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. 2021 Mar 17;7(1):67. doi: 10.1186/s43094-021-00217-3

Therapeutic role of corticosteroids in COVID-19: a systematic review of registered clinical trials

Reshma Raju 1, Prajith V 1, Pratheeksha Sojan Biatris 1, Sam Johnson Udaya Chander J 1,✉
PMCID: PMC7968560  PMID: 33754123

Abstract

Background

In March 2020, the World Health Organization declared the coronavirus disease 2019 as a global pandemic. Though antiviral drugs and antimalarial drugs are considered treatment options for treating coronavirus disease 2019 (COVID-19), no specific antivirals are currently available for its treatment. Efficient use of drug discovery approaches including repurposing or repositioning of drugs used in the treatment of severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) is considered recently. The widespread application of corticosteroid therapy in COVID-19 should be backed with careful documented pragmatic research of its use in this context.

Main body

This article aims to analyze various trials registered across the globe providing an overall picture of the use of corticosteroids in the treatment of COVID-19. An extensive search was conducted on the clinical trial registries around the world to identify all the trials reporting information regarding the use of corticosteroids in COVID-19. Our initial search returned 231 trials, out of which 60 trials were finally included in the analysis. Fifty-six studies were interventional trials, and all the trials had clearly defined primary and secondary outcomes of interest, of which only 11 trials had evaluation of respiratory rate as one of their outcomes.

Conclusion

Few preliminary trial findings show promising results and recommend the use of methylprednisolone and dexamethasone in the severe form of the disease; however, there is insufficient data to prove its benefits over its risks. Routine use of corticosteroids should be favored only after a better insight is obtained, with the completion of these trials.

Keywords: Methylprednisolone; Hydrocortisone; Steroids, COVID-19; SARS-CoV2, Clinical trial registry

Background

An outbreak of pneumonia caused by a new coronavirus spread in Wuhan province of China in December 2019. Sequencing of the sampling from patients with pneumonia revealed the viral genome phylogenetically closer to severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) [1]. The Coronavirus Study Group named the causative agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disease caused by this virus was named coronavirus disease 2019 (COVID-19 or 2019-nCoV) by the World Health Organization (WHO) [2, 3]. These viruses are enveloped, positive, single-stranded RNA viruses belonging to the family Coronaviridae, which can cause an array of symptoms including fever, dry cough, myalgia, fatigue, and dyspnea [4]. SARS-CoV-2 transmits from human-to-human by respiratory droplets caused by coughing or sneezing [5, 6]. The WHO declared COVID-19 as a Public Health Emergency of International Concern in January 2020 [7]. The infection has spread over to 216 countries (15,745,102 confirmed cases and 639,317 confirmed deaths) since its outbreak in November 2019 (as of 30 January 2021; Fig. 1).

Fig. 1.

Fig. 1

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Global COVID-19 spread showing number of confirmed cases as of 30 January 2021 (Source: https://covid19.who.int/)

Detection and diagnosis of this novel coronavirus mostly relied on molecular-based approaches such as nucleic acid testing, virus antigen, or serological antibody testing (against the N-protein of SARS-CoV) [8]. Treatment option includes antiviral drugs such as favipiravir, remdesivir, lopinavir, and ritonavir and antimalarial drugs such as chloroquine or hydroxychloroquine. Nevertheless, no vaccine or specific antiviral treatment recommended for COVID-19 is currently available [9]. The uncontrolled scenario of COVID-19 demands the use of effective drug discovery approaches for effective control of the disease [10–16]. Among these approaches, drug repurposing or drug repositioning is a time-effective way of treating a disease. One of the examples of successful application of drug discovery approach is drug repositioning of antivirals, and it has triggered a number of in vitro studies as well as clinical trials for a number of chemical molecules to evaluate their efficacy against COVID-19 [17–19]. Drug repurposing of corticosteroids has also been implemented recently as a part of a drug discovery approach. There are several studies reporting the use of corticosteroids in the treatment of severe coronavirus infections including COVID-19. The effectiveness of corticosteroids in some patients with SARS-CoV has resulted in a widespread application of this therapy in COVID-19, especially in patients in the ICU with severe infections, as these drugs prevent lung injury caused by severe community-acquired pneumonia (sCAP) due to their potential pharmacological effects on the suppression of exuberant and dysfunctional systematic inflammation [20].

Main body

Corticosteroids and their therapeutic role

The Infectious Diseases Society of America (IDSA) guidelines strongly recommends the use of dexamethasone in critically ill patients to treat acute respiratory distress syndrome (ARDS) and systemic inflammation, backed by moderate evidence. Dexamethasone at a total daily dose of 6 mg IV or PO for 10 days (or until discharge) or alternative glucocorticoids like methylprednisolone 32 mg and prednisone 40 mg are suggested. The level of recommendation decreases with decreasing severity of the disease. In non-severe COVID-19, the use of glucocorticoids is not recommended as there is a dearth of solid evidence. Additionally, experiences from SARS and MERS show risk of worsening clinical status, delayed viral clearance, and other adverse events [21]. Currently, available data on safety and effectiveness of corticosteroids in this setting is very few and inconclusive [20, 22, 23]. The value of corticosteroids as a treatment option in patients with severe COVID-19 infection needs careful documented pragmatic research in this context. In order to obtain strong clinical evidence, several studies have been launched that were registered on various clinical trial registries across the globe. The detailed analysis of these trials will give an overall picture of the use of corticosteroids in the treatment of COVID-19 around the world. This will help to identify the lacunae to be filled with definitive clinical evidence in order to reposition corticosteroid for COVID-19 treatment. Therefore, this study aims to analyze various trials registered across the globe providing an overall picture of the use of corticosteroids in the treatment of COVID-19.

