Warning: fopen(/home/virtual/enm-kes/journal/upload/ip_log/ip_log_2024-07.txt): failed to open stream: Permission denied in /home/virtual/lib/view_data.php on line 100 Warning: fwrite() expects parameter 1 to be resource, boolean given in /home/virtual/lib/view_data.php on line 101 Glucocorticoids as a Double-Edged Sword in the Treatment of COVID-19: Mortality and Severity of COVID-19 in Patients Receiving Long-Term Glucocorticoid Therapy

Glucocorticoids as a Double-Edged Sword in the Treatment of COVID-19: Mortality and Severity of COVID-19 in Patients Receiving Long-Term Glucocorticoid Therapy

Article information

Endocrinol Metab. 2023;38(2):223-225
Publication date (electronic) : 2023 April 27
doi : https://doi.org/10.3803/EnM.2023.201
Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
Corresponding author: Eun-Hee Cho. Department of Internal Medicine, Kangwon National University School of Medicine, 1 Gangwondaehak-gil, Chuncheon 24341, Korea Tel: +82-33-258-9167, Fax: +82-33-258-2455, E-mail: ehcho@kangwon.ac.kr
Received 2023 April 11; Accepted 2023 April 17.

Glucocorticoids (GCs) are steroid hormones produced in the adrenal cortex under the control of circadian rhythms and stress [1]. Since their discovery in the 1940s, GCs have been successfully used as a mainstay of therapy to treat a wide range of chronic inflammatory diseases and autoimmune diseases and used as an immunosuppressive therapy following organ transplantation.

However, long-term GC treatment is associated with diverse complications, such as infections, osteoporosis, cardiovascular disease, cancer, and mortality [2-4]. In particular, the long-term use of GCs at higher dosages may cause more adverse effects, and the actual level of harm of long-term GC treatment depends on both the dose and duration of GC therapy and patient-specific parameters such as underlying medical conditions [5]. A study demonstrated that the risk of harm is low for the majority of patients at long-term dosages of ≤5 mg prednisone equivalent per day, whereas the risk of harm is increased at dosages of >10 mg prednisone equivalent per day [6]. In 779 rheumatoid arthritis (RA) patients, GC use was associated with a dose-dependent increase in mortality rates, with a daily threshold dose of 8 mg prednisone [7]. In a study using the South Korean National Health Insurance Database [3], chronic low-dose and high-dose GC usage increased the risk of 5-year all-cause mortality, with a more prominent increase among high-dose GC users (>5 mg/day prednisolone and a duration of GC use ≥30 days), suggesting safety concerns for long-term low-dose GC therapy.

The risk of mortality associated with long-term GC therapy is dependent on clinical factors, such as the dosage and duration of GC treatment, and underlying medical conditions, such as diabetes, hypertension, and cardiovascular disease [8]. One mechanism underlying the potential detrimental effects of long-term GC use is a lack of an adequate immune response to clear viral infections in patients with chronic diseases. However, the mechanisms by which GC therapy increases mortality risk have not been fully clarified. A major burden for long-term GC regimens is the difficulty of perfectly matching the distinct circadian rhythm of circulating cortisol levels, and another issue is that the current dose equivalents of GCs used for replacement/therapy are based on the potency of anti-inflammatory action, not equivalent cardiovascular and bone safety effects [9]. The last issue is the insufficient scientific evidence regarding when to discontinue GCs, how rapidly to taper the dosage of GCs, and what are the differences among different GCs (e.g., cortisone, prednisone, dexamethasone, and triamcinolone). Double-blind placebo-controlled studies are warranted to evaluate the efficacy and safety of long-term GC therapy versus the discontinuation of GC therapy in chronic inflammatory diseases, such as RA and chronic obstructive pulmonary disease (COPD), adjusting for confounders such as the underlying disease itself and its severity.

In this issue of Endocrinology and Metabolism, Ku et al. [10] demonstrated that long-term exposure to at least 150 mg of prednisolone (≥5 mg/day and ≥30 days) or equivalent GCs 180 days before coronavirus disease 2019 (COVID-19) infection increased the mortality and severity of COVID-19 in a Korean nationwide cohort database of COVID-19 patients. Another study in Denmark showed that exposure to GCs (cumulative prednisolone-equivalent dose <2,000 or ≥2,000 mg) within 120 days was associated with increased risks of hospital admission and death [11].

