Rethinking Airway Reactivity in COPD
The push to revisit airway hyper-responsiveness (AHR) in chronic obstructive pulmonary disease (COPD) comes from a persistent gap in how heterogeneity is operationalized at the bedside. COPD has historically been defined by airflow limitation, but that metric alone does not explain why some patients experience disproportionate symptoms, exacerbations, or treatment responses.
Because of this, a recent review by Suter et. al examines AHR as a potentially overlooked physiologic feature that may help refine phenotyping, particularly in the subset of patients with type 2 inflammatory activity.
Reframing AHR Beyond Asthma
AHR is well established in asthma, where it reflects a core pathophysiologic process. In COPD, its role has been less clearly defined, despite evidence that a meaningful proportion of patients demonstrate this feature. The review notes that type 2 inflammation, characterized by eosinophils and cytokines such as IL-4, IL-5, and IL-13, is present in approximately 20-40% of COPD cases.
This overlap contributes to the emergence of phenotypes such as eosinophilic COPD and asthma-COPD overlap, though distinctions between these categories are not always clinically stable. AHR appears across these groups, complicating its use as a differentiating tool while supporting its consideration as an independent characteristic rather than a marker of a specific label.
Mechanistic Drivers of Airway Responsiveness
The review emphasizes that AHR in COPD arises from both inflammatory and structural mechanisms. Inflammatory pathways involve activation of eosinophils, mast cells, and other immune components, leading to mediator release and airway narrowing. This component tends to correlate with disease activity and biomarkers such as blood eosinophil count and fractional exhaled nitric oxide.
Structural contributors include airway smooth muscle changes, reduced airway caliber, and remodeling processes such as wall thickening. These alterations create a baseline susceptibility to exaggerated bronchoconstriction.
Variability in AHR Detection
A consistent limitation across the literature is the lack of standardization in how AHR is measured. The review describes substantial variability in challenge testing protocols, including differences in agents, dosing thresholds, and outcome definitions. For instance, methacholine challenge thresholds vary between studies, leading to markedly different reported prevalence rates.
Spirometry is the most commonly used assessment tool, but its reliability is constrained in COPD due to baseline airflow limitation and the influence of deep inspiration on airway tone. Alternative approaches such as oscillometry may provide greater sensitivity, particularly in detecting small airway dysfunction, though they are not yet widely implemented.
Clinical Correlations and Prognostic Relevance
AHR is associated with a range of clinical features that extend beyond airway physiology. Patients with AHR in COPD tend to report higher symptom burden, including wheeze and cough. Longitudinal studies cited in the review indicate patients with COPD and AHR show accelerated decline in lung function, increased risk of exacerbations, and higher mortality.
These associations persist even after accounting for smoking status and baseline disease severity in some analyses, suggesting that AHR captures an aspect of disease behavior not fully reflected by conventional metrics.
Treatment Response and Therapeutic Uncertainty
The relationship between AHR and treatment response remains incompletely defined. Inhaled corticosteroids have shown limited ability to directly reduce AHR in COPD in controlled studies, although patients with AHR may experience improvements in symptoms and quality of life compared with those without it.
Biologic therapies targeting type 2 pathways have demonstrated reductions in AHR in asthma populations, particularly through IL-4 and IL-13 signaling. However, the review notes that no studies have directly evaluated their effects on AHR in COPD, leaving uncertainty about their applicability in this context.
Implications for Phenotyping and Care
The evidence positions AHR as a measurable feature that intersects with both inflammatory and structural aspects of COPD. Its presence aligns with worse clinical outcomes and may help identify patients more likely to respond to certain therapies, although this relationship is not yet definitive.
The absence of standardized testing protocols and the limited data on targeted interventions remain barriers to routine use, indicating that further validation is required before AHR can be integrated into treatment algorithms with confidence.
Reference:
Suter P, Greig R, Chan R, Lipworth BJ. Revisiting type 2 inflammation and airway hyper-responsiveness in COPD. J Allergy Clin Immunol Pract. 2026;14(1):67-75. doi:10.1016/j.jaip.2025.10.033