Corticosteroids in COVID-19: is discretion the better part of valor?

Introduction

The COVID-19 pandemic has been raging for well over a year in most parts of the world. Several therapeutic agents have been employed, many based on little scientific reasoning, often dictated by desperation. After several months of research, dexamethasone emerged as a possible therapeutic modality that may improve survival in patients with severe COVID-19. This finding was a turning point in the treatment of COVID-19, in contrast to previous evidence with corticosteroids in the treatment of viral pneumonia. Corticosteroids had been previously investigated in epidemics of viral pneumonia, including severe acute respiratory syndrome (SARS), the Middle East respiratory syndrome (MERS), influenza, and respiratory syncytial virus infection. No significant benefit was observed, and some studies even suggested possible harm.¹

There appears to be considerable variation among clinicians regarding the type, dose, and duration of corticosteroid treatment in COVID-19. Many continue to go by personal preferences and anecdotal experience, particularly with the use of high-dose pulsed therapy with methylprednisolone. Let us review the evidence available with corticosteroid therapy in COVID-19, particularly with the type, dosing, and duration of treatment. 

Dexamethasone

The RECOVERY trial

The RECOVERY trial randomized hospitalized patients with COVID-19 in a 2:1 ratio to receive usual care alone (n = 4321) or in combination with dexamethasone, 6 mg once daily (n = 2104) for a maximum of 10 days.² The 28-day mortality was significantly lower with dexamethasone compared to usual care alone (22.9 vs. 25.7%; p <0.001). Mortality reduction was highest in patients who received invasive mechanical ventilation, followed by those who received supplemental oxygen alone or in combination with non-invasive ventilation. Dexamethasone resulted in a 35% reduction in mortality among patients who were invasively ventilated (RR 0.65; 95% CI: 0.51–0.82; P <0.001). A 20% reduction in mortality was noted in patients who received supplemental oxygen alone or combined with noninvasive ventilation (RR 0.80; 95% CI: 0.70–0.92; P = 0.002). Interestingly, there was no difference in 28‐day mortality among dexamethasone-treated patients who did not require supplemental oxygen or respiratory support. 

Although the RECOVERY trial revealed a 2.8% absolute difference in survival with dexamethasone use at 28 days, an important question to ask is regarding long-term outcomes. This is relevant considering the fairly significant number of severely ill patients who remain hospitalized for longer periods of time, or continue to remain on home oxygen therapy, and develop late complications leading to mortality. Hence it will be important to evaluate longer-term survival at 90 days or at 6 months in subsequent analyses. This appears to be especially pertinent considering widespread reports of fungal infections, especially mucormycosis, in corticosteroid-treated covid patients.³

The CODEX trial

The CODEX randomized controlled trial, including 299 patients, was conducted in 41 intensive care units in Brazil. This trial used a higher dose of dexamethasone compared to the RECOVERY trial (20 mg daily for 5 days, followed by 10 mg daily for 5 days or until discharge from ICU). Ventilator-free days at 28 days were significantly higher in the dexamethasone group; however, there was no difference in all-cause mortality, ICU-free days, or clinical status on a 6-point ordinal scale at 15 days.⁴

Hydrocortisone

The CAPE COVID trial

The CAPE COVID multicentric French study included patients with acute respiratory failure due to COVID-19, admitted to the intensive care unit.⁵ Patients were randomized to receive hydrocortisone 200 mg/day as a continuous infusion and compared with placebo. This randomized clinical trial, including 149 patients was terminated early as there was no significant difference in the need for continued respiratory support at 21 days between the hydrocortisone and the control groups.  

The REMAP-CAP trial

Intravenous hydrocortisone was evaluated among patients admitted to the intensive care unit for respiratory or cardiovascular support in REMAP‐CAP randomized controlled trial.⁶ Patients were administered a fixed duration of hydrocortisone 50 mg 6 hourly for 7 days or for the duration of shock (maximum of 28 days) and compared with usual care alone. The trial was stopped when the report of the RECOVERY trial was released. Although underpowered due to early cessation, Bayesian modeling revealed a 93% and 80% probability of an increase in the number of organ support-free days at 21 days with the fixed and shock-dependent course, respectively. 

Methylprednisolone

Low-dose methylprednisolone

Jeronimo et al. studied hospitalized patients with clinical or radiological suspicion of COVID-19 with SpO2 ≤ 94% on room air or requiring respiratory support with supplemental oxygen or invasive mechanical ventilation. Methylprednisolone, 0.5 mg/kg, was administered twice daily for 5 days and compared with placebo. One hundred and ninety-four patients received methylprednisolone, while 199 received placebo. On the modified intention to treat analysis, there was no difference in the 28-day mortality between groups (methylprednisolone vs. placebo: 37.1% vs.38.2%; p = 0.629). This adequately powered randomized controlled trial clearly showed no mortality benefit with a total dose of 1mg/kg/day of methylprednisolone.

