Beyond the airways: asthma as a systemic disorder

Asthma is one of the most common chronic respiratory diseases worldwide, traditionally defined as airway inflammation, reversible obstruction, and hyperresponsiveness. While this framework has guided decades of research and treatment, it fails to capture asthma as a heterogeneous and systemic condition. This pathology is shaped by complex interactions among genetic, epigenetic, immunological, neuroendocrine, metabolic, and environmental factors. Its coexistence with chronic obstructive pulmonary disease (COPD) in overlapping syndromes further complicates diagnosis and therapeutic decision-making. Asthma etiology involves oxidative stress, genetic susceptibility, and epigenetic regulation, along with age- and sex-dependent hormonal influences that modulate immune responses. Emerging evidence shows that structural and functional changes in the respiratory epithelium, airway smooth muscle (ASM), and alveoli extend the pathology beyond acute inflammation, involving processes such as epithelial barrier dysfunction, airway remodeling, and impaired mucociliary clearance (MCC). Neuro-immune-endocrine interactions have emerged as central contributors to asthma pathogenesis. Endocrine regulation shapes inflammatory activity and treatment responsiveness. Metabolic factors such as obesity introduce additional complexity by generating low-grade systemic inflammation, oxidative stress, adipokine imbalance, and steroid resistance, resulting in a distinct and often more severe asthma phenotype. Parasympathetic and sensory neural pathways amplify bronchoconstriction and inflammation through reciprocal communication with eosinophils, mast cells, innate lymphoid cells, and pulmonary neuroendocrine cells (PNECs). Neurotrophins and neuropeptides further promote airway hyperreactivity and remodeling. Current management integrates inhaled corticosteroids, bronchodilators, and targeted biologics—such as thymic stromal lymphopoietin (TSLP) inhibitors—alongside emerging non-pharmacological strategies. Psychological interventions, particularly mindfulness-based approaches, have demonstrated improvements in quality of life, stress reduction, and patient-reported asthma control, supporting the relevance of addressing the psychosocial dimensions of chronic disease. Understanding asthma as a systemic disorder underscores the need for personalized, multidimensional treatment strategies that integrate pharmacological, behavioral, and lifestyle components. This paradigm provides a more comprehensive framework for improving long-term outcomes and reducing the global burden of asthma.