Search strategy

An extensive search was conducted to identify all the trials reporting information regarding the use of corticosteroids in COVID-19. We searched the following clinical trial registries: Clinicaltrials.gov, Chinese Clinical Trial Registry (ChiCTR), Clinical Research Information Service (CRiS)–Republic of Korea, EU Clinical Trials Register, ISRCTN Registry, Iranian Registry of Clinical Trials (IRCT), German Clinical Trials Register (DRKS), Japan Primary Registries Network (JPRN), and Clinical Trial Registry–India. The search was run until 23 June 2020. In Clinicaltrials.gov, the following keywords were used for search: “(COVID-19 OR SARS-CoV-2 OR 2019-nCoV OR severe acute respiratory syndrome coronavirus 2 OR Wuhan coronavirus OR 2019 novel coronavirus OR novel coronavirus–infected Pneumonia) AND (“glucocorticoids” OR “steroids” OR “corticosteroids” OR “hydrocortisone” OR “prednisone” OR “methylprednisolone” OR “dexamethasone” OR “prednisolone”). A similar strategy was adapted for the other registries. We included the English language and interventional and non-interventional studies. No restrictions were placed on the dose or formulation of the intervention. All trials must have studied the safety and efficacy of steroids in COVID-19 care.

Recovery of trials

Our initial search returned 231 trials, out of which 62 potentially relevant trials were identified. Potentially eligible trials were identified by three authors by screening titles and study description. All eligible trials were then assessed independently by three authors, and potentially relevant trials were selected in accordance with the predefined inclusion criteria. Any disagreement was reviewed and resolved by a fourth independent reviewer. Authors of individual trials were contacted if necessary. After a careful review of the study description, out of 62 articles, 2 trials did not satisfy the inclusion criteria and were excluded from the analysis. Finally, data from 60 trials were included in the final review and synthesis of results. This is shown in Fig. 2.

Fig. 2.

Fig. 2

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PRISMA flow diagram of reporting search results

Data abstraction and study appraisal

We extracted the following general data from each study: trial number, title, origin (country) of study, intervention, treatment arms, doses, mean age of participants, stage of COVID–19, expected start and end date of trial, primary outcomes of the study, blinding, randomization, and study design.

Scrutiny of trials

Our initial search of the clinical trial registries resulted in 231 trials, of which 167 trials did not satisfy the inclusion criteria and three trials did not have complete data, and after removing the duplicates, 60 trials were included in the final analysis. Thus, 60 trials with 31,732 patients were included in this systematic review. The included trials were classified into trials that included only steroid therapy and those that included steroids in addition to other standard treatment as shown in Table 1.

Table 1.

General characteristics of the included trials

Trial identifier Country Number of sites Start date Expected completion date Stage of COVID-19 Outcome measures
NCT04425863 Argentina Single May 2020 July 2020 Severe acute respiratory syndrome

1. Illness development

2. Reduction of ICU admission

3. Mortality rate
NCT04395105 Argentina Multi May 2020 January 2021 Respiratory distress syndrome Ventilator-free days at 28 days
NCT02735707 Australia, Belgium, Canada, Croatia, Germany, Hungary, Ireland, Netherlands, New Zealand, Portugal, Romania, Spain, UK Multi April 2020 December 2023 Pneumonia

1. All-cause mortality

2. Days alive and outside of ICU
NCT04343729 Brazil Single April 2020 September 2020 Severe acute respiratory syndrome (SARS) Mortality rate
NCT04327401 Brazil Multi April 2020 August 2020 Moderate/severe ARDS Ventilator-free days
NCT04377503 Brazil Not available May 2020 November 2020 Cytokine release syndrome Patient clinical status 15 days after randomization
NCT04374474 Canada Single January 2021 March 2022 Not defined

1. Change from Baseline Snap and Sniff Threshold Test at 3 months

2. Score from the Snap and Sniff Olfactory Test results

3. Change from baseline Smell Identification Test (SIT) at 3 months

4. Score from the Smell Identification test results.

5. Change from Baseline Snap and Sniff Threshold Test at 6 months

6. Score from the Snap and Sniff Olfactory Test results

7. Change from baseline Smell Identification Test (SIT) at 6 months
NCT04263402 China Not available February 2020 July 2020 Severe pneumonia

1. Rate of disease remission

2. Rate and time of entering the critical stage
NCT04244591 China Completed January 2020 April 2020 Severe acute respiratory failure Murray lung injury score
NCT04273321 China Completed February 2020 April 2020 Pneumonia The incidence of treatment failure in 14 days
ChiCTR2000029386 China Single January 2020 January 2021 Pneumonia SOFA score
ChiCTR2000029656 China Single February 2020 April 2020 Pneumonia ECG, chest imaging, complications, vital signs, and NEWS2 score
ChiCTR2000030481 China Multi January 2020 April 2020 Pneumonia The time of duration of COVID-19 nucleic acid RT-PCR test results of respiratory specimens (such as throat swabs) or blood specimens change to negative
NCT04348305 Denmark Multi April 2020 December 2021 COVID-19 hypoxia Days alive without life support at day 28
2020-001395-15 Denmark Multi April 2020 Not available Severe hypoxia 1. Days alive without life support (i.e., invasive mechanical ventilation, circulatory support or renal replacement therapy) from randomization to day 28).
NCT04331054 France Multi April 2020 July 2020 COVID-19 infection Time (in days) to clinical improvement within 30 days after randomization
NCT04361474 France Multi May 2020 May 2021 Hyposmia Patient with more than 2 points on the ODORATEST
NCT04359511 France Not available June 2020 December 2020 Pneumonia Clinical improvement defined by the improvement of 2 points on a 7-category ordinal scale, at 14 days
NCT04347980 France Multi April 2020 August 2020 Acute respiratory distress syndrome (ARDS) 28-day mortality
NCT04344730 France Single April 2020 December 2020 Pneumonia

1. Time-to-death from all causes within the first 60 days after randomization

2. Time to need for mechanical ventilation
NCT04344288 France Multi April 2020 November 2020 Pneumonia Respiratory indication for transfer to intensive care unit evaluated by a SpO2 < 90%
NCT04331470 Iran Single April 2020 May 2020 Not defined Clear chest CT scan and PCR test
IRCT20200204046369N1 Iran Multi Not available Not available Not defined PAO2/FiO2 through ABG method
IRCT20151227025726N17 Iran Single Not available Not available ARDS

