kg ED
Low: < 1 mg/kg ED
72
Severe and critical patients
x
x
x
x
  
6
Corticosteroids cannot reduce the hospital mortality and is not associated with delayed viral clearance, but it could relieve the inflammatory storm and improve clinical symptoms in brief. Patients with severe COVID-19 could benefit from low-dose corticosteroids
27
Ma Zeng
53
Retrospective Observational
Methylprednisolone ≥ 1 mg/kg ED
450
Severe and non-severe patients
x
x
x
x
 
x
4
Corticosteroids use may be accompanied by increased use of antibiotics, longer hospitalization, and prolonged viral shedding
28
Majmundar
54
Retrospective Observational
Prednisolone, dexamethasone, methylprednisolone
 > 1 mg/kg ED
205
Hospitalized patients
x
 
x
x
x
 
6
Corticosteroids were associated with a significantly lower risk of the ICU transfer, intubation, or in-hospital death,
29
Mikulska
55
Retrospective Observational
Methylprednisolone high and low ED
215
Hospitalized non-intubated patients
x
   
x
 
6
Early adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients
30
Nelson
56
Retrospective Observational
Methylprednisolone ≥ 1 mg/kg ED
117
ICU patients on mechanical ventilation
x
 
x
x
  
8
Methylprednisolone was associated with increased ventilator-free days and higher probability of extubation in a propensity-score matched cohort
31
Rodriquez
57
Retrospective Observational
Methylprednisolone ≥ 1 mg/kg ED
1014
Hospitalized patients
x
  
x
x
 
7
Tocilizumab should be prioritized for being tested in randomized trials targeting patients with data suggestive of a hyperinflammatory state. The results for PDC were less consistent but are also encouraging
32
Rubio
68
Retrospective Observational
Unknown
92
ICU and general ward patients
x
  
x
  
5
The early use of GC pulses could reduce the use of tocilizumab and might decrease events such as intubation and death
33
Salton
58
Retrospective Observational
Methylprednisolone ≥ 1 mg/kg ED
173
ARDS patients
x
 
x
x
  
8
Per-protocol administration of prolonged low-dose methylpred-nisolone treatment is associated with a significantly lower hazard of death, reduced ICU burden and decreased ventilator dependence
34
Shen Zheng
59
Retrospective Observational
Methylprednisolone unknown dose
325
Hospitalized patients
 
x
    
4
COVID-19 cases in Shanghai were imported. Rapid identification and effective control measures helped to contain the outbreak and prevent community transmission
35
Shi Wu
71
Retrospective Observational
Unknown
99
Hospitalized patients
 
x
    
4
SARS-CoV-2 RNA clearance time was associated with sex, disease severity and lymphocyte function. The current antiviral protocol and low-to-moderate dosage of corticosteroid had little effect on the duration of viral excretion
36
Tomazini
37
Randomized controlled trial
Dexamethasone
 > 1 mg/kg ED
299
ICU patients with moderate-to-severe ARDS
x
  
x
 
x
Risk of biasd
Dexamethasone plus standard care compared with standard care alone resulted in a significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days
37
Wang Jiang
60
Retrospective Observational
Methylprednisolone
 > 1 mg/kg ED
46
Severe hospitalized patients
x
  
x
x
 
7
early, low-dose and short-term application of methylprednisolone was associated with better clinical outcomes in severe CoVID-19 patients and should be considered before onset of ARDS
38
Wang Yang
67
Retrospective Observational
Unknown
69
Hospitalized patients
x
     
4
COVID-19 shows frequently fever, dry cough, and increase of inflammatory cytokines, and induced a mortality rate of 7.5%. Older patients or those with comorbidities are at higher risk of death
38
Wang Zhang
69
Retrospective Observational
Unknown
548
Not Reported
x
     
6
Low-dose or no glucocorticoid treatment was associated with a lower hazard compared with high-dose treatment (≥ 1 mg/kg) for 15 days in hospital death
40
Wu Chen
61
Retrospective Observational
Methylprednisolone unknown dose
201
Hospitalized patients
x
     
4
Treatment with methylprednisolone may be beneficial for patients who develop ARDS
41
Wu Huang
62
Retrospective Observational
Methylprednisolone
 < 1 mg/kg ED
1763
Severe or critical patients
x
     
7
Corticosteroid use was not associated with beneficial effect in reducing in-hospital mortality for severe or critical cases in Wuhan
42
Xu Chen
63
Retrospective Observational
Methylprednisolone
 < 1 mg/kg ED
113
Hospitalized patients
x
x
    
5
Prolonged SARS-CoV-2 RNA shedding was associated with male sex (P = .009), old age (P = .033), concomitant hypertension (P = .009), delayed admission to hospital after illness onset (P = .001), severe illness at admission (P = .049), invasive mechanical ventilation (P = .006) and corticosteroid treatment (P = .025)
43
Yang Lipes
64
Retrospective Observational
Methylprednisolone, hydrocortisone or dexamethasone
 > 1 mg/kg ED
15
ICU patients
x
   
x
 
6
Possible short-term clinical improvements with corticosteroid. Emphasis the urgent need for high-quality studies on steroids and outcome in critically ill COVID-19 patients
44
Zha Li
65
Retrospective Observational
Methylprednisolone
 < 1 mg/kg ED
31
Hospitalized patients
x
x
x
   
