Aspergillus sensitisation: an underappreciated treatable trait in airway disease

In 2006, Denning et al. [1] first proposed, in the European Respiratory Journal, the term “severe asthma with fungal sensitisation (SAFS)” to describe a distinct phenotype of severe asthma characterised by an elevated IgE-mediated response towards fungal allergens. Since then, SAFS has been widely studied and is generally considered to sit within a spectrum of disease ranging from uncomplicated asthma to frank allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) [2, 3]. Fungal sensitisation, particularly towards Aspergillus species, has been highlighted as a potential “treatable trait” in airway disease, with anti-fungal therapy and inhaled/oral corticosteroids forming the basis of treatment [2, 4, 5].

However, the clinical relevance of fungal sensitisation is not limited to asthma, and sensitisation to fungal allergens is increasingly observed in respiratory conditions such as bronchiectasis and COPD, with similar associations of increased disease severity, poor lung function and worse clinical outcomes being reported [5, 6]. However, studies aiming to understand the clinical relevance of fungal sensitisation in COPD and bronchiectasis are few and have produced conflicting results [7–9]. Fungal sensitisation is under-recognised as a trait in COPD and bronchiectasis, and consequently few patients are tested in routine practice. As such, the equivalent of SAFS in COPD (COPD and fungal sensitisation, or CAFS) and/or bronchiectasis (bronchiectasis and fungal sensitisation, BAFS) is not yet widely recognised.

In this issue of the European Respiratory Journal, Tiew et al. [10] provide compelling evidence for considering fungal sensitisation as a potentially treatable risk factor for exacerbations in patients with COPD. The authors report a prospective multicentre study of 614 stable COPD patients recruited between 2012 and 2020 from five hospitals in Singapore, Malaysia and Hong Kong. The study population was relatively elderly (mean age of 74 years) with 95.9% of the population being male. In addition, patients had relatively severe COPD, with 56.6% receiving inhaled corticosteroid treatment and around one-third (34.9%) having more than two exacerbations per year [10]. Importantly, participants were screened for ABPA using the diagnostic criteria proposed by the International Society of Human and Animal Mycology (box 1) [11], and those with a diagnosis of ABPA were excluded.

Overall, fungal sensitised patients were found to have 80% more exacerbations than patients without sensitisation. Digging deeper, 130 patients were sensitised to A. fumigatus, 273 to non-A. fumigatus Aspergillus species, and 157 to other fungi. A. fumigatus sensitisation was associated with a profound increase in exacerbation (rate ratio 3.48, 95% CI 1.38–8.75). These data therefore provide convincing evidence that Aspergillus sensitisation is associated with increased exacerbation risk [10].

An important issue addressed in this study is the methodology for detecting fungal sensitisation using crude and recombinant fungal allergens. Crude allergens, or whole-allergen extracts, are frequently used to clinically assess allergic sensitisation [12]. However, given the nature of these allergens and their method of extraction, there are a number of disadvantages to their use, including batch-to-batch variation and frequent contamination. As such, the use of more modern recombinant allergens – produced using allergen-encoding DNA, protein expression systems and subsequent methods of protein purification – appears more attractive to achieve more accurate and standardised testing to identify the allergen(s) driving an individual's allergic sensitisation response [12]. To date, 23 recombinant Aspergillus allergens have been established, yet only eight have been widely studied in respiratory disease and their use in clinical settings is still limited. A key finding of the study by Tiew et al. [10] is that diagnosis of Aspergillus sensitisation depends critically on the antigens used. 63.8% of Aspergillus-sensitised COPD patients in this study did not show a sensitisation response to crude A. fumigatus allergens, despite showing sensitisation when tested against recombinant A. fumigatus allergens [10]. These data suggest that the use of crude allergens alone would lead to an underdiagnosis of fungal sensitisation in practice.

The authors used a combination of deep learning-based clustering techniques and Topological Data Analysis (TDA), a computation-based method of studying complex datasets by looking at the “shape” the data take following the clustering of data with shared attributes [10, 13], to identify groups of patients with similar fungal sensitisation profiles and associated clinical outcomes. Here the authors report the presence of two distinct fungal sensitisation groups, where individuals in group 1 showed increased sensitisation to crude and recombinant Aspergillus-related allergens and had significantly worse clinical outcomes, evidenced by increased exacerbation rates, poor lung function and overall worse prognosis. In comparison, individuals in group 2 showed increased sensitisation to Cladosporium-related allergens with increased symptom severity. While clearly in line with existing literature highlighting an association between fungal sensitisation and disease severity in COPD [5], these findings also highlight that sensitisation to specific fungal species may drive distinct clinical phenotypes with differing clinical outcomes.