1. Daily need for invasive mechanical ventilation

2. Death at the end of the study
IRCT20120225009124N4 Iran Single Not available Not available Not defined Improvement in SpO2 measured by pulse oximeter
IRCT20200406046963N1 Iran Single Not available Not available ARDS( acute respiratory distress syndrome)

1. Mortality rate after 60 days

2. Blood O2 saturation measurement

3. Need for oxygen therapy
IRCT20200404046947N1 Iran Multi Not available Not available Not defined

1. Findings on the CT scan

2. Mortality rate

3. O2 saturation levels

4. Need an oxygen therapy at day 3 and discharge time
IRCT20081027001411N3 Iran Multi Not available Not available ARDS

1. Findings on the CT scan

2. Mortality rate

3. O2 saturation levels

4. Need an oxygen therapy at day 3 and discharge time
IRCT20120215009014N354 Iran Single Not available Not available Mild-to-moderate acute respiratory distress syndrome

1. Need to mechanical ventilation

2. The patient’s clinical status

3. Mortality rate
IRCT20080901001165N52 Iran Single Not available Not available Moderate to severe pneumonia Need to receive ICU service
NCT04323592 Italy Single March 2020 May 2020 Acute respiratory distress syndrome

1. Admission to ICU and need for Invasive mechanical ventilation

2. In-hospital death within 28 days

3. Endotracheal intubation
KCT0005105 Korea Multi April 2020 September 2020 Mild Rate of SARS-CoV-2 eradication at day 14 from study enrollment
IRCT20200318046812N2 Iran Multi Not available Not available Not defined Admission to intensive care unit
NCT04345445 Malaysia Single April 2020 October 2020 Pneumonia

1. The proportion of patients requiring mechanical ventilation

2. Mean days in ventilation
NCT04360876 Not available Single May 2020 December 2020 ARDS Ventilator-free days (VFD) at day 28
NCT04366115 Not available Not available June 2020 June 2023 Not defined

1. Dose-limiting toxicities

2. 28-day all-cause mortality for phases 1 and 2
NCT04435795 Not available Not available June 2020 March 2021 Not defined Improvement in dyspnea at day 7
NCT04355247 Puerto Rico Multi April 2020 April 2021 High-risk COVID-19

1. Clinical complete response criteria

2. Need for ventilatory support

3. O2 Saturation of >/= 93% by day 14 of therapy

4. Mortality at day 28

5. Findings on CT chest on day 28
NCT04438980 Spain Multi May 2020 February 2021 Pneumonia

1. Proportion of patients developing treatment failure

2. Need for mechanical ventilation

3. Decrease in SpO2 < 90% (in ambient air) or PaO2 < 60 mmHg (in ambient air) or PaO2FiO2 < 300 mmHg
NCT04394182 Spain Multi April 2020 April 2021 Pneumonia Oxygen saturation at day 2
NCT04380818 Spain Multi June 2020 July 2021 Pneumonia Efficacy of low-dose pulmonary irradiation assessed by change in PAFiO2 by 20%
NCT04355637 Spain Multi April 2020 October 2020 Pneumonia Proportion of patients developing treatment failure
NCT04341038 Spain Single April 2020 June 2020 Severe lung injury secondary to COVID-19 Time to reach clinical stability
NCT04329650 Spain Multi April 2020 May 2020 Pneumonia Proportion of patients requiring ICU admission at any time within the study period
NCT04325061 Spain Multi April 2020 October 2020 ARDS 60-day mortality
2020-001827-15 Spain Single Not available Not available Pneumonia

1. Proportion of patients with treatment failure up to 14 days after randomization

2. Mortality rate

3. ICU admission

4. Number of patients requiring mechanical ventilation

5. Clinical deterioration/worsening, defined as decrease in SpO2 below 90% or PaO2 below 60 mmHg in ambient air + radiological progression.
2020-001622-64 Spain Single April 2020 Not available Not defined

1. Measurement of O2 saturation and/or blood gas, findings on chest x-ray, CBC, including inflammatory markers and blood biometrics, and ECG

2. 30-day ICU admission and hospital stay

3. Outbreaks of steroid-related psychosis
2020-001934-37 Spain Multi May 2020 Not available Not defined

1. Mortality rate

2. Number of days of ICU stay

3. Number of patients requiring non-invasive ventilation (NIV)
2020-001413-20 Spain Single April 2020 Not available Pneumonia Proportion of patients requiring ICU admission at any time within the study period
2020-001445-39 Spain Single March 2020 Not available Pneumonia Time (days) to clinical stability after initiation of trial treatment for severe pneumonia secondary to COVID-19 and elevated inflammatory parameters
2020-001307-16 Spain Single April 2020 Not available ARDS Death from any cause in the first 28 days after randomization
NCT04381364 Sweden Multi May 2020 December 2020 Pneumonia Duration of supplemental oxygen therapy
NCT04416399 UK Not available June 2020 December 2020 Early infection Emergency department visit related to COVID-19
NCT04381936 UK Multi March 2020 June 2021 SARS All-cause mortality
NCT04411667 USA Multi April 2020 November 2020 Not defined Number of subjects requiring mechanical ventilation
NCT04377711 USA Multi June 2020 December 2020 Symptomatic COVID-19 infection Percentage hospital admission or death by day 30
NCT04349410 USA Not available April 2020 November 2020 Pneumonia

1. Improvement in FMTVDM measurement with nuclear imaging

2. Ventilator status

3. Extubation status

4. Survival status in 30 days
NCT04193878 USA Multi June 2020 June 2024 Pneumonia, acute respiratory failure Number of patients with acute respiratory failure (ARF) within 10 days of randomization
NCT03852537 USA Single December 2019 July 2022 Pneumonia

1. Feasibility of the timely initiation of corticosteroids and implementation of biomarker-titrated corticosteroid dosing

2. Percentage of eligible patients adhered to the timely initiation within 30 days
NCT04374071 USA Completed March 2020 April 2020 Pneumonia

1. Number of patients transferred to ICU is each of the group

2. Number of patients requiring mechanical ventilation

3. Mortality rate
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Type of trials

Among the included trials, 57 trials were quantitative studies and the remaining three trials were qualitative studies, i.e., non-interventional studies, as shown in the Table 2.