5
No evidence of clinical benefit of corticosteroids was found for those without acute respiratory distress syndrome. Virus clearance may be slower in people with chronic HBV infections
aM = mortality; V = viral clearance; H = length of hospital stay; R = mechanical ventilator/respirator; O = oxygenation; I = secondary infections
bRandomized Embedded Multifactorial Adaptive Platform trial
cED = Prednisolone Equivalent Dose
d Newcastle Ottawa Scale (N.O.S.) for retrospective observational studies. Risk of bias (R.O.B.) for randomized controlled trials: see Fig. 2
Thirty-one of the 44 studies originated in China, 11 in Europe, five in North America, two in South America and one study were multi-continental. The inclusion period of patients ranged from late December 2019 until August 20, 2020. The majority of studies were retrospective observational studies (37/44), five were RCTs [23, 3437], and there were two studies with historical controls [38, 40]. The study population varied from hospitalized patients (28/44) to patients admitted to the Intensive Care Unit (ICU) (15/44), and one study included discharged patients for viral clearance assessment. The median age of patients ranged from 34 to 75 years.
For the observational studies, the median NOS score was 5 (2–8) points (Additional file 5). For the RCT, the risk of bias table is depicted in Fig. 2.

Corticosteroid regimen (Table 1 and Additional file 6)

In the 44 studies, very diverse corticosteroid strategies were used. If reported (n = 35), methylprednisolone was the most frequently prescribed (n = 28) [35, 36, 3865]. Prednisone (n = 5) and dexamethasone (n = 5) and hydrocortisone (n = 4) were also used, some in studies that allowed multiple corticosteroid regimens (n = 9).
The indication to start corticosteroids was described in 12 studies (Additional file 6): In three studies, corticosteroids were started at diagnosis/hospital admission. [38, 41, 56] In five studies, ICU admission or respiratory deterioration were the indications to start, either randomized according to study protocol [23, 34, 35, 37] or not randomized [38, 48, 49, 60, 64].
In 29 studies, the dose of corticosteroids was reported: In 16 studies, an equivalent dose of > 1 mg/kg prednisolone was used [3739, 41, 43, 44, 4851, 53, 54, 5658, 64] and in 11 studies a lower equivalent dose than 1 mg/kg prednisolone [23, 3436, 40, 42, 47, 52, 62, 63, 65]. In two studies, a low- and high-dose group were present [45, 46]. The duration of therapy varied within a range of 5–10 days, in observational studies frequently dependent on clinical condition of patients.

Effect of steroids on primary and secondary outcomes (Table 2, Additional file 7)

