Aspergillus sensitisation & allergic bronchopulmonary aspergillosis in chronic obstructive pulmonary disease: Redefining a treatable trait

Prevalence of Aspergillus sensitisation and allergic bronchopulmonary aspergillosis in chronic obstructive pulmonary disease

The true prevalence of Aspergillus sensitisation in COPD remains unclear. A 2020 systematic review estimated Aspergillus sensitisation prevalence at 13.6 per cent across five studies, though methodological heterogeneity limited confidence in this estimate^4,5. However, a quick literature review on PubMed (2010-2025) revealed 12 studies encompassing 2,158 COPD patients from India, the United Kingdom, Belgium, Singapore, and China (Supplementary Table)^6-18. Most cohorts included moderate-to-severe COPD (GOLD 2-4). The ImmunoCAP fluorescent enzyme immunoassay (8 studies) was the most common diagnostic modality, with older studies employing intradermal or skin prick tests.

Using Bayesian meta-analysis, the pooled prevalence of Aspergillus sensitisation and allergic bronchopulmonary aspergillosis in COPD was found to be ⁓12.9 per cent [95% credible interval (95% CrI, 105-15.4)] and 4.4% (95% CrI, 2.6-7.5), respectively. This brief estimate, though variable across studies, indicates that fungal sensitisation is not uncommon in COPD and deserves greater clinical attention. The observed heterogeneity stemmed from diagnostic methodology (serological versus cutaneous testing), screening approaches (routine versus selective), geographic and ethnic diversity, COPD severity, and coexistent bronchiectasis. While the prevalence estimates for Aspergillus sensitisation and allergic bronchopulmonary aspergillosis fall below those observed in asthma (AS; 25%; ABPA: 11%) or cystic fibrosis (AS: 39%; ABPA: 9%)^19-21, these findings nonetheless suggest that millions of COPD patients worldwide may harbour undiagnosed Aspergillus sensitisation or allergic bronchopulmonary aspergillosis, entities that may influence disease course and treatment response.

Clinical consequences of Aspergillus sensitisation in chronic obstructive pulmonary disease

Beyond serological abnormalities, Aspergillus sensitisation in COPD carries tangible clinical consequences. Sensitised patients have been reported to demonstrate: (i) worsened lung function, with lower FEV₁ values compared to non-sensitised counterparts; (ii) increased exacerbation frequency and healthcare utilisation; and (iii) higher prevalence of bronchiectasis^14,22-25. These effects are magnified when allergic bronchopulmonary aspergillosis develops^14,26.

In the bronchiectasis-COPD overlap (BCO) phenotype, allergic bronchopulmonary aspergillosis marks a distinct high-risk subgroup characterised by maximal disease severity, frequent exacerbations, and lowest lung function^11,14. This pattern supports ABPA as a critical disease modifier in overlap syndromes, potentially explaining steroid dependence or treatment-refractory phenotypes.

Polysensitisation to recombinant Aspergillus allergens (rAsp f 1, 2, 6, 15, and 17) correlated with greater symptom burden, independent of spirometry²⁴. Moreover, patients with structural lung damage from bronchiectasis or BCO have been reported to demonstrate similar sensitisation profiles¹⁴, suggesting a reciprocal relationship between airway structural abnormalities and fungal sensitisation.

Pathophysiology: A self-perpetuating cycle

The A. fumigatus-COPD relationship is bidirectional. Chronic airway inflammation, mucus hypersecretion, and impaired mucociliary clearance in COPD create a permissive environment for Aspergillus colonisation²⁷. Fungal proteases cause epithelial injury and induce IL8-mediated neutrophilic inflammation. In genetically susceptible individuals, this milieu promotes Th2 polarisation, IL5-mediated eosinophilia, and ultimately allergic bronchopulmonary aspergillosis.

Elevated serum IgE levels in COPD correlates with dyspnoea duration and FEV₁ decline, implicating IgE-mediated pathways in disease progression⁸. Furthermore, AS-positive COPD patients may also exhibit altered airway mycobiome composition, notably increased Saccharomyces abundance²³, adding complexity to our understanding of fungal-host interactions in diseased airways.

Environmental exposures modulate this risk. Bidi smokers have been reported to show higher Aspergillus sensitisation rates (27.8%) than cigarette smokers (16%)^9,15, while biomass fuel exposure, prevalent in developing countries, may differentially influence fungal sensitisation risk. These patterns highlight the interplay of microbial, environmental, and host factors in fungal-COPD pathogenesis.

The diagnostic challenge

Despite its significance, Aspergillus sensitisation and allergic bronchopulmonary aspergillosis remain underdiagnosed in COPD for several reasons. First, the absence of interventional trials demonstrating therapeutic benefit has discouraged routine screening. Second, COPD’s clinical heterogeneity, combined with symptomatic overlap between exacerbations and ABPA, obscures recognition. Third, COPD-associated allergic bronchopulmonary aspergillosis may present atypically compared to asthma-associated allergic bronchopulmonary aspergillosis, leading to missed diagnoses when conventional criteria are applied rigidly²⁸. Finally, diagnostic testing requires specific intent and is not incorporated into standard COPD evaluation protocols. Together, these barriers perpetuate clinical neglect of this potentially treatable trait.

The way forward: four critical priorities

The accumulated evidence demands a paradigm shift in COPD management:

First, randomised controlled trials of antifungal therapy (oral or inhaled azoles) in COPD patients with Aspergillus sensitisation/allergic bronchopulmonary aspergillosis and frequent exacerbations, focusing on exacerbation reduction as a primary endpoint are urgently needed, to establish therapeutic benefit directly.

Second, Aspergillus sensitisation may represent a steroid-responsive treatable trait analogous to eosinophilic COPD²⁹. Trials comparing inhaled corticosteroid and long-acting β2 agonists combinations versus LABA and long-acting muscarinic antagonist combinations in Aspergillus sensitisation-positive COPD patients with recurrent exacerbations could define optimal inhaler strategies for this phenotype, potentially reducing both exacerbations and lung function decline.

Third, future COPD guidelines should explicitly address fungal sensitisation, providing recommendations for screening high-risk populations, particularly those with frequent exacerbations, comorbid bronchiectasis, or BCO syndrome.

Finally, we need prospective, longitudinal studies to determine temporal relationships. Does allergic bronchopulmonary aspergillosis predispose to BCO development, or does BCO create conditions favouring allergic bronchopulmonary aspergillosis emergence? Understanding these causal pathways will inform prevention strategies and guide targeted interventions.

Overall, Aspergillus sensitisation and allergic bronchopulmonary aspergillosis represent under recognised yet clinically important entities in COPD. Their associations with impaired lung function, higher symptom burden, and increased exacerbation rates, particularly in overlap syndromes, underscore their role as disease modifiers. As COPD management transitions toward precision medicine, identifying and treating fungal sensitisation offers a novel route to improving outcomes in select patients. The question is no longer ‘Does Aspergillus matter in COPD?’ but rather ‘How should we optimally detect and manage it to improve patient outcomes?’ Given COPD’s immense burden in India, recognising Aspergillus sensitisation and allergic bronchopulmonary aspergillosis as treatable traits may meaningfully reduce morbidity, mortality, and healthcare costs.