Table 2.

Methodological quality of included trials

Trial identifier Estimated sample size Allocation (randomized/non-randomized) Blinding/masking Study design
NCT04438980 72 Randomized Double Interventional
NCT04435795 454 Randomized Triple Interventional
NCT04425863 10 Not available Not available Non-interventional, prospective cohort
NCT04416399 478 Randomized Open label Interventional
NCT04411667 40 Randomized Open label Interventional
NCT04395105 284 Randomized Open label Interventional
NCT04394182 15 Not available Open label Interventional
NCT04381936 12000 Randomized Open label Interventional
NCT04348305 1000 Randomized Quadruple Interventional
NCT04331054 436 Randomized Open label Interventional
NCT04360876 90 Randomized Double Interventional
NCT04355247 20 Not available Open label Interventional
NCT04381364 446 Randomized Open label Interventional
NCT04380818 106 Non-randomized Open label Interventional
NCT04377711 400 Randomized Double Interventional
NCT04377503 40 Randomized Open label Interventional
NCT04374474 75 Randomized Open label Interventional
NCT04366115 126 Randomized Open label Interventional
NCT04361474 120 Randomized Single Interventional
NCT04359511 210 Randomized Single Interventional
NCT04355637 300 Randomized Open label Interventional
NCT04349410 500 Randomized Single Interventional
NCT04347980 122 Randomized Single Interventional
NCT04263402 100 Randomized Single Interventional
NCT04193878 600 Randomized Triple Interventional
NCT03852537 90 Randomized Double Interventional
NCT02735707 7100 Randomized Open label Randomized, multifactorial trial
NCT04345445 310 Randomized Open label Interventional
NCT04344730 550 Randomized Quadruple Interventional
NCT04344288 304 Randomized Open label Interventional
NCT04343729 425 Randomized Quadruple Interventional
NCT04341038 84 Randomized Single Interventional
NCT04331470 30 Randomized Double Interventional
KCT0005105 141 Randomized Open label Interventional
NCT04329650 200 Randomized Open label Interventional
NCT04327401 350 Randomized Open label Interventional
NCT04325061 200 Randomized Open label Interventional
NCT04323592 173 Non-randomized Open label Non-interventional, prospective cohort
NCT04374071 250 Non-randomized Not available Non-interventional, retrospective cohort
NCT04244591 80 Randomized Open label Interventional
NCT04273321 86 Randomized Open label Interventional
IRCT20080901001165N52 50 Randomized Open label Interventional
IRCT20200406046963N1 40 Randomized Open label Interventional
IRCT20200404046947N1 68 Randomized Single Interventional
IRCT20081027001411N3 60 Randomized Single Interventional
IRCT20120215009014N354 81 Randomized Double Interventional
IRCT20200204046369N1 48 Non-randomized Open label Interventional
IRCT20200318046812N2 906 Randomized Open label Interventional
IRCT20151227025726N17 48 Randomized Open label Interventional
IRCT20120225009124N4 105 Randomized Open label Interventional
ChiCTR2000029386 24 Randomized Not available Interventional
ChiCTR2000029656 50 Randomized Open label Interventional
ChiCTR2000030481 75 Randomized (static) Not available Interventional
2020-001827-15 72 Randomized Double Interventional
2020-001307-16 104 Randomized Open label Interventional
2020-001395-15 1000 Randomized Double Interventional
2020-001622-64 200 Randomized Open label Interventional
2020-001934-37 200 Randomized Open label Interventional
2020-001413-20 100 Randomized Open label Interventional
2020-001445-39 84 Randomized Open label Interventional
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Heterogeneity of trials

All 60 trials included were heterogenous in that they had various inclusion and exclusion criteria and different treatment protocols for the treatment of various stages of COVID-19. The most common stage of COVID-19 among these trials is pneumonia, which is shown in Table 1.

Methodological quality of the trials

Among the 60 trials, 54 were randomized. It was unclear how randomization was carried out in three of the trials. Among 54 randomized trials, only 21 trials were blinded, of which 8 were single blinded, 8 were double blinded, 2 were triple blinded, and 3 were quadruple blinded, as shown in Table 2.

Steroid treatment

Regarding the steroid treatment, the most common steroid used is methylprednisolone (used in 28 trials) at various dosages depending on the age of the patients. Maximum loading dose of methylprednisolone used is 500 mg IV infusion over 1h in a trial (IRCT20080901001165N52). Steroids were given from a minimum of 3 days to a maximum of 21 days. Other steroids used are budesonide, ciclesonide, dexamethasone, formoterol, prednisolone, prednisone, and hydrocortisone. In 10 trials, the dose of the steroids used was unclear, and in one trial (ChiCTR2000030481), the treatment regimen was not mentioned. This is shown in Table 3.

Table 3.

Steroid treatment in patients with COVID-19

Trial identifier Title Interventions Dose Age (in years)
NCT04425863 Evaluation of ivermectin, aspirin, dexamethasone, and enoxaparin as treatment of Covid19 Ivermectin; aspirin; dexamethasone; enoxaparin Dexamethasone 4 mg/day IV ≥ 5
NCT04395105 Dexamethasone versus usual care for the treatment of COVID-19 related ARDS: a multicenter and randomized open-label clinical trial Dexamethasone Dexamethasone 16 mg IV OD from days 1 to 5 and 8 mg from days 6 to 10 ≥ 18
NCT02735707 Randomized, embedded, multifactorial adaptive platform trial for community-acquired pneumonia

1. Fixed-duration Hydrocortisone

2. Shock-dependent hydrocortisone

3. Ceftriaxone

4. Moxifloxacin or Levofloxacin

5. Piperacillin-tazobactam

6. Ceftaroline

7. Amoxicillin-clavulanate

8. Macrolide administered for 3–5 days

9. Macrolide administered for up to 14 days

10. Five days of oseltamivir

11. Ten days of oseltamivir

12. Lopinavir/ritonavir

12. Hydroxychloroquine

13. Hydroxychloroquine + lopinavir/ritonavir

14. Interferon-β1a

15. Anakinra

16. Fixed-duration higher dose hydrocortisone

17. Tocilizumab

18.Sarilumab

1. Fixed-duration hydrocortisone 50 mg IV q 6 h × 7 days

2. Shock-dependant hydrocortisone 50 mg IV q 6 h while in septic shock

3. Fixed-duration higher dose hydrocortisone—100 mg IV every 6 h × 7 days

 > 18
NCT04377503 Comparison of the efficacy and safety of tocilizumab versus methylprednisolone in the cytokine release syndrome of patients with COVID-19. A prospective randomized controlled phase II trial

