Corticosteroids in ARDS: old controversies, new insights, and future directions.

Corticosteroids modulate key inflammatory and fibroproliferative pathways involved in ARDS through genomic and non-genomic glucocorticoid receptor signaling. Advances in ARDS pathophysiology have highlighted the importance of timing, inflammatory burden, and host response in determining treatment efficacy. Clinical evidence supports corticosteroid use in moderate-to-severe ARDS, particularly in COVID-19 ARDS and severe community-acquired pneumonia, with reductions in mortality and duration of mechanical ventilation. However, treatment effects remain heterogeneous across etiologies and biological subphenotypes. Recent identification of hyperinflammatory and hypoinflammatory ARDS phenotypes suggests that corticosteroid responsiveness is not uniform. Hyperinflammatory phenotypes and septic ARDS appear more likely to benefit, whereas evidence remains limited or conflicting in influenza-associated and non-septic ARDS. Long-term effects and adverse outcomes, including metabolic complications and ICU-acquired weakness, remain insufficiently characterized. Future research is increasingly focused on precision medicine approaches integrating biomarkers, adaptive platform trials, and phenotype-guided strategies. Emerging developments include lung-targeted corticosteroid delivery systems and selective glucocorticoid receptor modulators designed to improve efficacy while reducing systemic toxicity. Corticosteroids should therefore be considered a context-dependent therapy whose benefit is influenced by etiology, disease stage, inflammatory phenotype, and timing of administration.