Table 2
Summary of findings
Outcomes
Total no events/total no of patients
Relative effect
(95% CI)
No of participants (studies)
Certainty of evidence
(Grade a)
Comments
Standard care
Corticosteroids
Effect of corticosteroids in hospitalized CoVID-19 patients. Intervention: Corticosteroids; Comparison: Standard of Care
In-hospital mortality
1547/9080
(17.0%)
1173/5234
(22.4%)
Estimate
0.72
(0.57–0.87)
14.187b
(22)
RCT: moderate
Non RCT: Very low
Corticosteroids reduce mortality in CoVID-19 hospitalized patients
Requirement of mechanical ventilation
124/467
(26,6%)
89/472
(18,9%)
Estimate
0.70
(0.54–0.91)
939
(7)
All studies: Very low
17 studies reported on mechanical ventilation, but effects could only be quantified in 7 studies
Descriptive results: Data too heterogeneous for quantification of effect
Viral Clearance
In corticosteroid group viral clearance time ranged from 10 to 29 days in corticosteroids group and from 8 to 24 days in standard of care group
2.556
(13)
0 × RCT
13 × retrospective observational study
Heterogeneous outcome reporting. Corticosteroids are associated with a probable delay in viral clearance
Length of hospital stay
Conflicting results both in favor and against the use of corticosteroids
9.433
(12)
2 × RCT,
10 × retrospective observational study
Effect of corticosteroids on length of hospital stay is uncertain
Mechanical ventilation
In 14 out of 17 studies, corticosteroids therapy is associated with beneficial effects on ventilator-free days, on respiratory failure requiring mechanical ventilation and time on mechanical ventilator
12.114
(17)
5 × RCT,
12 × retrospective observational study
Beneficial effects of corticosteroids on mechanical ventilation different definitions used)
Oxygenation
Outcome reporting in saturation, p/F ratio and oxygen demand. Conflicting results in favor and against the use of corticosteroids
3.211
(11)
1 × RCT,
10 × retrospective observational study
Outcome definition too heterogeneous to draw conclusions
Secondary infections
In five out of six studies, secondary infections and antibiotic use are increased
2.145
(6)
3 × RCT
3 × retrospective observational study
Corticosteroids are associated with an increase in infectious complications
a Details on GRADE score are available in Additional file 10
b Due to mortality analyses in subsets of patients, this number of participants is lower than the sum of sample sizes from the included study
Thirty-five of 44 studies reported on Mortality. Thirteen of these could not be integrated in the meta-analysis due to only overall mortality reporting (n = 5), [45, 63, 64, 66, 67] or only descriptive reporting (n = 8), i.e., of a trend toward better outcome (n = 3), [42, 68, 69], no effect (n = 3) [44, 49, 65] or negative effect on outcome (n = 2) [50, 52]. For the remainder of 22 studies, a pooled estimate was calculated and graphically summarized in a forest plot (Fig. 2). The mortality reported in these studies was mainly 28-day mortality (11 studies), in six studies in-hospital mortality of shorter duration and in five studies there was an unreported follow up period (Additional file 7). The overall risk estimate (OR) was 0.72 (95%CI 0.57–0.87), suggesting a beneficial effect of steroids use in COVID-19 patients hospitalized with moderate or severe respiratory failure on mortality. Studies were heterogeneous (overall I2 of 51.1%, p = 0.002) with a between-study variance (tau2) of 0.048. For the subset of RCTs, the risk estimate was 0.84 (95%CI 0.72–0.96) and I2 and tau2 were 31.2% (p = 0.213) and 0.0096, corresponding to less heterogeneity and less between-study variance.
Thirteen of 44 studies reported on viral clearance, which most frequently was defined as two consecutive negative RT-PCR on nasopharyngeal swabs, or a cycle time value of 40 or more. In the corticosteroid group, viral clearance time ranged from 5 to 29 days, in the standard of care group from 8 to 24 days. In nine of 13 studies, viral shedding was delayed in the corticosteroid group. [40, 43, 46, 47, 53, 59, 63, 65, 70] In the other four studies, viral clearance was equal (n = 2) [50, 71] or even better in the corticosteroid group (n = 2) [44, 52]. The numbers are too small to quantify the effect of corticosteroids on viral shedding, or to compare viral shedding duration in subgroups of severity of COVID illness, dose, type or timing of corticosteroids administered. (Additional file 8).
In twelve studies, length of hospital stay was compared in corticosteroid versus non-corticosteroid groups. The outcomes varied between studies: six reported longer hospital stay in the corticosteroid group [36, 47, 53, 56, 66] and five reported the opposite [23, 34, 38, 52, 54] or no effect on hospital stay [58].
Fourteen of 17 studies reported a positive effect of corticosteroids on ventilator-free days [34, 37, 56], on the number of patient requiring mechanical ventilation for respiratory insufficiency [23, 35, 38, 48, 54, 57, 58, 60, 68, 72] or on the time on mechanical ventilator [52]. In the pooled analyses fewer patients required mechanical ventilation in the corticosteroids group (RR 0.71 (95%CI 0.54–0.97) (Fig. 3) though only seven studies supplied sufficient data for this analysis. Jeronimo and Keller failed to demonstrate significant differences [36, 73] and one study reported the opposite effect [53]. The dose of corticosteroids could not be related to respiratory outcomes.
Eleven studies reported on the effect of corticosteroids on oxygenation. Various definitions were used: liters per minute of oxygen needed, oxygen saturation, PaO2/FiO2 ratio. The effect of corticosteroids on oxygenation was very heterogeneous: In four studies, there was no significant effect [41, 42, 51, 55], in three studies significant improvement was described [50, 60, 64] and in four studies worse outcome was observed. [35, 39, 54, 57]
Six studies addressed secondary infections. More frequently broad spectrum antibiotics were used in the corticosteroid group [39, 47, 53] and more secondary infections or sepsis episodes were described [35, 36]. Only Tomazini found a lower percentage of secondary infections in the corticosteroid group [37]. A dose effect of steroids on development of infections or antibiotic need could not be demonstrated.

