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Corticosteroids for early stage COVID-19

Synthetic corticosteroids are widely available medications used to treat chronic inflammatory and autoimmune diseases.

Systemic corticosteroids for COVID-19 management

Based on evidence from previous coronavirus outbreaks ( eg, SARS-CoV and MERS-CoV ), the use of systemic corticosteroids in COVID-19 was initially discouraged due to the potential risk of secondary infections, long-term complications, and delayed viral clearance.
However, the RECOVERY trial, published in 2021, showed reduced mortality with Dexamethasone in patients hospitalised with COVID-19 who required mechanical ventilation or supplemental Oxygen, but not among those receiving no respiratory support.

Largely based on these findings, WHO guidance strongly recommended systemic corticosteroids in patients with severe and critical COVID-19.

Data regarding the use of these drugs during the initial phase of COVID-19, when patients are not hospitalised, are scant. Anecdotal evidence from case reports and observational studies suggested that early outpatient treatment with systemic corticosteroids at the time of viral replication ( ie, within the first few days of symptoms onset ) was associated with an increased risk of delayed recovery and worse clinical outcomes.

Systemic corticosteroids cause widespread immunosuppression, which could be useful during the late inflammatory phase of severe COVID-19 but cause harm in the early disease phase by suppressing host antiviral responses.

Inhaled corticosteroids for COVID-19 management

Inhaled corticosteroids have been proposed as an early COVID-19 treatment on the basis of their targeted anti-inflammatory effects in the lung and their antiviral properties.
To date, five randomised controlled trials have explored treatment with inhaled corticosteroids in outpatients with COVID-19 within 7–14 days of the onset of mild to moderate symptoms.

The STOIC study has shown that among 146 outpatients with mild COVID-19, inhaled Budesonide reduced the composite endpoint of emergency department assessment or hospitalisation, and improved time to recovery, compared with usual care.

The larger PRINCIPLE study found that in 1856 outpatients with COVID-19 at high risk of disease progression, inhaled Budesonide has improved time to recovery and has reduced the combined endpoint of hospital admission or death compared with usual care, although statistical significance was not achieved for the combined endpoint.

The COVERAGE study, which aimed to test inhaled Ciclesonide in outpatients with COVID-19 at risk of disease aggravation, was prematurely stopped after the first interim analysis revealed no efficacy with regard to reducing the primary composite endpoint of a need for Oxygen therapy at home, hospitalisation, or death.

Notably, these randomised controlled trials had an open-label design, and inhaled medications are known to have placebo effects in respiratory diseases, which could have introduced bias in subjective endpoints.

Two double-blind, placebo-controlled, randomised controlled trials have examined the effects of inhaled Ciclesonide in patients with early stage COVID-19 in the community.
An industry-sponsored study involving 400 people with mild to moderate COVID-19 disease found that inhaled Ciclesonide did not decrease time to symptom alleviation, but it did reduce the combined endpoint of emergency department visit or hospitalisation.
Instead, the CONTAIN study showed that among 203 young outpatients ( median age of 35 years ) with COVID-19, the combination of inhaled and intranasal Ciclesonide did not improve the resolution of symptoms, nor did it reduce the incidence of hospitalisation.

Overall, evidence from randomised controlled trials has suggested that the use of inhaled corticosteroids in outpatients with COVID-19 did not adversely affect clinical outcomes nor did it increase the risk of side-effects compared with usual care or placebo.
Nonetheless, the effectiveness of these medications in early COVID-19 management remains ill-defined. ( Xagena )

Perico N et al, Lancet Infectious Diseases, 2022