1. Tocilizumab 180 mg/ml

2. Methylprednisolone sodium succinate

 Methylprednisolone sodium succinate 1.5 mg/kg/day BD × 7 days followed by 1 mg/kg/day × 7 days, finally 0.5 mg/kg/day × 21 days ≥ 18
NCT04343729 Methylprednisolone in the treatment of patients with signs of severe acute respiratory syndrome in Covid-19 (MetCOVID) Methylprednisolone sodium succinate Methylprednisolone sodium succinate 0.5 mg/kg ≥ 18
NCT04327401 COVID-19-associated ARDS treated with dexamethasone: Alliance Covid-19 Brasil III (CoDEX) Dexamethasone Dexamethasone 20 mg IV 1/day × 5 days followed by 10 mg IV 1/day × 5 days ≥ 18
NCT04374474 Olfactory retraining therapy and budesonide nasal rinse for anosmia treatment in patients post-CoVID 19. A randomized controlled trial

1. Corticosteroid nasal irrigation

2. Smell household items; olfactory retraining

 Budesonide 240 ml nasal irrigation with Pulmicort Respules (0.5 mg) across both nose sides ≥ 18
NCT04263402 An open, prospective/retrospective, randomized controlled cohort study to compare the efficacy of different hormone doses in the treatment of 2019-nCoV severe pneumonia Methylprednisolone

1. Methylprednisolone < 40 mg/day IV drip × 7 days

2. Methylprednisolone 40 to 80 mg/day IV drip × 7 days

 ≥ 18
NCT04244591 Glucocorticoid therapy for critically ill patients with severe acute respiratory infections caused by COVID-19: a prospective, randomized controlled trial Methylprednisolone therapy. Others: standard care Methylprednisolone 40 mg q. 12 h × 5 days ≥ 18
NCT04273321 Efficacy and safety of corticosteroids in COVID-19: a prospective randomized controlled trials Methylprednisolone Accord with the clinical diagnosis and/or etiological diagnosis diagnostic criteria 18–75
ChiCTR2000029386 Effectiveness of glucocorticoid therapy in patients with severe novel coronavirus pneumonia: a randomized controlled trial Methylprednisolone and intravenous injection Methylprednisolone 1–2 mg/kg/day IV × 3 days ≥ 18
ChiCTR2000029656 A randomized, open-label study to evaluate the efficacy and safety of low-dose corticosteroids in hospitalized patients with novel coronavirus pneumonia (COVID-19) Methylprednisolone Not available ≥ 18
ChiCTR2000030481 The clinical value of corticosteroid therapy timing in the treatment of novel coronavirus pneumonia (COVID-19): a prospective randomized controlled trial Not mentioned Not available ≥ 18
NCT04348305 Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia - the COVID STEROID Trial Hydrocortisone Hydrocortisone continuous infusion: 200 mg q 24 h bolus injections 50 mg (10 ml) every 6 h × 7 days ≥ 18
NCT04331054 Protective role of inhaled steroids for Covid-19 infection

1. Usual practice

2. Usual practice + Symbicort Rapihaler

 Symbicort (budesonide, formoterol) 200/6 μg, 2 puffs bid × 30 days 18–75
NCT04361474 A randomized controlled trial evaluating the efficacy of local budesonide therapy in the management of hyposmia in COVID-19 patients without signs of severity

1. Budesonide nasal spray

2. Physiological serum

 Budesonide 1 mg/2 ml diluted in 250 ml of physiological saline 3 syringes of 20 ml in each nasal cavity BD × 30 days ≥ 18
NCT04359511 Efficacy and safety of corticosteroids in oxygen-dependent patients with COVID-19 pneumonia in Grand Ouest Interregion France

1. Prednisone

2. Hydrocortisone

 Prednisone 0.7 mg/kg/day PO OD × 10 days or hydrocortisone hemisuccinate 3.5 mg/kg/day continuous infusion × 10 days ≥ 18
NCT04347980 Dexamethasone combined with hydroxychloroquine compared to hydroxychloroquine alone for treatment of severe acute respiratory distress syndrome induced by coronavirus disease 19 (COVID-19): a multicentre, randomised controlled trial

1. Dexamethasone and hydroxychloroquine

2. Hydroxychloroquine

 Dexamethasone 20 mg IV OD for 15 min × 5 days followed by 10 mg OD × 5 days ≥ 18
NCT04344730 Dexamethasone and oxygen support strategies in ICU patients with Covid-19 pneumonia (COVIDICUS) Dexamethasone injection + conventional oxygen Dexamethasone 20 mg/5 ml IV 18–80
NCT04344288 Corticosteroids during Covid-19 viral pneumonia related to SARS-Cov-2 infection (CORTI-Covid) Prednisone Prednisone 0.75 mg/kg/day × 5 days then 20 mg/day × 5 more days ≥ 18
NCT04331054 Protective role of inhaled steroids for Covid-19 infection

1. Usual practice

2. Usual practice + Symbicort Rapihaler

 Symbicort (budesonide, formoterol) 200/6 μg 2 puffs bid × 30 days 18–75
NCT04331470 Evaluation of efficacy of levamisole and formoterol + budesonide in treatment of COVID-19

1. Levamisole pill + budesonide + formoterol inhaler/lopinavir/ritonavir + hydroxychloroquine

2. Lopinavir/ritonavir + hydoxychloroquine

 Budesonide + formoterol inhalation 1–2 puffs q 12 h 15–100
IRCT20080901001165N52 Investigating the efficacy of high dose of glucocorticoid in patients with moderate to severe pneumonia related to COVID-19 Methylprednisolone and prednisolone

Day 1: Amp. methylprednisolone 500 mg IV infusion over 1 hour.