Discussion

In this systematic review and meta-analysis on effectiveness and safety of corticosteroids in COVID-19 patients, the pooled estimate of the observational retrospective studies and the RCTs supported the positive effect of corticosteroids therapy on mortality in COVID-19 disease as first reported in the RECOVERY trial. [23] Furthermore, in already respiratory compromised COVID-19 patients, the need for mechanical ventilation was lower in corticosteroid treated COVID-19 patients. And although data in the studies were too sparse to draw any firm conclusions, there might be a signal of delayed viral clearance and an increase in antibiotic use and infections in the corticosteroid group. However, this did not seem to lead to prolonged hospital stay or increased mortality.
Besides reviews extrapolating knowledge on SARS-CoV or MERS-CoV [21] or on non-viral ARDS [4], or combining studies on SARS-CoV and MERS-CoV [2, 18, 74], to our knowledge, only three other meta-analyses on this subject were conducted with the conflicting results. [24, 75, 76] Sarkar et al. found low‐quality evidence with high variability, showing that in patients with COVID‐19 corticosteroids may be associated with an around twofold increase in mortality [75]. Tlayjeh et al. [76] found no significant difference in mortality or mechanical ventilation need, at the cost of a prolonged viral clearance time. The investigators explained that the discordance in studies was due to bias in the large number of non-RCTs. In the third, very robust, prospective meta-analysis of published and pending trials (inclusion has pretty much stopped since the recovery trial was published), Sterne et al. [24], found that in critically ill patients with COVID-19, the administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. A downside of this rather robust study was that almost 60 percent of the population consisted of the RECOVERY study population and a reasonable amount of data was generated from unpublished, unfinished studies.
Compared to these other systematic reviews on corticosteroids and COVID-19, ours was able to include the largest number of studies and COVID-19 patients. Furthermore, we included both observational studies and RCTs to be able to assess adverse effects such as viral clearance and risk of infections. To obtain the highest possible quality, we excluded non-peer reviewed pre-published manuscripts and furthermore, if available, we included adjusted estimates in the meta-analysis, reducing bias by incongruent study groups (Additional file 9).
Our review has several limitations. The first is that we retrospectively registered our systematic review and meta-analysis. Indeed, it is very important, especially in COVID-19 pandemic times with a high number of publications on COVID-19, to register beforehand to avoid redundancy and inefficiency and to prevent flooding. The review arose from a clinical point of view to gather all literature on corticosteroids and COVID-19, as we clinicians were in doubt whom to administer this drug to. Doing so, we thought it would be best to summarize our findings in a review, since we presumed other clinicians would be struggling with the same questions.
Furthermore, most of the included studies were retrospective cohort studies with increased risk of bias and lower level of evidence, as we confirmed by the GRADE classification (Table 2, Additional file 10). Besides that, large heterogeneity in the studies was present (i.e., study population, type, dose, initiation and duration of corticosteroids and outcome measures) and we emphasize that definitions of primary and secondary outcome measures varied substantially per included article and pooled data from this review should be interpreted cautiously. However, we decided beforehand to only include short-term mortality, i.e., 28-day or closely related short-term in-hospital mortality. Furthermore, we decided to carefully note the applied definitions in the studies in our data extraction tables and include only outcomes as defined by the investigators if they filled our inclusions criteria. We agree that the remaining variation in definitions is indeed a drawback of this review. And although the pooled data from this review should therefore be interpreted cautiously, they represent the effect of corticosteroids on short-term 28-day mortality and the pooled estimates for RCTs and adjusted and unadjusted observational studies pointed toward the same direction, i.e., of a beneficial effect. In many studies, confounding by indication was evidently present: two studies described that corticosteroid administration was “at the discretion of the treating physician” [40, 41] and four reported that severe patients were more likely to receive corticosteroid treatment. [40, 49, 60, 66] 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 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 included studies, 26 originated in China, with 13 from the hotspot regions (Wuhan, Hubei and Shanghai). This might impair generalizability but although overlapping study populations were present within the included studies (see table in Additional file 4.), this was only incidentally the case for secondary outcome measures. For the main outcome, multiple publication bias was unlikely (Additional file 11). Furthermore, 42% of the study population was included from outside China. 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 USA 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. [77, 78] Despite aforementioned limitations, still, this systematic review and meta-analysis confirms the conclusion of the meta-analysis of the RCTs that critically ill COVID-19 patients hospitalized for moderate or severe respiratory failure, with or without mechanical ventilation, should receive corticosteroids.
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 [79]. On the other hand, there is a need to clear the viral infection itself. This primary phenomenon suggests a possible target for corticosteroids [17]. Thus, the confirmation that there is predominantly a beneficial effect of corticosteroids on mortality is congruent with pathophysiological reasoning and prior knowledge. In our study we, found a signal of delayed viral clearance, but data in the studies were too sparse to draw any firm conclusions. Therefore, what is lacking is knowledge on the optimal start of corticosteroid administration after the start of illness, specific subpopulations and type, dose and duration of corticosteroids. RCTs so far reported a strongly beneficial effect on mortality but did not investigate optimal timing and indication of corticosteroid administration [24], and our study was not able to provide an answer to the latter issues, either. Therefore, future research should focus on which patient characteristics, laboratory and radiological markers can be used to guide indication and timing of corticosteroid treatment, particularly in relation to safety (e.g., delayed viral clearance and increased incidence of secondary infections).

Conclusion

Our findings from both observational studies and RCTs confirm a beneficial effect of corticosteroids on short-term mortality and a reduction in the need for mechanical ventilation. And although data in the studies were too sparse to draw any firm conclusions, there might be a signal of delayed viral clearance and an increase in secondary infections related to corticosteroid use. Optimal timing, dose and duration of corticosteroids, in relation to safety, remain subject for further investigation. Since corticosteroids are affordable and easily accessible in healthcare systems quivering under the pressure of the global outbreak of this rapidly spreading coronavirus, this field of research should be a universal priority.

Supplementary information

Supplementary information accompanies this paper at https://​doi.​org/​10.​1186/​s13054-020-03400-9.

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 plots.
Not applicable.
Not applicable.

