A slew of “gold standard” clinical trials offer new hope for patients battling severe COVID-19: cheap, common drugs known as corticosteroids appear to cut the death rate by a third.
Publication of new data on treatment with corticosteroids such as hydrocortisone or dexamethasone “represents an important step forward in the treatment of patients with COVID-19,” said Dr. Hallie Prescott of the University of Michigan, Ann Arbor, and Dr. Todd Rice, of Vanderbilt University in Nashville, Tenn.
They wrote an editorial accompanying four studies on corticosteroids and COVID-19, all published online Sept. 2 in the Journal of the American Medical Association (JAMA).
One of the studies was a “meta-analysis”—a review of data looking at the combined results of seven different clinical trials.
Those trials involved more than 1,700 critically ill COVID-19 patients treated at medical centers in 12 countries.
The data showed that the use of corticosteroids in the care of these patients cut the death rate (after one month of treatment) by about one-third, according to researchers led by Jonathan Sterne, of the University of Bristol in the United Kingdom.
This finding was true for patients requiring mechanical ventilation as well as those who required supplemental oxygen but not a ventilator, the research team added.
Overall, “these trial results from diverse clinical and geographical settings suggest that in the absence of compelling contraindications, a corticosteroid regimen should be a component of standard care for critically ill patients with COVID-19,” Sterne’s group concluded.
Quieting the storm
How might corticosteroids – which have been around for decades—help save lives threatened by COVID-19?
As Prescott and Rice explained, these drugs work to counter the runaway inflammatory response—the so-called “cytokine storm” – that can drive late-stage COVID-19 and overwhelm patients’ defenses.
In addition, many patients treated for COVID-19 in the intensive care unit (ICU) require ventilators to breathe because they develop a condition known as acute respiratory distress syndrome (ARDS). ARDS is often seen in advanced cases of pneumonia and other illnesses, and can easily prove fatal.
But Prescott and Rice noted that, as early as 1967, experts noted that “corticosteroids appeared to have value in the treatment of patients” with severe pneumonia and ARDS.
In June, the first solid evidence that the drugs might fight COVID-19 also emerged, with the publication of results from a British trial of more than 6,400 patients.
That trial found that use of dexamethasone cut the death rate by about one-third for patients on ventilators, and by about one-fifth for those requiring supplemental oxygen.
In the latest issue of JAMA, researchers working on three new clinical trials found preliminary results indicating that corticosteroids would help against COVID-19.
One trial from Brazil, involving 299 patients treated in ICUs, found that adding dexamethasone to treatment “resulted in a statistically significant increase in the number of ventilator-free days” over 28 days of treatment.
Two other trials – one from France and the other including American patients – also suggested real improvement from the use of corticosteroids.
The ‘clearest answer’
The U.S. trial involved 403 COVID-19 patients treated in an ICU between March and June. It found a 93% probability that adding intravenous hydrocortisone to patients’ treatment would end in better outcomes.
“This gives physicians like me, who treat the sickest of the sick, hope. We are beginning to get a handle on the deadly side of this disease,” study co-author Dr. Bryan McVerry said in a University of Pittsburgh news release. He’s an associate professor of pulmonology, allergy and critical care medicine at Pitt.
Study lead author Dr. Derek Angus, who directs the department of critical care medicine at Pitt, added that “it is relatively rare in medicine that you find drugs where the evidence of their effectiveness in saving lives is so consistent.
This is, in many respects, the single clearest answer we’ve had so far on how to manage terribly ill COVID-19 patients. People on ventilators or oxygen and under intensive care should definitely be given corticosteroids.”
However, publication of clear evidence of benefit from the British trial in June meant that withholding corticosteroid treatment from patients in the “control” arms of the Brazilian, French and U.S. trials was no longer ethical, so each of those trials were discontinued early.
The meta-analysis of data from seven different studies was completed, however, and shows clear benefit from corticosteroid treatment.