At days 2 and 3: Amp. methylprednisolone 250 mg IV infusion over 1 h.

At days 4 and 5: Amp. methylprednisolone 100 mg IV infusion over 1 h.

Then, tab. prednisolone 25 mg PO daily until the day of discharge, then tab. prednisolone will gradually tapered off over 1 month

 18–85
IRCT20200204046369N1 Evaluation of methylprednisolone administration as a therapeutic option in the 2019 novel coronavirus (COVID-19): a non-randomized controlled study Methylprednisolone Methylprednisolone 20 mg/day ≥ 18
IRCT20200318046812N2 Safety and efficacy of “Hydroxychloroquine + Azithromycin + naproxen + Prednisolone” and “Hydroxychloroquine + Azithromycin + naproxen” regimens in comparison with “Hydroxychloroquine + kaletra” on the need for intensive care unit treatment in patients with COVID-19; a randomized, multicenter, parallel Hydroxychloroquine, azithromycin, naproxen , prednisolone Prednisolone five 5 mg tablets a day × 5 days 16–100
IRCT20151227025726N17 Evolution of the efficacy and safety of Dexamethasone administration in patients with mild to moderate COVID-19 acute respiratory disease syndrome Dexamethasone Dexamethasone 20 mg IV days 1–5, then 10 mg days 6–10 ≥ 18
IRCT20120225009124N4 Efficacy of different methods of administration of combination regimen including dexamethasone, IV-IG and interferon beta for treatment of patients with severe COVID-19: a randomized controlled trial Dexamethasone, IV-IG and interferon beta Not available 18–70
IRCT20200406046963N1 Evaluation of the efficacy and safety of methylprednisolone pulse therapy in treatment of COVID-19 patients with ARDS. Methylprednisolone Methylprednisolone 1000 mg for 3 days 18–90
IRCT20200404046947N1 Study of methylprednisolone effects on treatment and clinical symptoms and laboratory signs of Iranian COVID-19 patients: a clinical trial study Methylprednisolone Methylprednisolone 250 mg for 3 days ≥ 18
IRCT20081027001411N3 Study of prednisolone effects on treatment and clinical symptoms and laboratory signs of Iranian COVID-19 patients: a clinical trial study Prednisolone Prednisolone 0.5 mg/kg in three divided doses up to 30 mg per day for 5–7 days ≥ 18
IRCT20120215009014N354 Evaluating the effect of intravenous hydrocortisone, methylprednisolone, and dexamethasone in treatment of patients with moderate to severe acute respiratory distress syndrome caused by COVID-19: a double blind randomized clinical trial Hydrocortisone, methylprednisolone, and dexamethasone

Group 1: Hydrocortisone 50 mg IV q. 6 h × 5 days Group 2: Methylprednisolone 40 mg IV q 12 h ×5 days

Group 3: Dexamethasone IV 20 mg daily × 5 days

 18–70
NCT04323592 Methylprednisolone for patients with COVID-19 severe acute respiratory syndrome (MP-C19) Methylprednisolone and other standard care Methylprednisolone 80 mg/kg IV bolus 18–80
KCT0005105 A trial of ciclesonide in adults with mild COVID-19

1. Ciclesonide (Alvesco®) 320 μg inhalation twice a day for 14 days

2. Ciclesonide (Alvesco®) 320 μg inhalation twice a day for 14 days + hydroxychloroquine 400 mg per day for 10 days

 Ciclesonide (Alvesco®) 320 μg inhalation BD × 14 days 19–100
NCT04345445 Study to evaluate the efficacy and safety of tocilizumab versus corticosteroids in hospitalized COVID-19 patients with high risk of progression

1. Tocilizumab IV

2. Methylprednisolone IV

 Methylprednisolone 120 mg/day for 3 days 18–80
NCT04435795 Ciclesonide clinical trial for COVID-19 treatment Ciclesonide Ciclesonide 600 μg BID inhaled with aerochamber + Nasal ciclesonide 200 μg DIE ≥ 18
NCT04360876 Targeted steroids for ARDS due to COVID-19 pneumonia: a pilot randomized clinical trial

1. Dexamethasone injection

2. Placebo

 Dexamethasone 20 mg IV OD 5 days followed by 10 mg OD × 5 days ≥ 18
NCT04366115 A randomized, double-blind, placebo-controlled, phase 1/2 study evaluating AVM0703 in patients with COVID-19

1. AVM0703

2. Placebo

3. Hydrocortisone

1. AVM0703 (dexamethasone sodium phosphate) 10 mg/ml single IV infusion in NS over 1 hour

2. Hydrocortisone dose not available

 ≥ 18
NCT04355247 Prophylactic corticosteroid to prevent COVID-19 cytokine storm Methylprednisolone 80 mg/ml injectable suspension Methylprednisolone 80 mg IV bolus injection OD × 5 days ≥ 18
NCT04438980 Treatment of COVID-19 pneumonia with glucocorticoids. A randomized controlled trial

1. Methylprednisolone

2. Placebo

 Methylprednisolone 120 mg/day IV infusion × 3 days 18–80
NCT04394182 Low doses of lung radiation therapy in cases of COVID-19 pneumonia: prospective multicentric study in radiation oncology centers

1. Ultra-low-dose radiotherapy

2. Ventilatory support with oxygen therapy

3. Lopinavir/ritonavir, hydroxychloroquine, azithromycin, piperacillin/tazobactam, Low molecular weight heparin, corticosteroid injection, tocilizumab

 Methylprednisolone 250 mg × 3 boluses 18–120
NCT04380818 Low dose anti-inflammatory radiotherapy for the treatment of pneumonia by COVID-19: multi-central prospective study

1. Low-dose radiotherapy; hydroxychloroquine Sulfate

2. Ritonavir/lopinavir

3. Tocilizumab Injection (Actemra)

4. Azithromycin

5. Corticosteroid

6. Low molecular weight heparin; oxygen supply

 Not available 18–99
NCT04355637 Treatment with inhaled corticosteroids in patients hospitalized because of COVID19 pneumonia Inhaled budesonide Not available 18–79
NCT04341038 Clinical trial to evaluate methylprednisolone pulses and tacrolimus in patients with COVID-19 lung injury (TACROVID)

