Safety and efficacy of glucocorticoids in the treatment of COVID-19: A meta-analysis of randomized control trials

Figures & data

Figure 1. Study selection process.

Table 1. Included trails and characteristics.

Author	Published time	Country	Design	Age	Mean age ((male/female)	Sex(male/female)	No. of participants(experiment/control)	Control	Glucocorticoid species	Dose and duriation	Inclusion criteria	The main outcome
Ramakrishnan et al [16].	2021	Britain	open-label, parallel-group, phase 2, randomized controlled trial	>18	44/46	59/80	139 (70/69)	Usual care	Inhaled budesonide	400 μg twice daily until symptom resolution	Adults who have developed COVID-19 symptoms within 7 days (new-onset cough and fever or loss of smell, or both).	COVID-19-related urgent care visits, including emergency department assessment or hospitalization.
Yu et al [17].	2021	Britain	multicentre, open-label, multi-arm, randomized, controlled, adaptive platform trial	>50	64.7/63.8	Unclear	1856 (787/1069)	Usual care	Inhaled budesonide	800 μg twice daily for 14 days	Eligible participants felt unwell for up to 14 days with suspected COVID-19 but not admitted to hospital.	Time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days
Ezer et al [18].	2021	Canada	randomized, double blind, placebo controlled trial	>18	32/35	Unclear	203 (105/98)	Placebo	Inhaled and intranasal ciclesonide	inhaled ciclesonide (600 μg twice daily) and intranasal ciclesonide (200 μg daily)	PCR confirmed COVID-19, presenting with fever, cough, or dyspnea.	Symptom resolution at day 7
Clemency et al [19].	2022	America	phase 3, multicenter, double-blind, randomized clinical trial	>12	43.7/42.9	179/221	400 (197/203)	Placebo	Inhaled Ciclesonide	160 μg twice daily	(1)PCR confirmed COVID-19 during the previous 72 hours, presenting with fever, cough, or dyspnea. (2) were not hospitalized or under consideration for hospitalization, (3) Spo2 < 93%.	Time to alleviation of all COVID-19–related symptoms (cough, dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell) by day 30.
Jamaati et al [20].	2021	Iran	randomized, controlled, clinical trial	>18	62/62	36/24	50 (25/25)	Usual care	Intravenous dexamethasone	20 mg/day from day 1–5 and then 10 mg/day from day 6–10.	(1) PCR confirmed COVID-19; (2) PaO2/FiO2 were between 100 and 300 mmHg; (3) bilateral lung infiltration.	The need for invasive mechanical ventilation and death rate
Tomazini et al [21].	2020	Baxi	multicenter, randomized, open-label, clinical trial	>18	60.1/62.7	187/112	299 (151/148)	Standard care	Intravenous dexamethasone	20 mg daily for 5 days, 10 mg daily for 5 days or until ICU discharge,	PCR confirmed COVID-19, and received mechanical ventilation within 48 hours of meeting criteria for moderate to severe ARDS with PaO2:FIO2 < 200 mmHg.	Ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation.
Ghanei et al [22].	2021	America	multicenter, randomized open-label trial	>16	58.2/57.6	112/114	226 (116/110)	Azithromycin	Prednisolone	25 mg daily for 5 days	PCR confirmed COVID-19 and Spo2 < 94%	Admission to ICU
Tang et al [23].	2021	Beijing	prospective, multicenter, single-blind, randomized control trial	>18	57/55	41/45	86 (43/43)	Usual care	Intravenous methylprednisolone	1 mg/kg daily for 7 days	Confirmed COVID-19.	The incidence of clinical deterioration 14 days after randomization.
Edalatifard et al. [24]	2020	Iran	single-blind, randomized, controlled, clinical trial	>18	55.8/61.7	39/23	62 (34/28)	Standard care	Intravenous methylprednisolone	250 mg/day for 3 days	Confirmed COVID-19 with Spo2 < 90%, CRP >10, and interleukin-6 (>6) at the early pulmonary phase of disease before connecting to the ventilator and intubation.	The time of clinical improvement or death, whichever came first.
Jeronimo et al [25].	2021	Baxi	randomized, Double-Blind, Phase IIb, Placebo-Controlled Trial	≥ 18	54/57	254/139	393 (194/199)	Placebo	Intravenous methylprednisolone	0.5 mg/kg twice daily for 5 days	Hospitalized patients with clinical, epidemiological and/or radiological suspected COVID-19	28-day mortality
Luis Corral-Gudino et al [26].	2021	Spain	randomized, open-label, controlled, two-arm, parallel-group, trial	>18	73/66	39/25	64 (35/29)	Standard care	Intravenous methylprednisolone	40 mg bid for 3 days followed by 20 mg bid for 3 days	PCR confirmed COVID-19.	Composite endpoint, including in-hospital all-cause mortality, escalation to ICU admission, or progression of respiratory insufficiency that required NIV.
Dequin et al [27].	2020	France	multicenter randomized double-blind sequential trial	≥ 18	54/50	105/45	149 (76/73)	Placebo	low-dose hydrocortisone	200 mg/d until day 7 and then decreased to 100 mg/d for 4 days and 50 mg/d for 3 days, for a total of 14 days	PCR confirmed COVID-19.	Treatment failure on day 21, defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy.
Angus et al [28].	2020	multicenter	randomized controlled, ongoing, international, multicenter, open label trial	≥ 18	60.4/59.9	170/68	238 (137/101)	Usual care	Intravenous hydrocortisone	50 mg, every 6 hours for 7 days	Patients with a presumed or confirmed SARS-CoV-2 infection are admitted to ICU to provide respiratory or cardiovascular organ support.	Organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days.
Marie et al [29].	2021	Denmark	multicentre, parallel-group, placebo-controlled, blinded, centrally randomized, stratified clinical trial	≥ 18	59/62	24/6	30 (16/14)	Placebo	Intravenous hydrocortisone	200 mg/d for 7 days	Adults with a confirmed diagnosis of COVID-19 and severe hypoxia (using mechanical ventilation or supplemental oxygen, with a flow rate of at least 10 L/min)	The number of days alive without life support at day 28

