Adjuvant therapies in acute exacerbations of chronic obstructive pulmonary disease: mechanistic rationale and emerging clinical strategies

Abstract Background Acute exacerbations of chronic obstructive pulmonary disease are critical clinical events that substantially contribute to morbidity, mortality, and healthcare utilization. Standard management with bronchodilators, systemic corticosteroids, and antibiotics remains central to acute care; however, these therapies incompletely address the complex and multifactorial pathophysiological processes that drive exacerbation severity, delayed recovery, and early readmission. Persistent oxidative stress, corticosteroid-resistant inflammation, mucus hypersecretion, systemic inflammatory activation, and metabolic dysfunction often continue despite optimal guideline-directed treatment. Main body This review synthesizes current evidence on pharmacological and non-pharmacological adjuvant therapies for acute exacerbations of chronic obstructive pulmonary disease, integrating mechanistic rationale with emerging data from experimental and clinical studies. Pharmacological adjuvants—including thiol-based antioxidants and mucolytics, non-adrenergic bronchodilators, metabolic and mitochondrial modulators, and selected precision-targeted agents—may enhance standard therapy by restoring redox balance, improving mucus clearance, modulating inflammatory signaling, and supporting systemic recovery. In parallel, non-pharmacological interventions such as early pulmonary rehabilitation, nutritional optimization, individualized oxygen titration, and non-invasive ventilation target functional impairment and systemic stress that are insufficiently addressed by pharmacotherapy alone. The review also explores the potential utility of readily available systemic inflammatory biomarkers, including the neutrophil-to-lymphocyte ratio and composite inflammation indices, for risk stratification and individualized selection of adjuvant interventions. Key limitations of the current evidence base—such as heterogeneity in study design, variability in clinical endpoints, and underrepresentation of severe exacerbations—are critically discussed. Conclusion Integrating adjuvant therapies within a biomarker- and phenotype-informed framework represents a promising strategy to accelerate recovery, reduce early readmission, and improve short- and long-term outcomes in patients with acute exacerbations of chronic obstructive pulmonary disease. Well-designed, biomarker-stratified randomized trials are needed to define the optimal selection, timing, and duration of adjuvant interventions.