Competing interests

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.
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Literatur
2.
Zurück zum Zitat Li H, Chen C, Hu F, et al. Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis. Leukemia. 2020;34(6):1503–11.PubMedCrossRefPubMedCentral Li H, Chen C, Hu F, et al. Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis. Leukemia. 2020;34(6):1503–11.PubMedCrossRefPubMedCentral
4.
Zurück zum Zitat Villar J, Confalonieri M, Pastores SM, et al. Rationale for prolonged corticosteroid treatment in the acute respiratory distress syndrome caused by coronavirus disease 2019. Crit Care Explor. 2020;2(4):e0111.PubMedPubMedCentralCrossRef Villar J, Confalonieri M, Pastores SM, et al. Rationale for prolonged corticosteroid treatment in the acute respiratory distress syndrome caused by coronavirus disease 2019. Crit Care Explor. 2020;2(4):e0111.PubMedPubMedCentralCrossRef
5.
Zurück zum Zitat Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62.PubMedPubMedCentralCrossRef Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62.PubMedPubMedCentralCrossRef
6.
Zurück zum Zitat Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region. Italy JAMA. 2020;323(16):1574–81.PubMedCrossRef Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region. Italy JAMA. 2020;323(16):1574–81.PubMedCrossRef
7.
Zurück zum Zitat Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475–81.PubMedPubMedCentralCrossRef Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475–81.PubMedPubMedCentralCrossRef
8.
Zurück zum Zitat Ziehr DR, Alladina J, Petri CR, et al. Respiratory Pathophysiology of Mechanically Ventilated Patients with COVID-19: A Cohort Study. Am J Respir Crit Care Med. 2020;201(12):1560–4.PubMedPubMedCentralCrossRef Ziehr DR, Alladina J, Petri CR, et al. Respiratory Pathophysiology of Mechanically Ventilated Patients with COVID-19: A Cohort Study. Am J Respir Crit Care Med. 2020;201(12):1560–4.PubMedPubMedCentralCrossRef
9.
Zurück zum Zitat Guan W-j, Ni Z-y, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. New Engl J Med. 2020;382(18):1708–20.PubMedCrossRef Guan W-j, Ni Z-y, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. New Engl J Med. 2020;382(18):1708–20.PubMedCrossRef
10.
Zurück zum Zitat Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.PubMedPubMedCentralCrossRef Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.PubMedPubMedCentralCrossRef
11.
Zurück zum Zitat Jamilloux Y, Henry T, Belot A, et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev. 2020;19(7):102567.PubMedPubMedCentralCrossRef Jamilloux Y, Henry T, Belot A, et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev. 2020;19(7):102567.PubMedPubMedCentralCrossRef
12.
Zurück zum Zitat Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39(5):529–39.PubMedPubMedCentralCrossRef Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39(5):529–39.PubMedPubMedCentralCrossRef
13.
14.
Zurück zum Zitat Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol. 2020;214:108393.PubMedPubMedCentralCrossRef Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol. 2020;214:108393.PubMedPubMedCentralCrossRef
15.
Zurück zum Zitat Alijotas-Reig J, Esteve-Valverde E, Belizna C, et al. Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: a comprehensive review. Autoimmun Rev. 2020;19(7):102569.PubMedPubMedCentralCrossRef Alijotas-Reig J, Esteve-Valverde E, Belizna C, et al. Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: a comprehensive review. Autoimmun Rev. 2020;19(7):102569.PubMedPubMedCentralCrossRef
16.
Zurück zum Zitat Jiang S, Liu T, Hu Y, et al. Efficacy and safety of glucocorticoids in the treatment of severe community-acquired pneumonia: a meta-analysis. Medicine (Baltimore). 2019;98(26):e16239.CrossRef Jiang S, Liu T, Hu Y, et al. Efficacy and safety of glucocorticoids in the treatment of severe community-acquired pneumonia: a meta-analysis. Medicine (Baltimore). 2019;98(26):e16239.CrossRef
17.
Zurück zum Zitat Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267–76.PubMedCrossRef Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267–76.PubMedCrossRef
18.
Zurück zum Zitat Singh AK, Majumdar S, Singh R, et al. Role of corticosteroid in the management of COVID-19: A systemic review and a Clinician’s perspective. Diabetes Metab Syndr. 2020;14(5):971–8.PubMedPubMedCentralCrossRef Singh AK, Majumdar S, Singh R, et al. Role of corticosteroid in the management of COVID-19: A systemic review and a Clinician’s perspective. Diabetes Metab Syndr. 2020;14(5):971–8.PubMedPubMedCentralCrossRef
19.
Zurück zum Zitat Veronese N, Demurtas J, Yang L, et al. Use of corticosteroids in coronavirus disease 2019 pneumonia: a systematic review of the literature. Front Med (Lausanne). 2020;7:170.CrossRef Veronese N, Demurtas J, Yang L, et al. Use of corticosteroids in coronavirus disease 2019 pneumonia: a systematic review of the literature. Front Med (Lausanne). 2020;7:170.CrossRef
20.
Zurück zum Zitat Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757–67.PubMedCrossRef Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757–67.PubMedCrossRef
21.
Zurück zum Zitat Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473–5.PubMedPubMedCentralCrossRef Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473–5.PubMedPubMedCentralCrossRef