PaO2/FiO2: ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen; ICU: the intensive care unit; Spo2: oxygen saturation; CRP: C-reactive protein; NIV: noninvasive ventilation

Figure 2. Risk of bias summary.

Table 2. The Jadad modified rating scale.

RCT	Random	Allocation	Blinding	Loss of follow-up	Score
Ramakrishnan	2	0	0	1	3
Yu	2	2	0	1	5
Ezer	2	1	1	1	5
Clemency	2	2	1	1	6
Jamaati	1	0	0	1	2
RECOVERY	2	2	0	1	5
Tomazini	2	2	0	1	5
Ghanei	2	2	0	1	5
Tang	2	2	1	1	6
Edalatifard,	2	1	1	1	5
Jeronimo	2	0	1	1	4
Luis Corral-Gudino	2	2	0	1	5
Dequin	2	2	1	1	6
Angus	1	1	0	1	3
Marie	2	2	1	1	6

The score is 1–3 for low quality literature and 4–7 for high quality literature.

Figure 3. All-cause mortality.

Figure 4. Adverse reactions.

Table 3. Types of adverse reactions.

	Illustrative comparative risks* (95% CI)
Outcomes	Assumed riskControl			Corresponding risk Glucocorticoid			Relative effect(95% CI)			No of Participants(studies)				Quality of the evidence(GRADE)	Comments
All-cause mortality
Patient or population: patients with COVID-19 Settings: all-cause mortality Intervention: glucocorticoid
All-cause mortality	Study population						OR 0.85 (0.76 to 0.94)			10,481(14 studies)				⊕⊕⊕⊕high
	214 per 1000			188 per 1000(171 to 204)
	Moderate
	215 per 1000			189 per 1000(172 to 205)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Adverse reaction
Patient or population: patients with COVID-19 Settings: Intervention: glucocorticoid
Adverse reactions		Study population						OR 1.18 (0.77 to 1.8)			3875(11 studies)		⊕⊕⊕⊝moderate^1
		121 per 1000			140 per 1000(96 to 199)
		Moderate
		71 per 1000			83 per 1000(56 to 121)
Hyperglycemia		Study population						OR 1.25 (0.67 to 2.33)			796(4 studies)		⊕⊕⊝⊝low^2
		343 per 1000			395 per 1000(259 to 548)
		Moderate
		223 per 1000			264 per 1000(161 to 401)
Infection		Study population						OR 0.85 (0.53 to 1.37)			511(4 studies)		⊕⊕⊕⊝moderate^2
		181 per 1000			159 per 1000(105 to 233)
		Moderate
		29 per 1000			25 per 1000(16 to 39)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^1 The funnel plot was asymmetrical. ^2 The number of included studies is small.
Type of glucocorticoids
Patient or population: patients with COVID-19 Settings: Intervention: glucocorticoids
Dexamethasone			Study population						OR 0.86 (0.76 to 0.97)			6774(3 studies)		⊕⊕⊕⊝moderate^1
			271 per 1000			242 per 1000(220 to 265)
			Moderate
			600 per 1000			563 per 1000(533 to 593)
Prednisolone			Study population						OR 0.62 (0.17 to 2.26)			226(1 study)		⊕⊝⊝⊝very low^1,2,3
			55 per 1000			35 per 1000(10 to 115)
			Moderate
			55 per 1000			35 per 1000(10 to 116)
Methylprednisolone			Study population						OR 0.54 (0.18 to 1.63)			603(4 studies)		⊕⊕⊝⊝low^2
			314 per 1000			198 per 1000(76 to 428)
			Moderate
			277 per 1000			171 per 1000(65 to 384)
Hydrocortisone			Study population						OR 0.8 (0.37 to 1.72)			558(3 studies)		⊕⊕⊝⊝low^1,4,5
			293 per 1000			249 per 1000(133 to 416)
			Moderate
			274 per 1000			232 per 1000(123 to 394)
Budesonide			Study population						OR 0.38 (0.08 to 1.75)			1995(2 studies)		⊕⊕⊝⊝low^1,4,5
			19 per 1000			7 per 1000(2 to 33)
			Moderate
			85 per 1000			34 per 1000(7 to 140)
Ciclesonide			Study population						OR 1.4 (1.01 to 1.96)			603(2 studies)		⊕⊕⊝⊝low^1,4
			575 per 1000			654 per 1000(577 to 726)
			Moderate
