Monographic Issue on Glucocorticoid Therapy in Critical Illness and Respiratory Disease

Guanfranco Umberto Meduri, MD, FCCP

Antoni Torres, MD, PhD, FERS, FCCP, ATSF

We are at a pivotal moment in understanding and applying glucocorticoid (GC) therapy in critical illness. For decades, clinical practice has been shaped by paradigms from the 1970s and 1980s that primarily defined GCs as anti-inflammatory agents. However, emerging insights from molecular biology and translational research now call for a comprehensive re-evaluation—one that redefines how GC therapy is conceptualized, studied, and applied across critical care and respiratory medicine.

At the heart of this evolving paradigm is the glucocorticoid receptor α (GRα)—a master regulator of systemic adaptation. Beyond its traditional anti-inflammatory role, GRα activation orchestrates phase-specific responses across metabolic, immune, vascular, and neuroendocrine networks, driving the homeostatic corrections essential for recovery and survival. This receptor-centered perspective serves as the unifying framework for this monographic issue.

The first three articles of the issue, authored by Dr. Gianfranco Umberto Meduri and colleagues, establish the biological and mechanistic foundations of GC therapy in critical illness.[1] [2] [3] The first article by Meduri et al introduces a three-phase model of critical illness—Priming, Modulatory, and Restorative—in which GRα signaling governs bioenergetics, vascular tone, mitochondrial resilience, and immune modulation.[1] The second article explores GRα's role in preserving endothelial and gut barrier function, two essential interfaces often compromised during systemic inflammation.[2] The third article by Meduri presents a translational framework for addressing GC resistance, incorporating insights into oxidative stress, mitochondrial dysfunction, and the use of adjunctive strategies, such as micronutrient support, to restore GRα activity.[3]

Rest of the articles of this issue explain transition from foundational principles to clinical translation, applying GRα-focused concepts to specific syndromes across pulmonary and systemic critical illness. These chapters collectively illustrate how emerging pathobiological insights can inform indication-specific, personalized GC therapy, while addressing lingering controversies in evidence and practice.

Dequin and Confalonieri explore community-acquired pneumonia (CAP), a leading cause of ICU admissions and mortality worldwide. The article critically examined the heterogeneous results of randomized controlled trials involving corticosteroids in CAP, attributing variability to differences in host response, pathogen virulence, and timing of intervention. The authors advocate for refined patient phenotyping, incorporating inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) to identify subgroups likely to benefit from GC therapy. Special consideration is given to the context of COVID-19, where corticosteroids have demonstrated clear benefit, underscoring the need for syndrome-specific guidance.[4]

Poulain et al address hospital-acquired and ventilator-associated pneumonia (HAP/VAP), conditions often complicated by immune dysregulation and antibiotic resistance. Despite sparse data, the article reviewes the emerging role of GCs as adjunctive immunomodulators, especially in trauma-related pneumonia and postsurgical patients. The authors emphasize the value of biomarker-guided corticosteroid administration and explore how inflammatory phenotypes—rather than microbiological etiology alone—may guide clinical decisions. Two ongoing RCTs are highlighted, aiming to define the safety and efficacy of GC use in HAP/VAP with unprecedented rigor.[5]

Liu et al revisit septic shock, one of the earliest contexts in which corticosteroids were trialed. This article reevaluate historical trials through the lens of updated pharmacodynamics and GR signaling, demonstrating that fixed-dose, short-course regimens often failed to account for patient heterogeneity, critical illness-related corticosteroid insufficiency, and dynamic stress responses. The authors propose a phase-specific, receptor-saturating approach, including prolonged tapering and adjunctive interventions to support GRα function, such as micronutrient optimization and mitochondrial support.[6]

Guglielmi et al focus on acute respiratory distress syndrome, where mounting evidence supports the use of early, high-dose, receptor-saturating GCs (e.g., dexamethasone or methylprednisolone) during the exudative and early proliferative phases.[7] This article synthesizes the findings of key randomized trials and meta-analyses, presenting a compelling case for timely, sustained intervention to accelerate resolution of lung injury, reduce ventilator dependence, and improve survival. Emphasis is also placed on avoiding delayed initiation, which may coincide with fibroproliferative transitions and carry increased risk.