1. Tacrolimus

2. Methylprednisolone

 Methylprednisolone 120 mg daily × 3 days Not available
NCT04329650 Efficacy and safety of siltuximab vs. corticosteroids in hospitalized patients with COVID-19 pneumonia

1. Siltuximab

2. Methylprednisolone

 Methylprednisolone 250 mg/24 h ≥ 18
NCT04325061 Efficacy of dexamethasone treatment for patients with ARDS caused by COVID-19 (DEXA-COVID19) Dexamethasone Dexamethasone 20 mg/IV/daily × 5 days > 18
2020-001827-15 Early treatment of pneumonia Covid-19 with glucocorticoids. randomized controlled clinical trial Methylprednisolone and hydroxychloroquine Not available ≥ 18
2020-001622-64 Outpatient treatment of Covid-19 with early pulmonary corticosteroids as an opportunity to modify the course of the disease Prednisone Not available 18–74
2020-001934-37 Use of corticosteroids in patients with SARS-CoV2 coronavirus infection (glucocovid) pragmatic trial inserted in real practice during a pandemic covid-19 Methylprednisolone Not available 18–85
2020-001413-20 Phase 2, randomized, open-label study to compare the efficacy and safety of siltuximab vs. corticosteroids in hospitalized patients with COVID-19 pneumonia Methylprednisolone and siltuximab Not available ≥ 18
2020-001445-39 Pragmatic, controlled, open, single center, randomized, phase Ii clinical trial to evaluate methylprednisolone pulses and tacrolimus in hospitalized patients with severe pneumonia secondary to COVID-19.

1. Methylprednisolone

2. Tacrolimus

 Not available ≥ 18
2020-001307-16 Efficacy and safety of corticoids in patients with adult respiratory distress syndrome (ARDS) secondary to COVID-19. Methylprednisolone hemisuccinate Not available ≥ 18
NCT04381364 Inhalation of ciclesonide for patients with COVID-19: a randomised open treatment study (HALT COVID-19) Ciclesonide inhalation Ciclesonide inhalation 320 μg BD × 14 days 18–84
NCT04416399 Use of high dose inhaled corticosteroids as treatment of early COVID-19 infection to prevent clinical deterioration and hospitalization Budesonide dry powder inhaler Budesonide 400 μg per inhalation, 2 inhalations twice a day × 28 days > 18
NCT04381936 Randomized evaluation of COVID-19 therapy

1. Lopinavir-ritonavir

2. Dexamethasone/prednisolone

3. Hydroxychloroquine

4. Azithromycin

5. Biological: convalescent plasma

6. Tocilizumab

 Dexamethasone 6 mg PO OD × 10 days Child, adult, older adult
NCT04411667 Randomized open label study of standard of care plus intravenous immunoglobulin (IVIG) compared to standard of care alone in the treatment of COVID-19 infection IVIG (Octagam) premedication and methylprednisolone Methylprednisolone 40 mg IV push × 1 30–50 min before each IVIG infusion ≥ 18
NCT04377711 A phase 3, multicenter, randomized, double-blind, placebo-controlled study to assess the safety and efficacy of ciclesonide metered-dose inhaler in non-hospitalized patients 12 years of age and older with symptomatic COVID-19 infection

1. Ciclesonide

2. Placebo

 Alvesco (ciclesonide) 320 μg b.i.d. × 30 days via pMDI 12–100
NCT04349410 The fleming [FMTVDM] directed CoVid-19 treatment protocol

1. Hydroxychloroquine, azithromycin

2. Hydroxychloroquine, doxycycline

3. Hydroxychloroquine, clindamycin

4. Hydroxychloroquine, clindamycin, primaquine—low dose

5. Hydroxychloroquine, clindamycin, primaquine—high dose

6. Remdesivir

7. Tocilizumab

8. Methylprednisolone

9. Interferon-Alpha2B

10: Losartan plus convalescent serum

 Methylprednisolone 80 mg IV over 30 min b.i.d. × 7 days, then taper off Child, adult, older adult
NCT04193878 Arrest respiratory failure from pneumonia (Arrest pneumonia)

1. Inhaled budesonide and formoterol

2. Inhaled placebo

 Formoterol aerosolized—20 μg/2 ml) and budesonide—1.0 mg/2 ml q 12 h × 14 doses ≥ 18
NCT03852537 SMART Trial: steroid dosing by biomarker guided titration in critically ill patients with pneumonia Methylprednisolone. Other: usual care Methylprednisolone—predetermined dosing table—discontinue if CR < 0.5 mg; 0.5 mg if CRP is 51–100 mmol/L or 0.75 mg/kg if CRP level is 101–150 mmol/L; 1 mg/kg if CRP 151–200 mmol/L or 1.5 mg/kg if CRP level > 200 mmol/L or dose equivalent of oral prednisone for the above ≥ 18
NCT04374071 Early short course corticosteroids in hospitalized patients with COVID-19 Methylprednisolone

1. Methylprednisolone 0.5 to 1 mg/kg/day IV in two divided doses × 3 days

2. Hydroxychloroquine and IV methylprednisolone 0.5 to 1 mg/kg/day in 2 divided doses × 3–7 days

 ≥ 18
Open in a new tab

Figure 3 depicts the number of trials studying different types of steroids, showing majority of the trials (N = 28) have decided to study the effectiveness of methylprednisolone in the treatment of COVID-19.

Fig. 3.

Fig. 3

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Number of trials using different kinds of steroids

Primary and secondary outcomes

Table 1 summarizes results from all 60 studies. All the trials had clearly defined primary and secondary outcomes of interest, in which only 11 trials had evaluation of respiratory rate as one of their outcomes. Common outcomes measured are respiratory rate, mortality rate, ventilation free days, days in ICU, patient Sequential Organ Failure Assessment (SOFA) score, Murray lung injury score, National Early Warning Score 2 (NEWS2) score, number of patients with treatment failure, rate of remission and progression, blood oxygen saturation, chest x-ray, steroid-related adverse effect, and toxicity monitoring. Table 4 summarizes the consolidation of completed trials with results. All the completed trials have used methylprednisone, dexamethasone, and hydrocortisone as drug of choices.