According to the meta-analysis, the steroid dexamethasone was used in three trials involving a total of almost 1,300 patients, and seemed to cut the death risk by 36% compared to standard care.
Hydrocortisone was employed in three trials involving a smaller number of patients (374) and cut the death risk by 31%, Sterne’s group reported.
Corticosteroids can have serious side effects, but the meta-analysis revealed little difference in “serious adverse events” for patients who got the drugs versus those who did not.
Still, some questions remain.
According to editorialists Prescott and Rice, those questions include: “Does inflammation rebound after cessation of corticosteroids? … Should less severely ill or non-hospitalized patients be treated with corticosteroids?
… Should remdesivir or other potentially active therapeutics be administered with corticosteroids?”
Overall, however, the results of the new trials published online Sept. 2 in JAMA are encouraging, Prescott and Rice said.
“The COVID-19 pandemic has brought fear and a sea of change to the world,” they said.
“These studies provide evidence and some hope that an effective, inexpensive and safe treatment has been identified.”
Patients with severe COVID-19 can develop a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction.
It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these deleterious effects. The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, a multicenter, randomized, open-label trial in hospitalized patients with COVID-19, showed that the mortality rate was lower among patients who were randomized to receive dexamethasone than among those who received the standard of care.1
This benefit was observed in patients who required supplemental oxygen at enrollment. No benefit of dexamethasone was seen in patients who did not require supplemental oxygen at enrollment. Details of the RECOVERY trial are discussed in Clinical Data to Date below.1
Recommendations for Patients with COVID-19
- On the basis of the preliminary report from the RECOVERY trial, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using dexamethasone 6 mg per day for up to 10 days or until hospital discharge, whichever comes first, for the treatment of COVID-19 in hospitalized patients who are mechanically ventilated (AI) and in hospitalized patients who require supplemental oxygen but who are not mechanically ventilated (BI).
- The Panel recommends against using dexamethasone for the treatment of COVID-19 in patients who do not require supplemental oxygen (AI).
- If dexamethasone is not available, the Panel recommends using alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone (see Additional Considerations below for dosing recommendations) (AIII).
Rationale for Use in Patients With COVID-19
Both beneficial and deleterious clinical outcomes have been reported with use of corticosteroids (mostly prednisone or methylprednisolone) in patients with other pulmonary infections. In patients with Pneumocystis jirovecii pneumonia and hypoxia, prednisone therapy reduced the risk of death;2 however, in outbreaks of other novel coronavirus infections (i.e., Middle East respiratory syndrome [MERS] and severe acute respiratory syndrome [SARS]), corticosteroid therapy was associated with delayed virus clearance.3,4
In severe pneumonia caused by influenza viruses, corticosteroid therapy appears to result in worse clinical outcomes, including secondary bacterial infection and death.5
Corticosteroids have been studied in critically ill patients with acute respiratory distress syndrome (ARDS) with conflicting results.6-8 Seven randomized, controlled trials that included 851 patients evaluated use of corticosteroids in patients with ARDS.7-13
A meta-analysis of these trial results demonstrated that, compared with placebo, corticosteroid therapy reduced the risk of all-cause mortality (risk ratio 0.75; 95% CI, 0.59–0.95) and duration of mechanical ventilation (mean difference, -4.93 days; 95% CI, -7.81 to -2.06 days).14,15
Monitoring, Adverse Effects, and Drug-Drug Interactions
- Clinicians should closely monitor patients with COVID-19 who are receiving dexamethasone for adverse effects (e.g., hyperglycemia, secondary infections, psychiatric effects, avascular necrosis).
- Prolonged use of systemic corticosteroids may increase the risk of reactivation of latent infections (e.g., hepatitis B virus [HBV], herpesvirus infections, strongyloidiasis, tuberculosis).