Several explanations exist for the association of long-term GC therapy with increased mortality in COVID-19 patients. First, patients receiving long-term GC therapy are exposed to supra-physiological dosage of GCs (prednisolone equivalent ≥ 5 mg/day) for at least 30 days, which may suppress the hypothalamus-pituitary-adrenal axis, causing secondary adrenal insufficiency in some people. Patients with adrenal insufficiency are more likely to have an infection-induced adrenal crisis than those without, potentially leading to death. Second, a significantly larger proportion of patients receiving long-term GC therapy had underlying chronic diseases, including COPD, asthma, and RA, than the control group. Third, long-term GC therapy may be related to impaired viral clearance, persistent COVID-19 viral replication, lower interferon production, and an increased risk for secondary infections [12,13]. Lastly, chronic GC exposure also has pleiotropic metabolic effects, including impaired glucose metabolism and skeletal muscle catabolism, which may contribute to adverse outcomes.

It is well-known that high-dose GC treatment (intravenous dexamethasone) in patients with severe COVID-19 disease increases ventilator-free days [14] and reduces mortality [15]. Half of the patients in this study [10] were admitted to the hospital, but there was a lack of laboratory information about the severity of COVID-19, except for oxygen therapy use, invasive mechanical ventilation, and intensive care unit admission. These findings raise questions regarding whether patients previously on long-term GC therapy require increased doses during COVID-19, as with sick day rules for other inter-current illnesses, or reduced doses to improve COVID-19 outcomes, and further research will be necessary to clarify these issues [11].

In summary, patients on long-term GC therapy may have an increased risk of severe COVID-19 and mortality. Therefore, physicians may need to carefully weigh the benefits and risks of continuing GC therapy during the COVID-19 pandemic based on the drug (dose and duration), pre-existing comorbidities, COVID-19 severity and GC-related adverse effects. This balance between the benefits and risks of GCs is important for clinical practice.



No potential conflict of interest relevant to this article was reported.


1. Shimba A, Ikuta K. Control of immunity by glucocorticoids in health and disease. Semin Immunopathol 2020;42:669–80.
2. Seguro LP, Rosario C, Shoenfeld Y. Long-term complications of past glucocorticoid use. Autoimmun Rev 2013;12:629–32.
3. Oh TK, Song IA. Trends in long-term glucocorticoid use and risk of 5-year mortality: a historical cohort study in South Korea. Endocrine 2020;69:634–41.
4. Einarsdottir MJ, Ekman P, Molin M, Trimpou P, Olsson DS, Johannsson G, et al. High mortality rate in oral glucocorticoid users: a population-based matched cohort study. Front Endocrinol (Lausanne) 2022;13:918356.
5. Strehl C, Buttgereit F. Long-term glucocorticoid therapy: is there a safe dosage? Internist (Berl) 2016;57:934–9.
6. Strehl C, Bijlsma JW, de Wit M, Boers M, Caeyers N, Cutolo M, et al. Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force. Ann Rheum Dis 2016;75:952–7.
7. del Rincon I, Battafarano DF, Restrepo JF, Erikson JM, Escalante A. Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol 2014;66:264–72.
8. Boers M, Pincus T. Long-term glucocorticoid use in rheumatoid arthritis. J Rheumatol 2021;48:1342.
9. Debono M, Ross RJ, Newell-Price J. Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy. Eur J Endocrinol 2009;160:719–29.
10. Ku EJ, Song KH, Kim KM, Seo GH, Yoo SJ. Mortality and severity of coronavirus disease 2019 in patients with long-term glucocorticoid therapy: a Korean nationwide cohort study. Endocrinol Metab (Seoul) 2023;38:253–9.
11. Ward D, Gortz S, Thomson Ernst M, Andersen NN, Kjaer SK, Hallas J, et al. The effect of immunosuppressants on the prognosis of SARS-CoV-2 infection. Eur Respir J 2022;59:2100769.
12. Li J, Liao X, Zhou Y, Wang L, Yang H, Zhang W, et al. Association between glucocorticoids treatment and viral clearance delay in patients with COVID-19: a systematic review and meta-analysis. BMC Infect Dis 2021;21:1063.
13. Baang JH, Smith C, Mirabelli C, Valesano AL, Manthei DM, Bachman MA, et al. Prolonged severe acute respiratory syndrome coronavirus 2 replication in an immunocompromised patient. J Infect Dis 2021;223:23–7.
14. Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, 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;324:1307–16.
15. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JA, Murthy S, Diaz JV, Slutsky AS, Villar J, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA 2020;324:1330–41.

Article information Continued