Table 4.

Characteristics of published completed trials

Ref Country Year of publication Steroid used Primary outcomes P value
[24] China 2020 Methylprednisolone 396 of 409 [96.8%], dexamethasone 32 of 409 [7.8%] patients—hydrocortisone equivalent Corticosteroid therapy had higher 28-day mortality rate. Delay in SARS-CoV RNA clearance (P = 0.00017) < 0.05
[25] USA 2020 Hydrocortisone 200 mg/day and tapered till 50 mg/day Treatment failure occurred in hydrocortisone patient is 42.1% compared to placebo 50.7% < 0.045
[26] Netherlands 2020 Methylprednisolone 80 mg, 250 mg There was a 79% higher likelihood of two stage improvement in respiratory status < 0.025
[27] USA 2020 Hydrocortisone 50 mg, 100 mg The in-hospital death in treatment group is 30% and 26% compared to no hydrocortisone, i.e. 33% < 0.05
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The data obtained from this review shows that steroids of different doses and types were included in numerous ongoing clinical trials. Their safety and efficacy in managing symptoms of COVID-19, especially in the pneumonia stage, were tested. The trials also included patients of different age groups at different stages of COVID-19. The COVID-19 infection goes through three stages from asymptomatic phase to ARDS (acute respiratory distress syndrome) phase. The 2019-nCoV, after entering the nasal cavity, adheres to the epithelial cells and binds to ACE2 receptor [24]. Owing to this reason, it may be evident that different corticosteroids act through different mechanisms to minimize the symptoms of COVID-19 infection. Table 3 represents the total number of population recruited in each trial, from which we estimate the total ARDS population recruited to be 3880 patients with disease stages ranging from moderate to severe respiratory distress of which methylprednisolone was the most commonly used corticosteroids. A study by H.P. Wiedemann et al. showed that methylprednisolone increased mortality rates by at least 14 days after the onset of ARDS, which gives an impression that the routine use of methylprednisolone is not effective in ARDS [25]. Another study by Nelson Lee et al. shows that SARS-CoV RNA concentrations in the second and third week of illness were significantly higher in patients who received early hydrocortisone treatment compared to placebo; thus, it is recommended to be avoided, but can be cautiously used in SARS [26]. The potential risks associated with high-dose corticosteroids in treating 2019-nCoV pneumonia include secondary infections, long-term complications, and prolonged virus shedding and escalating towards advanced stages [27]. Another study conducted by G.C. Khilnani and H. Vijay registered increased mortality rate (35.7%) with the use of corticosteroids [28–33]. Positively, the RECOVERY trial (Randomised Evaluation of COVID-19 therapy) concluded that in hospitalized patients with COVID-19, corticosteroid reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support [34]. Moreover, excessive levels of glucocorticoids have shown to precipitate heart failure by aggravating fluid retention, triggering risk factors like glucose intolerance and dyslipidemia, and by worsening atheromatous vascular disease. Additionally, increased risk of mortality with high serum levels of cortisol have been reported, further establishing a link between use of corticosteroids and increased heart failure risk [35]. Thus, the usage of corticosteroids at various stages of COVID-19 is still questionable with higher mortality rates than the comparator. More information can be gained from results from the completed trials. Though four trials have completed its recruitment, results were not available in the registry. The completed four trials were registered in the Iranian clinical trial registry. The outcomes measured in these trials were mortality rate, need for ICU services, duration of stay in the hospital, assessment of side effects, readmission rate, need for oxygen therapy, blood O2, levels, chest x-ray, PAO2/fio2, and need for invasive mechanical ventilation and intubation.

Conclusion

Numerous interventional and non-interventional studies are being conducted to study the efficacy of corticosteroids in COVID-19. Corticosteroids can regulate immune-mediated lung injury and decrease the development to respiratory failure and death. Dexamethasone has been reported to reduce the duration of mechanical ventilation. Long-term glucocorticoid therapy has displayed significant improvement in indices of alveolar–capillary membrane permeability and mediators of inflammation and tissue repair. Few preliminary trial findings show promising results and recommend the use of methylprednisolone and dexamethasone in the severe form of the COVID-19. Few studies have reported that early administration of dexamethasone could reduce duration of mechanical ventilation and overall mortality in patients with established moderate to severe ARDS; however, there is insufficient data to prove its benefits over its risk. Routine use of corticosteroids should be favored only after a better insight is obtained, with the completion of these trials.

Acknowledgements

Not applicable

Abbreviations

ACE

Angiotensin-converting enzyme

ARDS

Acute respiratory distress syndrome

ChiCTR

Chinese Clinical Trial Registry

COVID-19

Coronavirus disease 2019

CRiS

Clinical Research Information Service–Republic of Korea

EU

European Union

ICU

Intensive care unit

IRCT

Iranian Registry of Clinical Trials

MERS-CoV

Middle East respiratory syndrome coronavirus

NEWS2

National Early Warning Score 2

RNA

Ribonucleic acid

SARS-CoV

Severe acute respiratory syndrome coronavirus

sCAP

Severe community-acquired pneumonia

SOFA

Sequential Organ Failure Assessment

WHO

World Health Organization

Authors’ contributions

RR and PSB contributed in the literature search, data collection, data analysis, and writing. PV did the data analysis, data interpretation, figures, and writing. SJUCJ is responsible for the concept, design, methods, data interpretation, writing, and proof reading. The authors read and approved the final manuscript.

Funding

Not applicable.

Availability of data and materials

The datasets analyzed during the current study will be available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher’s Note

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

Contributor Information

Reshma Raju, Email: reshmaraju602@gmail.com.

Prajith V., Email: prajithkanna@gmail.com.

Pratheeksha Sojan Biatris, Email: pratheekshasojan00417@gmail.com.

Sam Johnson Udaya Chander J., Email: mail2samjohnson@gmail.com.

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Associated Data

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Data Availability Statement

The datasets analyzed during the current study will be available from the corresponding author on reasonable request.

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