- The risk of reactivation of latent infections for a 10-day course of dexamethasone (6 mg once daily) is not well-defined. When initiating dexamethasone, appropriate screening and treatment to reduce the risk of Strongyloides hyperinfection in patients at high risk of strongyloidiasis (e.g., patients from tropical, subtropical, or warm, temperate regions or those engaged in agricultural activities) or fulminant reactivations of HBV should be considered.16-19
- Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer. As such, it may reduce the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates. Clinicians should review a patient’s medication regimen to assess potential interactions.
- Coadministration of remdesivir and dexamethasone has not been formally studied, but a clinically significant pharmacokinetic interaction is not predicted.
- Dexamethasone should be continued for up to 10 days or until hospital discharge, whichever comes first.
- Whether use of other corticosteroids (e.g., prednisone, methylprednisolone, hydrocortisone) for the treatment of COVID-19 provides the same benefit as dexamethasone is unclear. The total daily dose equivalencies for these drugs to dexamethasone 6 mg (oral or intravenous [IV])20 are:
- Prednisone 40 mg
- Methylprednisolone 32 mg
- Hydrocortisone 160 mg
- Half-life, duration of action, and frequency of administration vary among corticosteroids.
- Long-acting corticosteroid: dexamethasone; half-life: 36 to 72 hours, administer once daily.
- Intermediate-acting corticosteroids: prednisone and methylprednisolone; half-life: 12 to 36 hours, administer once daily or in two divided doses daily.
- Short-acting corticosteroid: hydrocortisone; half-life: 8 to 12 hours, administer in two to four divided doses daily.
- Hydrocortisone is commonly used to manage septic shock in patients with COVID-19; please refer to the Critical Care section for more information. Unlike other corticosteroids previously studied in ARDS, dexamethasone lacks mineralocorticoid activity and thus has minimal effect on sodium balance and fluid volume.10
Considerations in Pregnancy
A short course of betamethasone and dexamethasone, which are known to cross the placenta, is routinely used to decrease neonatal complications of prematurity in women with threatened preterm delivery.21,22
Given the potential benefit of decreased maternal mortality, and the low risk of fetal adverse effects for a short course of dexamethasone therapy, the Panel recommends using dexamethasone in hospitalized pregnant women with COVID-19 who are mechanically ventilated (AIII) or who require supplemental oxygen but who are not mechanically ventilated (BIII).
Considerations in Children
The safety and effectiveness of dexamethasone or other corticosteroids for COVID-19 treatment have not been sufficiently evaluated in pediatric patients.
Importantly, the RECOVERY trial did not include a significant number of pediatric patients, and mortality rates are significantly lower among pediatric patients with COVID-19 than among adult patients with the disease.
Thus, caution is warranted when extrapolating the results of this trial to patients aged <18 years. Dexamethasone may be beneficial in pediatric patients with COVID-19 respiratory disease who require mechanical ventilation.
Use of dexamethasone in patients who require other forms of supplemental oxygen support should be considered on a case-by-case basis and is generally not recommended for pediatric patients who require only low levels of oxygen support (i.e., nasal cannula only).
Additional studies are needed to evaluate the use of steroids for the treatment of COVID-19 in pediatric patients, including for multisystem inflammatory syndrome in children (MIS-C).
Clinical Data to Date
Multicenter, Randomized, Controlled Trial of Dexamethasone Versus Standard of Care in Hospitalized Patients
The RECOVERY study is an ongoing, multicenter, open-label, adaptive trial sponsored by the National Health Service in the United Kingdom.
Eligible participants were randomized to receive one of several potential treatments for COVID-19 plus the standard of care or standard of care alone. In one of the study arms, dexamethasone 6 mg daily was administered either orally or intravenously for up to 10 days or until hospital discharge, whichever came first.
The primary study endpoint was all-cause mortality at 28 days after randomization. Secondary endpoints included time to hospital discharge, cause-specific mortality, need for renal replacement, major cardiac arrhythmia, and receipt and duration of ventilation.1
Hospitalized patients in the United Kingdom with clinically suspected COVID-19 or laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were eligible for enrollment. Patients were not enrolled into the dexamethasone study arm (or included in the analysis) if their physicians determined that the risks of participation were too great based on their medical history or that corticosteroid therapy was indicated. Recruitment into the dexamethasone arm was stopped by the study steering committee on June 8, 2020, when enough participants were enrolled to assess the benefit of dexamethasone therapy.