24.
Zurück zum Zitat Sterne JAC, Murthy S, Diaz JV, et al. Association between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19: a meta-analysis. JAMA. 2020. Sterne JAC, Murthy S, Diaz JV, et al. Association between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19: a meta-analysis. JAMA. 2020.
26.
Zurück zum Zitat Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854–87.PubMedCrossRefPubMedCentral Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854–87.PubMedCrossRefPubMedCentral
27.
Zurück zum Zitat Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1.PubMedPubMedCentralCrossRef Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1.PubMedPubMedCentralCrossRef
28.
Zurück zum Zitat Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000;53(11):1119–29.PubMedCrossRef Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000;53(11):1119–29.PubMedCrossRef
30.
Zurück zum Zitat Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;18(343):d5928.CrossRef Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;18(343):d5928.CrossRef
34.
Zurück zum Zitat Angus DC, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020;324(13):1317–29.PubMedCrossRefPubMedCentral Angus DC, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020;324(13):1317–29.PubMedCrossRefPubMedCentral
35.
Zurück zum Zitat Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1–9.CrossRefPubMedCentral Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1–9.CrossRefPubMedCentral
36.
Zurück zum Zitat Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (metcovid): a randomised, double-blind, phase IIb, placebo-controlled trial. Clin Infect Dis. 2020. Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (metcovid): a randomised, double-blind, phase IIb, placebo-controlled trial. Clin Infect Dis. 2020.
37.
Zurück zum Zitat Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020.
39.
Zurück zum Zitat Bani-Sadr F, Hentzien M, Pascard M, et al. Corticosteroid therapy for patients with COVID-19 pneumonia: a before-after study. Int J Antimicrob Agents. 2020;56(2):106077.PubMedPubMedCentralCrossRef Bani-Sadr F, Hentzien M, Pascard M, et al. Corticosteroid therapy for patients with COVID-19 pneumonia: a before-after study. Int J Antimicrob Agents. 2020;56(2):106077.PubMedPubMedCentralCrossRef
40.
Zurück zum Zitat Fang X, Mei Q, Yang T, et al. Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19. J Infect. 2020;81(1):147–78.PubMedPubMedCentral Fang X, Mei Q, Yang T, et al. Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19. J Infect. 2020;81(1):147–78.PubMedPubMedCentral
41.
Zurück zum Zitat Fernández-Cruz A, Ruiz-Antorán B, Muñoz-Gómez A, et al. A retrospective controlled cohort study of the impact of glucocorticoid treatment in SARS-CoV-2 infection mortality. Antimicrob Agents Chemother. 2020;64:9.CrossRef Fernández-Cruz A, Ruiz-Antorán B, Muñoz-Gómez A, et al. A retrospective controlled cohort study of the impact of glucocorticoid treatment in SARS-CoV-2 infection mortality. Antimicrob Agents Chemother. 2020;64:9.CrossRef
42.
Zurück zum Zitat Gazzaruso C, Carlo Stella N, Mariani G, et al. Impact of anti-rheumatic drugs and steroids on clinical course and prognosis of COVID-19. Clin Rheumatol. 2020;39(8):2475–7.PubMedCrossRef Gazzaruso C, Carlo Stella N, Mariani G, et al. Impact of anti-rheumatic drugs and steroids on clinical course and prognosis of COVID-19. Clin Rheumatol. 2020;39(8):2475–7.PubMedCrossRef
43.
Zurück zum Zitat Gong Y, Guan L, Jin Z, 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. J Med Virol. 2020. Gong Y, Guan L, Jin Z, 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. J Med Virol. 2020.
44.
Zurück zum Zitat Hu Y, Wang T, Hu Z, et al. Clinical efficacy of glucocorticoid on the treatment of patients with COVID-19 pneumonia: a single-center experience. Biomed Pharmacother. 2020;130:110529.PubMedPubMedCentralCrossRef Hu Y, Wang T, Hu Z, et al. Clinical efficacy of glucocorticoid on the treatment of patients with COVID-19 pneumonia: a single-center experience. Biomed Pharmacother. 2020;130:110529.PubMedPubMedCentralCrossRef
45.
Zurück zum Zitat Huang H, Song B, Xu Z, et al. Predictors of coronavirus disease 2019 severity: a retrospective study of 64 cases. Jpn J Infect Dis. 2020. Huang H, Song B, Xu Z, et al. Predictors of coronavirus disease 2019 severity: a retrospective study of 64 cases. Jpn J Infect Dis. 2020.
46.
Zurück zum Zitat Li Q, Li W, Jin Y, et al. Efficacy evaluation of early, low-dose, short-term corticosteroids in adults hospitalized with non-severe COVID-19 pneumonia: a retrospective cohort study. Infect Dis Therapy. 2020. Li Q, Li W, Jin Y, et al. Efficacy evaluation of early, low-dose, short-term corticosteroids in adults hospitalized with non-severe COVID-19 pneumonia: a retrospective cohort study. Infect Dis Therapy. 2020.
47.
Zurück zum Zitat Li S, Hu Z, Song X. High-dose but not low-dose corticosteroids potentially delay viral shedding of patients with COVID-19. Clin Infect Dis. 2020. Li S, Hu Z, Song X. High-dose but not low-dose corticosteroids potentially delay viral shedding of patients with COVID-19. Clin Infect Dis. 2020.
48.
