Corticosteroids in COVID-19: Answering all ifs, whens and buts for physicians.

However, physicians need to be aware about the appropriate indications for steroid use in COVID-19 and how to monitor for any adverse effects. The following article explores the various beneficial assets of steroid use in COVID-19 and revisits the literature to suggest appropriate use criteria for steroid use in COVID-19.

Mechanism of corticosteroid benefit in COVID-19 infection

Corticosteroids have pleiotropic effects resulting from complex molecular mechanisms including non-genomic and genomic effects. Briefly, glucocorticoids exert anti-inflammatory by stimulating the synthesis and release of anti-inflammatory proteins and by inhibiting that of pro-inflammatory proteins. Yao M et al (2) have proposed two putative mechanisms by which steroids improve immune-mediated systemic damage: the improvement of Acute Fibrinous and Organizing Pneumonia (AFOP) which precedes ARDS in COVID-19 and replacement for endogenous corticosteroids when adrenal functioning is impacted by COVID cytokine storm.

Corticosteroid formulations for use in COVID-19 infections

The recommended corticosteroids for use in the hyperimmune phase of coronavirus infection include methylprednisolone, prednisolone, dexamethasone, and hydrocortisone. The ICMR recommendations from May 2021 (3), advocate the use of intravenous (IV) methylprednisolone, when indicated, in hospitalized COVID-19 patients. However, the oral formulation of the drug has been widely used for outpatient treatment across the nation.

Prednisone and methylprednisolone are intermediate-acting corticosteroids with a half-life of 12 to 36 hours, and are administered once or twice daily (4).

The clinical evidence available for corticosteroid benefit.

Judicious use of corticosteroids have been shown to improve several parameters of severe and critical COVID-19, including reduction of the duration of hospital stay, prevention of worsening of the ventilator parameters, progression to ARDS, and death (5), quicker normalization of pyrexia and improvement in the status of oxygenation (6), reduced incidence of intubation and subsequent ventilation (7).

Recommendations on the use of corticosteroids for COVID-19 are largely based on data from the RECOVERY trial, a large, multicenter, randomized, open-label trial that compared hospitalized patients who received up to 10 days of dexamethasone to those who received the standard of care. Mortality at 28 days was lower among patients who were randomized to receive dexamethasone than among those who received the standard of care. This benefit was observed in patients who were mechanically ventilated or required supplemental oxygen at enrollment. (1).

Tamura et al have demonstrated that pulse therapy with Methylprednisolone in COVID-19 infected patients with respiratory failure achieved successful discontinuation of oxygen therapy without any severe adverse events. (8)

The cortiCOVID study also resonated these findings and showed that in patients with severe pneumonia due to COVID-19, the administration of methylprednisolone pulses was associated with a lower rate of orotracheal intubation and/or death and a shorter hospitalization episode (9) Guillermo et al have shown methylprednisolone administered in 2^nd the week is effective in improving the prognosis of patients with COVID-19 pneumonia with features of inflammatory activity and respiratory deterioration entering the second week of disease. (10).

The dark side: "How our best ally may turn into an enemy?"

With increasing literature support and clinical experience, corticosteroid use has extended beyond the hospital setting to treat patients on an out-patient basis.

An unholy trinity of diabetes, non-judicious use of corticosteroids in the background of COVID-19 appears to increase the risk of mucormycosis and other opportunistic infections. (11) To avoid such adverse outcomes, the appropriate use criteria for steroids need to be defined.

1) A Clinician's guide to appropriate steroid use:

1. ICMR National Task Force guidelines (3) recommend using Inj. Methylprednisolone 0.5-1 mg/kg in two divided doses for Hospitalised patients with moderate disease and 1-2mg/kg dose in those with severe disease.
2. The therapy is to be continued for 5-10 days and switching to an oral formulation can be done if the patient is improving.
3. The administration of pulse therapy (500–1000 mg/d), induces a glucocorticoid-induced apoptotic effect occurs and explains the very rapid immunosuppressive and anti-inflammatory effects. In the early stage of the inflammatory cytokine storm, methylprednisolone pulses change the outcome of COVID-19 for a complete recovery. (9)
4. Maximum oral dose of methylprednisolone should be capped at 32 mg in two divided doses.
5. No oral or parenteral steroid formulation is recommended for mild COVID-19 infections. Only inhalational budesonide can be used in these settings.

2) Monitoring and drug interactions:

NIH COVID-19 management guidelines (12) recommend the following cautions with steroid use:

· Clinicians should closely monitor patients with COVID-19 who are receiving steroids 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).

· When initiating corticosteroids, 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.

3) Drug tapering: Although ICMR guidelines do not recommend a tapering of steroid when used for up to 10 days but recent research conducted in Indian setting showed that rather than the fixed duration of therapy, most of the physicians (66.9%) relied on "clinical improvement" before stopping steroids even if it meant continuing steroids for prolonged periods beyond 14 days (34.1%). (13) Some experts consider HPA-axis suppression with methylprednisolone likely in any adult receiving >16 mg/day (daytime dosing). Thus if steroids have been in use for more than 10 days tapering may be done by 2.5-5 mg equivalent of prednisone every 3-5 days till physiological daily dose of 5 mg is reached (40 mf prednisone is equivalent to 32 mg methylprednisolone). (14)

Methylprednisolone in ARDS management:

Methylprednisolone has been shown to prevent the development of ARDS in COVID-19 infections also to improve the outcomes of patients who have already developed respiratory failure. (8-10)

Early administration of corticosteroids within the first 72 hours of presentation, within 1 week of onset of viral illness, and continued for 3 to 5 days was thought to have allowed this subset of patients to avoid intubation and mechanical ventilation (15). The results from this study also suggest that the sickest patients with COVID-19 infection appears to benefit the most from corticosteroids. Chaudhuri et al in a meta-analysis have shown that the use of corticosteroids reduces mortality in patients who have developed ARDS. 8 studies in their analysis used methylprednisolone as the primary corticosteroid. (16)

CONCLUSION:

Steroids are a physician's sturdy companions in the fight against COVID-19. Regarding the choice of steroids used, the majority of Indian physicians prescribe Methylprednisolone (59.1%) followed by Dexamethasone (38.8%)

[13]. Battling the hyperimmune phase of COVID-19, these drugs provide remarkable morbidity and mortality benefits. The resurgence of opportunistic fungal infections due to indiscriminate steroid use has called for revisiting the basics of steroid therapy as the fight against COVID is far from over and physicians need to be well versed and informed about the practical aspects of safe steroid use.