- The preliminary analysis included 6,425 participants: 2,104 participants in the dexamethasone arm and 4,321 in the standard of care alone arm.
- SARS-CoV-2 infection was confirmed by laboratory testing in 89% of the participants.
- The mean age of the participants was 66.1 years, 64% of participants were male, and 56% had at least one major comorbidity, including 24% who had diabetes.
- At enrollment, 16% of participants required invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% had received supplemental oxygen but not invasive ventilation, and 24% required no oxygen supplementation.
- Few participants received remdesivir, hydroxychloroquine, lopinavir/ritonavir, or tocilizumab (0% to 3% of participants in both arms); approximately 8% of participants in the standard of care alone arm received dexamethasone after randomization. Use of azithromycin was balanced in both arms (24% in the dexamethasone arm vs. 25% in the standard of care alone arm).
Study endpoint analyses:
- Overall, 22.9% of participants in the dexamethasone arm and 25.7% in the standard of care alone arm died within 28 days of study enrollment (age-adjusted rate ratio 0.83; 95% CI, 0.75–0.93; P < 0.001).
- There was an interaction between baseline severity of COVID-19 and the treatment effect of dexamethasone.
- Survival benefit appeared greatest among participants who required invasive mechanical ventilation at randomization: 29.3% of participants in the dexamethasone arm died within 28 days of enrollment compared with 41.4% in the standard of care alone arm (rate ratio 0.64; 95% CI, 0.51–0.81).
- Among patients who required supplemental oxygen but not mechanical ventilation at enrollment, 23.3% of participants in the dexamethasone arm and 26.2% in the standard of care alone arm died within 28 days of enrollment (rate ratio 0.82; 95% CI, 0.72–0.94).
- No survival benefit was seen among participants who did not require oxygen therapy at enrollment; 17.8% of participants in the dexamethasone arm and 14.0% in the standard of care alone arm died within 28 days of enrollment (rate ratio 1.19; 95% CI, 0.91–1.55).
- The risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the standard of care alone group (rate ratio 0.77; 95% CI, 0.62–0.95).
- Results for several secondary endpoints (e.g., cause-specific mortality, need for renal replacement, major cardiac arrhythmia) have not yet been reported.
- The study was randomized, but open label.
- In this preliminary report, the results for key secondary endpoints, potential adverse events, and efficacy of dexamethasone in key subgroups (e.g., patients with comorbidities) have not been reported.
- Study participants with COVID-19 who, according to their providers, required oxygen but not mechanical ventilation were a heterogeneous group of patients with respect to their severity of illness; it is unclear whether use of dexamethasone will be beneficial for other participant subsets (e.g., those who require lower rather than higher levels of supplemental oxygen).
- There were also no standardized or objective criteria for oxygen supplementation.
- The age distribution of participants differed by respiratory status at randomization. The participants who received mechanical ventilation were more likely to be aged <70 years. Among the participants who were aged >80 years, only 1% were mechanically ventilated, while 62% and 37% were in the oxygen group and no oxygen group, respectively.
- Therefore, the survival benefit of dexamethasone for mechanically ventilated patients aged >80 years is unknown.
- Remdesivir was used in only five patients in the RECOVERY trial; therefore, the safety and efficacy of coadministering remdesivir and dexamethasone are not known.
- Very few pediatric or pregnant patients with COVID-19 were included in the RECOVERY trial; therefore, the safety and efficacy of dexamethasone for the treatment of COVID-19 in children or in pregnant individuals are unknown.
In patients with severe COVID-19 who required oxygen support, the use of dexamethasone 6 mg daily for up to 10 days reduced mortality at 28 days in a preliminary analysis. The benefit of dexamethasone was most apparent in hospitalized patients who were mechanically ventilated.