TDA also unearthed a subgroup of patients within group 1 who had increased sensitisation responses to recombinant A. fumigatus allergens 3, 6 and 34 who had the highest exacerbation frequency, the poorest lung function, and the worst overall prognosis. The authors also show that individuals sensitised to recombinant A. fumigatus allergens, with or without sensitisation to crude allergens, appeared more clinically severe in comparison to those sensitised to crude allergens alone, together hinting that recombinant allergens may have increased sensitivity for identifying subsets of patients who have more severe disease and are at increased risk of poor outcomes.

Many important questions stem from this work by Tiew et al. [10]. Aspergillus sensitisation is associated with a Th2-driven inflammatory process, often with eosinophilic airway inflammation (figure 1). A key aspect missing from the characterisation of these patients in the present study is the airway and systemic inflammatory profiles in “CAFS”. Previous work from the same group has defined distinct immunoallertypes with specific cytokine profiles in “BAFS” [6] and demonstrated changes in the airway mycobiome associated with outcomes in both bronchiectasis and COPD [4, 15, 16]. Exploration of the inflammatory makeup of fungal sensitised patients would be a step towards a much-needed, in-depth understanding of the pathogenesis of fungal sensitisation in comparison to that of ABPA/ABPM and contribute to identifying potential areas of therapeutic target. The present study has other important caveats, including the almost exclusively male cohort, enrolment from tertiary care centres, thus skewing the population towards more severe COPD, and the cross-sectional design.

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FIGURE 1

The immunopathogenesis of allergic fungal airway disease including fungal sensitisation and allergic bronchopulmonary mycosis (ABPM). Following exposure to fungal antigens, fungal allergens present within the airway provoke the airway epithelium to incite an inflammatory response. Airway epithelial cells release alarmins (interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP)) which act as an initial danger signal to recruit and activate local innate lymphoid cells 2 (ILC2s) and dendritic cells (DCs). While ILC2s rapidly respond in the form of secreted IL-5 and IL-13, recruited DCs extend their dendrites through the airway epithelium and into the airway lumen where they recognise and uptake fungal allergens. DCs migrate to the draining lymph node where they present these fungal antigens to naïve CD4+ T-cells, driving CD4+ Th2 cell differentiation. Back in the lung, a coordinated allergic Th2 immune response, characterised by eosinophilia, eosinophil activation (including eosinophil degranulation/eosinophil extracellular trap (EET) formation), excessive IgE production by plasma cells and subsequent mast cell degranulation, ensues, contributing to airway damage and inflammation. Th: T-helper cell. Adapted from Tiwary et al. [14], with permission. Created using BioRender.com (2022).

Nevertheless, these data raise important questions. There are few interventions capable of reducing exacerbations in COPD beyond inhaled bronchodilators, corticosteroids in eosinophilic patients, long term macrolides and pulmonary rehabilitation [17–21]. The identification of patient subgroups for whom there is a specific, effective treatment (endotypes or treatable traits) is therefore of paramount importance. The clear relationship between Aspergillus sensitisation and exacerbations in this study raises the question of whether anti-fungal treatment, corticosteroids or indeed biologics targeting type 2 inflammation may be effective in these patients. This hypothesis should be tested in controlled trials.

In addition, deciphering whether the panel of COPD-related recombinant A. fumigatus allergens are also clinically relevant in other respiratory diseases is important for the potential widespread implementation of recombinant A. fumigatus allergens in fungal sensitisation testing across different disease settings. It would also be valuable to look longitudinally to determine whether increased sensitisation to specific recombinant A. fumigatus allergens is a stable trait or if sensitisation progresses over time, with sensitisation acting as a predictive biomarker for the ultimate development of frank ABPA.

Current European Respiratory Society guidelines recommend universal Aspergillus testing for all new bronchiectasis cases [22], yet similar recommendations have not been proposed in COPD. These data indicate the potential value of screening patients with COPD, particularly patients with frequent exacerbations, for fungal sensitisation. The authors provide evidence for the use of recombinant allergens in clinical testing for fungal sensitisation and identify a clinically relevant panel of recombinant A. fumigatus allergens for the accurate diagnosis of Aspergillus sensitisation in COPD, and perhaps other respiratory diseases where Aspergillus sensitisation is apparent. Identification of sensitised individuals who would normally be overlooked using current diagnostic practice is important so we can effectively treat this treatable trait. Regardless, clearly severe asthma, bronchiectasis and COPD can all be associated with fungal sensitisation, and Aspergillus in particular is associated with increased exacerbations. Improved diagnostic testing should facilitate easier diagnosis and widespread recognition of the currently underappreciated CAFS and BAFS phenotypes. As such, there is now a clear need to develop an evidence base for the optimal treatment of fungal sensitisation across the spectrum of respiratory disease.

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