Zurück zum Zitat Li Y, Zhou X, Li T, et al. Corticosteroid prevents COVID-19 progression within its therapeutic window: a multicentre, proof-of-concept, observational study. Emerg Microbes Infect. 2020;9(1):1869–77.PubMedPubMedCentralCrossRef Li Y, Zhou X, Li T, et al. Corticosteroid prevents COVID-19 progression within its therapeutic window: a multicentre, proof-of-concept, observational study. Emerg Microbes Infect. 2020;9(1):1869–77.PubMedPubMedCentralCrossRef
49.
50.
Zurück zum Zitat Liu K, Fang Y-Y, Deng Y, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl). 2020;133(9):1025–31.CrossRef Liu K, Fang Y-Y, Deng Y, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl). 2020;133(9):1025–31.CrossRef
52.
Zurück zum Zitat Ma Q, Qi D, Deng XY, et al. Corticosteroid therapy for patients with severe novel Coronavirus disease 2019. Eur Rev Med Pharmacol Sci. 2020;24(15):8194–201.PubMed Ma Q, Qi D, Deng XY, et al. Corticosteroid therapy for patients with severe novel Coronavirus disease 2019. Eur Rev Med Pharmacol Sci. 2020;24(15):8194–201.PubMed
53.
Zurück zum Zitat Ma Y, Zeng H, Zhan Z, et al. Corticosteroid use in the treatment of COVID-19: a multicenter retrospective study in hunan, China. Front Pharmacol. 2020;11:1198.PubMedPubMedCentralCrossRef Ma Y, Zeng H, Zhan Z, et al. Corticosteroid use in the treatment of COVID-19: a multicenter retrospective study in hunan, China. Front Pharmacol. 2020;11:1198.PubMedPubMedCentralCrossRef
54.
Zurück zum Zitat Majmundar M, Kansara T, Lenik JM, et al. Efficacy of corticosteroids in non-intensive care unit patients with COVID-19 pneumonia from the New York Metropolitan region. PLoS ONE. 2020;15(9):e0238827.PubMedPubMedCentralCrossRef Majmundar M, Kansara T, Lenik JM, et al. Efficacy of corticosteroids in non-intensive care unit patients with COVID-19 pneumonia from the New York Metropolitan region. PLoS ONE. 2020;15(9):e0238827.PubMedPubMedCentralCrossRef
55.
56.
Zurück zum Zitat Nelson BC, Laracy J, Shoucri S, et al. Clinical outcomes associated with methylprednisolone in mechanically ventilated patients with COVID-19. Clin Infect Dis. 2020. Nelson BC, Laracy J, Shoucri S, et al. Clinical outcomes associated with methylprednisolone in mechanically ventilated patients with COVID-19. Clin Infect Dis. 2020.
57.
Zurück zum Zitat Rodríguez-Baño J, Pachón J, Carratalà J, et al. Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19). Clin Microbiol Infect. 2020. Rodríguez-Baño J, Pachón J, Carratalà J, et al. Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19). Clin Microbiol Infect. 2020.
58.
Zurück zum Zitat Salton F, Confalonieri P, Meduri GU, et al. Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia. Open Forum Infect Dis. 2020;7:10.CrossRef Salton F, Confalonieri P, Meduri GU, et al. Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia. Open Forum Infect Dis. 2020;7:10.CrossRef
59.
Zurück zum Zitat Shen Y, Zheng F, Sun D, et al. Epidemiology and clinical course of COVID-19 in Shanghai. China Emerg Microbes Infect. 2020;9(1):1537–45.PubMedCrossRef Shen Y, Zheng F, Sun D, et al. Epidemiology and clinical course of COVID-19 in Shanghai. China Emerg Microbes Infect. 2020;9(1):1537–45.PubMedCrossRef
60.
Zurück zum Zitat Wang Y, Jiang W, He Q, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther. 2020;5(1):57.PubMedPubMedCentralCrossRef Wang Y, Jiang W, He Q, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther. 2020;5(1):57.PubMedPubMedCentralCrossRef
61.
Zurück zum Zitat Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan. China JAMA Intern Med. 2020;180(7):934–43.PubMedCrossRef Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan. China JAMA Intern Med. 2020;180(7):934–43.PubMedCrossRef
62.
Zurück zum Zitat Wu J, Huang J, Zhu G, et al. Systemic corticosteroids and mortality in severe and critical COVID-19 patients in Wuhan. China J Clin Endocrinol Metab. 2020;105:12.CrossRef Wu J, Huang J, Zhu G, et al. Systemic corticosteroids and mortality in severe and critical COVID-19 patients in Wuhan. China J Clin Endocrinol Metab. 2020;105:12.CrossRef
63.
Zurück zum Zitat Xu K, Chen Y, Yuan J, et al. Factors associated with prolonged viral RNA shedding in patients with coronavirus disease 2019 (COVID-19). Clin Infect Dis. 2020;71(15):799–806.PubMedCrossRef Xu K, Chen Y, Yuan J, et al. Factors associated with prolonged viral RNA shedding in patients with coronavirus disease 2019 (COVID-19). Clin Infect Dis. 2020;71(15):799–806.PubMedCrossRef
64.
Zurück zum Zitat Yang SS, Lipes J. Corticosteroids for critically ill COVID-19 patients with cytokine release syndrome: a limited case series. Can J Anaesth. 2020;67(10):1462–4.PubMedCrossRefPubMedCentral Yang SS, Lipes J. Corticosteroids for critically ill COVID-19 patients with cytokine release syndrome: a limited case series. Can J Anaesth. 2020;67(10):1462–4.PubMedCrossRefPubMedCentral
65.
66.
Zurück zum Zitat Feng Y, Ling Y, Bai T, et al. COVID-19 with different severities: a multicenter study of clinical features. Am J Respir Crit Care Med. 2020;201(11):1380–8.PubMedPubMedCentralCrossRef Feng Y, Ling Y, Bai T, et al. COVID-19 with different severities: a multicenter study of clinical features. Am J Respir Crit Care Med. 2020;201(11):1380–8.PubMedPubMedCentralCrossRef