High-dose methylprednisolone 

How about high-dose methylprednisolone, often employed by clinicians, particularly in severe COVID-19? In a retrospective cohort study, Papamanoli et al. evaluated patients with COVID-19 pneumonia with severe respiratory distress, with SpO₂ of <93% on room air, and the requirement for high flow oxygen or non-invasive ventilation.⁷ Patients received a median daily dose of methylprednisolone of 160 mg (range: 120–180 mg) for a median duration of 5 days. One hundred and fifty-three patients who received methylprednisolone were compared with 294 who did not receive corticosteroids. At 28 days, although the requirement for mechanical ventilation was lower with methylprednisolone, there was no difference in mortality compared to the control group. 

Edalatifard et al. conducted a small, single-blind randomized controlled trial of pulse-dose methylprednisolone, 250 mg/day for 3 days compared to standard care.⁸ Thirty-four patients with respiratory failure were included in each group. The authors reported a shorter time to clinical improvement and lower mortality with pulse-dose methylprednisolone. However, this study is limited by inadequate sample size; besides, although six patients who received corticosteroids in the standard care arm were excluded, no separate intention to treat and per-protocol analysis was performed. The primary outcome was time to discharge or death; the composite of a positive and a negative outcome as an endpoint is difficult to rationalize. 

The WHO meta-analysis

The WHO REACT Working Group performed a meta-analysis of 7 randomized controlled trials of corticosteroid treatment in 1703 critically ill patients with COVID-19.⁹ There was minimal heterogeneity between studies. Different types and doses of corticosteroids were used, including dexamethasone (6–20 mg/day), hydrocortisone (200 mg/day), and methylprednisolone (40 mg twice daily). Overall, the use of corticosteroids was associated with lower 28-day mortality (OR: 0.66; 95% CI, 0.53–0.82; p <0.011). The reduction in mortality was similar across all types and dose ranges of corticosteroids. 

Duration of corticosteroid treatment

Dexamethasone was administered for a period of 10 days in the RECOVERY trial. It is plausible that an extended duration of corticosteroid treatment may lead to adverse effects.  Thrombotic complications are more likely with prolonged corticosteroid use in the procoagulant setting of COVID-19 infection.¹⁰ Besides, the risk of critical illness-related neuromuscular weakness is a well-known complication associated with prolonged corticosteroid therapy. Control of blood glucose levels may be a problem, particularly in diabetic patients. Indeed, treatment with corticosteroids in the late stage of acute respiratory syndrome beyond 2 weeks is associated with increased mortality.¹¹ Furthermore, there is increasing concern among clinicians regarding the possible association of prolonged, high-dose corticosteroid treatment in COVID-19 and life-threatening fungal infections, including mucormycosis.¹²  

Summary

• Judicious use of corticosteroids may save lives in patients with COVID-19 who require oxygen supplementation or respiratory support 
• Different types of corticosteroids may be equivalent in efficacy at appropriate doses; dexamethasone 6 mg, hydrocortisone 160 mg, methylprednisolone 32 mg, and prednisolone 40 mg are pharmacologically equivalent  
• There is no evidence to suggest that higher doses of corticosteroids might be more efficacious
• Critical illness-associated neuromuscular weakness and high blood glucose levels are common adverse effects of corticosteroids. Specifically, in COVID-19, an increase in the incidence of nosocomial infections, especially invasive fungal infections, are of increasing concern
• Corticosteroids may exacerbate the procoagulant state and lead to thrombotic events in severe COVID-19
• Several unanswered questions remain: At what level of severity should corticosteroid treatment be considered? Do we need taper corticosteroid dosage? Will corticosteroid treatment impair viral clearance? Future research should address these important questions

References

1.         Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. The Lancet. 2020;395(10223):473-475. doi:10.1016/S0140-6736(20)30317-2

2.         RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693-704. doi:10.1056/NEJMoa2021436

3.         Ahmadikia K, Hashemi SJ, Khodavaisy S, et al. The double-edged sword of systemic corticosteroid therapy in viral pneumonia: A case report and comparative review of influenza-associated mucormycosis versus COVID-19 associated mucormycosis. Mycoses. Published online February 16, 2021. doi:10.1111/myc.13256

4.         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;324(13):1307-1316. doi:10.1001/jama.2020.17021

5.         Dequin P-F, 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):1298. doi:10.1001/jama.2020.16761

6.         Angus DC, Derde L, Al-Beidh F, et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19. JAMA. 2020;324(13):1317-1329. doi:10.1001/jama.2020.17022

7.         Papamanoli A, Yoo J, Grewal P, et al. High‐dose methylprednisolone in nonintubated patients with severe COVID‐19 pneumonia. Eur J Clin Invest. 2021;51(2). doi:10.1111/eci.13458

8.         Edalatifard M, Akhtari M, Salehi M, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J. 2020;56(6). doi:10.1183/13993003.02808-2020

9.         The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020;324(13):1330. doi:10.1001/jama.2020.17023

10.       Brotman DJ, Girod JP, Posch A, et al. Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers. Thromb Res. 2006;118(2):247-252. doi:10.1016/j.thromres.2005.06.006

11.       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. doi:10.1056/NEJMoa051693

12.       Post COVID-19 Mucormycosis – from the Frying Pan into the Fire. Accessed May 17, 2021. https://www.japi.org/x27464c4/post-covid-19-mucormycosis-from-the-frying-pan-into-the-fire