Sartori et al address exacerbations of chronic obstructive pulmonary disease (COPD).[8] Although systemic corticosteroids remain standard for moderate-to-severe exacerbations, growing concern over their cumulative toxicity has led to interest in dose minimization and phenotype-driven care. The article reviewes biomarker thresholds, such as blood eosinophil counts, and highlights emerging evidence supporting short-course regimens and targeted biologics, particularly in eosinophilic COPD. These developments align with the broader theme of precision stewardship, where therapeutic intensity is matched to disease biology.

Pilia and colleagues offer a detailed review of severe asthma, an archetypal disease in which GC resistance poses significant challenges. This article explores how endotyping—especially the distinction between T2-high (eosinophilic, IL-4/IL-5/IL-13-driven) and non-T2 (neutrophilic, obesity- or smoking-related) variants—can predict GC responsiveness. The authors highlight how biologic therapies targeting IL-5, IL-4Rα, and TSLP have transformed care by enabling oral corticosteroid-sparing strategies, reducing long-term toxicity while improving control.[9] Additionally, the article reviewes the molecular mechanisms of GC resistance, linking them back to the foundational concepts discussed in the first three articles of the issue by Meduri.

In the second last article of the issue, Confalonieri and colleagues, address the complications associated with GC therapy in the critically ill. This evidence-based synthesis focuses on short-course, moderate-dose regimens and reviews key adverse effects, including hyperglycemia, infection risk, neuropsychiatric symptoms, myopathy, gastrointestinal events, and HPA axis suppression. The authors emphasize that most complications are transient, dose-dependent, and manageable with appropriate monitoring. Special attention is given to high-risk subgroups, including those with COVID-19, and the need for structured tapering to prevent adrenal insufficiency. The authors also discuss adjunctive strategies, including micronutrients and probiotics, to enhance GC safety and effectiveness. Overall, the authors advocate for individualized GC use informed by clinical severity and response, supported by proactive risk mitigation strategies.[10]

The volume concludes with the article by Meduri et al in which they address a significant translational gap: outdated trial designs.[11] They call for adaptive clinical protocols informed by real-time biomarkers (CRP, IL-6, lactate), AI-supported decision tools, and the integration of adjunctive micronutrients to enhance GRα function and systemic resilience.

Taken together, this monograph articulates a new standard for GC therapy: one that is mechanism-based, phase-specific, and biologically personalized. It invites clinicians and researchers to move beyond generic interventions and toward integrated strategies that match the complexity of critical illness. In doing so, it paves the way for innovative trial designs, more effective interventions, and ultimately, better outcomes for critically ill patients worldwide.

Publication History

Article published online:
19 December 2025

• References

• 1 Meduri GU. . Glucocorticoids and GRa signaling in critical illness: phase-specific homeostatic corrections across systems. Semin Respir Crit Care Med 2026;47(1):
• 2 Meduri GU. . Semin Respir Crit Care Med 2026;47(1):
• 3 Meduri GU. . Semin Respir Crit Care Med 2026;47(1):
• 4 Dequin P-F. ., Confalonieri M. Glucocorticoid treatment in community-acquired pneumonia. Semin Respir Crit Care Med 2026;47(1):
• 5 Poulain C, Bouras M, Roquilly A. . Glucocorticoid treatment for hospital-acquired and ventilator-associated pneumonia. Semin Respir Crit Care Med 2026;47(1):
• 6 Liu J, Xing Q, Pan X, Zhang S, Chen D, Annane D. . Corticosteroid treatment in septic shock. Semin Respir Crit Care Med 2026;47(1):
• 7 Guglielmi R, Campanella A, Villar J, Torres A, Ferrando C. . Corticosteroids for acute respiratory distress syndrome. Semin Respir Crit Care Med 2026;47(1):
• 8 Sartori F, Sartori G, Di ChiaraC, Fantin A, Crisafulli E. . Glucocorticoid treatment in severe COPD exacerbations: biological rationale, clinical effects, and practical advice. Semin Respir Crit Care Med 2026;47(1):
• 9 Pilia MF, Espejo-Castellanos D, Romero-Mesones C, Muñoz-Gall X, Ojanguren-Arranz I. . Glucocorticoid treatment in severe asthma. Semin Respir Crit Care Med 2026;47(1):
• 10 Confalonieri P, Reccardini N, Kette S, Salton F. . Complications associated with glucocorticoids treatment in critically ill patients. Semin Respir Crit Care Med 2026;47(1):
• 11 Meduri GU, Lanini S, Smith J. . Limitations in the design of critical care studies and suggestions for future research directions. Semin Respir Crit Care Med 2026;47(1):