There was no observed benefit of dexamethasone in patients who did not require oxygen support. Further clarity on the mortality benefit of dexamethasone by baseline levels of oxygenation, age, sex, comorbidities, and/or duration of symptoms would better inform application of these findings.
More details regarding the safety of dexamethasone and longer follow-up would assist in interpretation of this study.
Other Clinical Studies of Corticosteroid Use in COVID-19
Smaller retrospective cohort and case series studies have yielded conflicting results on the efficacy of corticosteroids for the treatment of COVID-19.23 Several studies demonstrated the clinical benefit of using low-dose methylprednisolone early in the course of infection, including more rapid resolution of hypoxia, less need for mechanical ventilation, fewer intensive care unit transfers, and shorter hospital stays.24
Additionally, other studies suggest a benefit of corticosteroids in lowering overall mortality in patients with moderate disease, severe disease, and ARDS,25-29 which is consistent with results from the RECOVERY study.
Conversely, results reported for other studies, including a meta-analysis of 15 studies in patients with coronavirus infections (e.g., COVID-19, SARS, MERS)30 and a retrospective review of critically ill patients with COVID-19, suggest an increased risk of multiorgan dysfunction and no mortality benefit (and potentially an increased risk of death) with use of corticosteroids.31
These study results should be interpreted with caution, as the studies are retrospective and have methodological problems.
Several clinical trials to evaluate corticosteroids for the treatment of COVID-19 are currently underway or in development. Please see ClinicalTrials.gov for the latest information.
- RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.
- Bozzette SA, Sattler FR, Chiu J, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med. 1990;323(21):1451-1457. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2233917.
- 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):757-767. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29161116.
- Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16968120.
- Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016;3:CD010406. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26950335.
- Meduri GU, Bridges L, Shih MC, Marik PE, Siemieniuk RAC, Kocak M. Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med. 2016;42(5):829-840. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26508525.
- Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007;131(4):954-963. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17426195.
- Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671-1684. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16625008.
- Liu L, Li J, Huang YZ, et al. [The effect of stress dose glucocorticoid on patients with acute respiratory distress syndrome combined with critical illness-related corticosteroid insufficiency]. Zhonghua Nei Ke Za Zhi. 2012;51(8):599-603. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23158856.
- Villar J, Ferrando C, Martinez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32043986.
- Rezk NA, Ibrahim AM. Effects of methyl prednisolone in early ARDS. Egypt J Chest Dis Tuberc. 2013;62(1):167-172. Available at: https://www.sciencedirect.com/science/article/pii/S0422763813000265.
- Tongyoo S, Permpikul C, Mongkolpun W, et al. Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial. Crit Care. 2016;20(1):329. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27741949.
- Zhao WB, Wan SX, Gu DF, Shi B. Therapeutic effect of glucocorticoid inhalation for pulmonary fibrosis in ARDS patients. Medical J Chinese People’s Liberation Army. 2014;39(9):741-745. Available at: http://www.plamj.org/index.php/plamj/article/view/1009.
- Mammen MJ, Aryal K, Alhazzani W, Alexander PE. Corticosteroids for patients with acute respiratory distress syndrome: a systematic review and meta-analysis of randomized trials. Pol Arch Intern Med. 2020;130(4):276-286. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32186831.
- Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e469. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32224769.
- Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-related strongyloides hyperinfection. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761166.
- Liu J, Wang T, Cai Q, et al. Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic HBV infection. Hepatol Res. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761993.
- Centers for Disease Control and Prevention. Parasites—strongyloides: resources for health professionals. 2020. Available at: https://www.cdc.gov/parasites/strongyloides/health_professionals/index.html. Accessed August 14, 2020.
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- Nelson BC, Laracy J, Shoucri S, et al. Clinical outcomes associated with methylprednisolone in mechanically ventilated patients with COVID-19. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32772069.
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More information:JAMA (2020). DOI: 10.1001/jama.2020.17021
JAMA (2020). DOI: 10.1001/jama.2020.17022
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