			542 per 1000			624 per 1000(544 to 699)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^1 The number of included studies is small.^2 The heterogeneity is high(>50%).^3 Wide confidence interval.^4 Blinding missing and no allocation concealment.^5 The heterogeneity is high, which may be caused by the lack of blinding, so there is no repeated degradation.
Different disease processes
Patient or population: patients with COVID-19 Settings: Intervention: glucocorticoid
Mild and ordinary			Study population						OR 0.64 (0.24 to 1.76)			3616(4 studies)		⊕⊕⊝⊝low^1,2
			75 per 1000			50 per 1000(19 to 126)
			Moderate
			82 per 1000			54 per 1000(21 to 136)
Severe and critically			Study population						OR 0.78 (0.69 to 0.88)			6386(7 studies)		⊕⊕⊕⊝moderate^2
			306 per 1000			256 per 1000(233 to 279)
			Moderate
			327 per 1000			275 per 1000(251 to 300)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^1 The heterogeneity is high, which may be caused by the lack of blinding, so there is no repeated degradation.^2 The number of included studies is small.
Different doses of glucocorticoids
Patient or population: patients with COVID-19 Settings: Intervention: Different doses of glucocorticoids
Low-dose			Study population						OR 0.86 (0.77 to 0.96)			8011(9 studies)		⊕⊕⊕⊝moderate^1
			246 per 1000			219 per 1000(201 to 239)
			Moderate
			172 per 1000			152 per 1000(138 to 166)
High-dose			Study population						OR 0.61 (0.28 to 1.34)			2470(5 studies)		⊕⊕⊝⊝low^2,3,4
			94 per 1000			60 per 1000(28 to 122)
			Moderate
			429 per 1000			314 per 1000(174 to 502)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^1 The funnel plot was asymmetrical. ^2 Blinding missing and no allocation concealment.^3 The heterogeneity is high, which may be caused by the lack of blinding, so there is no repeated degradation.^4 The number of included studies is small.

Table 4. The length of hospital stay in patients with COVID-19.

RCT	Usual care		Glucocorticoid		P
	Median	Average	Median	Average
Jamaati	6 (4–9)		11 (6–16)		0.036
Ghanei		ITT:6.4 PP:5.9		ITT:5.5 PP:4.4	0.09 0.03
Jeronimo	9 (7–12)		10 (9–13)		0.296

ITT: Intention-to-treat analysis, PP: Per-protocol analysis

Figure 5. Funnel plots.

Table 5. Types of adverse reactions.

		Types of adverse reactions
Author	Glucocorticoid species	Glucocorticoid	Control
Ramakrishnan et al. [16]	Inhaled budesonide	Sore throat; dizziness	Specific name not reported
Yu et al. [17]	Inhaled budesonide	Hospital admission unrelated to COVID-19	Hospital admission unrelated to COVID-19
Ezer et al. [18]	Inhaled Ciclesonide	Headache; nausea	Headache; nausea
Clemency et al. [19]	Inhaled Ciclesonide	Headache; Dry mouth	Headache, dry mouth
Tomazini et al. [21]	Intravenous dexamethasone	Hyperglycemia; secondary infection	Hyperglycemia; secondary infection
Tang et al. [23]	Intravenous methylprednisolone	Hyperglycemia; pneumonia	Hyperglycemia; pneumonia
Edalatifard et al. [24]	Intravenous methylprednisolone	Infection; edema	Shock
Jeronimo et al. [25]	Intravenous methylprednisolone	Hyperglycemia	Hyperglycemia
Luis Corral-Gudino et al. [26]	Intravenous methylprednisolone	Hyperglycemia; Nosocomial infection	Hyperglycemia, Nosocomial infection
Dequin et al. [27]	Intravenous hydrocortisone	Intra-abdominal hemorrhage; cardiac arrest; cerebral vasculitis	No adverse reaction
Angus et al. [28]	Intravenous hydrocortisone	Severe neuromyopathy; fungemia	Specific name not reported

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