67.
Zurück zum Zitat Wang Z, Yang B, Li Q, et al. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan. China Clin Infect Dis. 2020;71(15):769–77.PubMedCrossRef Wang Z, Yang B, Li Q, et al. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan. China Clin Infect Dis. 2020;71(15):769–77.PubMedCrossRef
68.
Zurück zum Zitat Callejas Rubio JL, Luna Del Castillo JD, de la Hera FJ, et al. Effectiveness of corticoid pulses in patients with cytokine storm syndrome induced by SARS-CoV-2 infection. Med Clin (Barc). 2020;155(4):159–61.CrossRef Callejas Rubio JL, Luna Del Castillo JD, de la Hera FJ, et al. Effectiveness of corticoid pulses in patients with cytokine storm syndrome induced by SARS-CoV-2 infection. Med Clin (Barc). 2020;155(4):159–61.CrossRef
69.
Zurück zum Zitat Wang K, Zhang Z, Yu M, et al. 15-day mortality and associated risk factors for hospitalized patients with COVID-19 in Wuhan, China: an ambispective observational cohort study. Intensive Care Med. 2020;46(7):1472–4.PubMedCrossRefPubMedCentral Wang K, Zhang Z, Yu M, et al. 15-day mortality and associated risk factors for hospitalized patients with COVID-19 in Wuhan, China: an ambispective observational cohort study. Intensive Care Med. 2020;46(7):1472–4.PubMedCrossRefPubMedCentral
70.
Zurück zum Zitat Chen X, Zhu B, Hong W, et al. Associations of clinical characteristics and treatment regimens with the duration of viral RNA shedding in patients with COVID-19. Int J Infect Dis. 2020;98:252–60.PubMedPubMedCentralCrossRef Chen X, Zhu B, Hong W, et al. Associations of clinical characteristics and treatment regimens with the duration of viral RNA shedding in patients with COVID-19. Int J Infect Dis. 2020;98:252–60.PubMedPubMedCentralCrossRef
71.
Zurück zum Zitat Shi D, Wu W, Wang Q, et al. Clinical characteristics and factors associated with long-term viral excretion in patients with severe acute respiratory syndrome coronavirus 2 infection: a single-Center 28-day study. J Infect Dis. 2020;222(6):910–8.PubMedCrossRef Shi D, Wu W, Wang Q, et al. Clinical characteristics and factors associated with long-term viral excretion in patients with severe acute respiratory syndrome coronavirus 2 infection: a single-Center 28-day study. J Infect Dis. 2020;222(6):910–8.PubMedCrossRef
72.
Zurück zum Zitat Chroboczek T, Lacoste M, Wackenheim C, et al. Corticosteroids in patients with COVID-19: what about the control group? Clin Infect Dis. 2020. Chroboczek T, Lacoste M, Wackenheim C, et al. Corticosteroids in patients with COVID-19: what about the control group? Clin Infect Dis. 2020.
73.
Zurück zum Zitat Keller MJ, Kitsis EA, Arora S, et al. Effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with COVID-19. J Hosp Med. 2020;15(8):489–93.PubMedCrossRefPubMedCentral Keller MJ, Kitsis EA, Arora S, et al. Effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with COVID-19. J Hosp Med. 2020;15(8):489–93.PubMedCrossRefPubMedCentral
74.
Zurück zum Zitat Yang Z, Liu J, Zhou Y, et al. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect. 2020;81(1):e13–20.PubMedPubMedCentralCrossRef Yang Z, Liu J, Zhou Y, et al. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect. 2020;81(1):e13–20.PubMedPubMedCentralCrossRef
75.
Zurück zum Zitat Sarkar S, Khanna P, Soni KD. Are the steroids a blanket solution for COVID-19? A systematic review and meta-analysis. J Med Virol. 2020. Sarkar S, Khanna P, Soni KD. Are the steroids a blanket solution for COVID-19? A systematic review and meta-analysis. J Med Virol. 2020.
76.
Zurück zum Zitat Tlayjeh H, Mhish OH, Enani MA, et al. Association of corticosteroids use and outcomes in COVID-19 patients: a systematic review and meta-analysis. Journal of Infection and Public Health. 2020. Tlayjeh H, Mhish OH, Enani MA, et al. Association of corticosteroids use and outcomes in COVID-19 patients: a systematic review and meta-analysis. Journal of Infection and Public Health. 2020.
80.
Zurück zum Zitat Cao J, Tu WJ, Cheng W, et al. Clinical features and short-term outcomes of 102 patients with coronavirus disease 2019 in Wuhan. China Clin Infect Dis. 2020;71(15):748–55.PubMedCrossRef Cao J, Tu WJ, Cheng W, et al. Clinical features and short-term outcomes of 102 patients with coronavirus disease 2019 in Wuhan. China Clin Infect Dis. 2020;71(15):748–55.PubMedCrossRef
81.
Zurück zum Zitat Huang M, Yang Y, Shang F, et al. Clinical characteristics and predictors of disease prgression in severe patients with COVID-19 infection in jiangsu province, China: a discriptive study. Am J Med Sci. 2020;360(2):120–8.PubMedCrossRefPubMedCentral Huang M, Yang Y, Shang F, et al. Clinical characteristics and predictors of disease prgression in severe patients with COVID-19 infection in jiangsu province, China: a discriptive study. Am J Med Sci. 2020;360(2):120–8.PubMedCrossRefPubMedCentral
Metadaten
Titel
Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes
verfasst von
Judith van Paassen
Jeroen S. Vos
Eva M. Hoekstra
Katinka M. I. Neumann
Pauline C. Boot
Sesmu M. Arbous
Publikationsdatum
01.12.2020
Verlag
BioMed Central
Erschienen in
Critical Care / Ausgabe 1/2020
Elektronische ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-020-03400-9

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