Advances in the Diagnosis and Management of Allergic Bronchopulmonary Aspergillosis/Mycosis

Abstract

Allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) is an immunologically mediated pulmonary disorder triggered by the colonization of filamentous fungi in the airways of patients with asthma or cystic fibrosis, leading to type I and III hypersensitivity responses, eosinophilic mucus plug formation, and central bronchiectasis. Over the past decade, advances in basic and clinical research have substantially reshaped the understanding and management of this disease. Although Aspergillus species, particularly Aspergillus fumigatus, remain the predominant causative fungi, epidemiological studies have identified Schizophyllum commune as an important and previously underrecognized pathogen responsible for ABPM. A major breakthrough in elucidating disease pathophysiology is the recognition of eosinophil extracellular trap cell death as a central mechanism driving highly viscous mucus impaction. Diagnostic criteria with improved accuracy and standardized treatment protocols have been established through randomized controlled trials, culminating in the 2024 revision of the International Society for Human and Animal Mycology guidelines. However, significant unmet needs remain. Despite high initial response rates to corticosteroids or azole antifungals, nearly half of patients fail to achieve remission. Predictors of treatment failure include heightened A. fumigatus-specific sensitization and radiological evidence of eosinophilic mucus impaction. Biologic agents targeting type 2 inflammation have emerged as promising options for difficult-to-treat disease, although their efficacy in acute ABPA is still uncertain. Frequent exacerbations also pose a major challenge, and the potential benefits of maintenance inhaled antifungals and environmental interventions are under investigation. Collectively, advances in pathophysiology, diagnostics, and therapeutics are transforming ABPA/ABPM management, yet substantial gaps persist in improving long-term outcomes.

Trial Registration

ClinicalTrials.gov Identifier: NCT04442269

INTRODUCTION

Allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) is characterized by type I and type III hypersensitivity reactions to filamentous fungi colonizing the airways, primarily in patients with asthma or cystic fibrosis.¹,² In addition to the presence of fungus-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) antibodies, hallmark clinical features include disease onset in middle-to-older age, prominent peripheral blood eosinophilia, and characteristic radiological and pathological findings in the lower airways, such as central bronchiectasis, bronchial mucus plugging, and transient pulmonary infiltrates.³,⁴ Based on these features, the classical diagnostic criteria proposed by Rosenberg and colleagues in the 1970s were widely used for decades.⁵ However, diagnosis was often substantially delayed, frequently resulting in irreversible structural damage to the bronchi and lung parenchyma.

A major turning point occurred in 2013, when the International Society for Human and Animal Mycology (ISHAM) published expert-opinion-based diagnostic criteria and management guidelines that focused primarily on ABPA.¹ In parallel, a national research program on ABPA/ABPM was launched in Japan. These developments accelerated progress in understanding disease pathogenesis, refining diagnostic approaches, and optimizing treatment and management strategies. Consequently, the clinical landscape of ABPA/ABPM has undergone a profound transformation over the past decade.

Schizophyllum commune, AN EMERGING FUNGUS CAUSING ABPM

ABPA/ABPM is caused by thermotolerant filamentous fungi with small spores/conidia, because saprophytic growth in the lower airways is essential for disease development. Aspergillus fumigatus is the most representative species causing ABPA, but Aspergillus flavus, Aspergillus niger, and Aspergillus terreus can also contribute to disease onset.⁶,⁷ In contrast, Cladosporium spp. and Alternaria spp. which are ubiquitous in indoor and outdoor environments, rarely cause ABPA/ABPM because of their larger spore/conidia size and suboptimal germination temperature for growth at human body temperature.

Until recently, there had been no systematic survey of causative fungi other than Aspergillus spp. in ABPA/ABPM.⁸ A second nationwide survey of ABPA/ABPM in Japan was conducted in 2020, revealing the importance of the previously underestimated S. commune as a major causative fungus of ABPM.⁹ S. commune, a basidiomycota that is ubiquitous in outdoor environments, was detected in approximately 40% of culture-positive ABPA/ABPM cases in sputum (Fig. 1A) and bronchoalveolar lavage fluids/mucus plugs (Fig. 1B), making it the second most common organism after Aspergillus sp. in Japan. However, reports of S. commune-associated ABPM are rare outside Japan, with only 2 cases reported from India and 4 from China, despite S. commune being a cosmopolitan pathogen known to cause sinusitis and other infections worldwide.¹⁰

Fig. 1. Number of culture-positive cases for Aspergillus spp. and/or Schizophyllum commune among patients with allergic bronchopulmonary aspergillosis/mycosis in which both (A) sputum and (B) mucus plugs or bronchial lavage fluid was examined microbiologically (n = 216).⁹ .

Several challenges have made it difficult to diagnose S. commune-associated allergic bronchopulmonary mycosis (ABPM-Sc): the difficulty to identify the pathogen in culture and the lack of specific serological tests. Unlike Aspergillus spp., S. commune forms non-distinctive white colonies on culture plates that are often dismissed as contaminants. Definitive identification of S. commune in sputum or bronchial lavage fluid requires isolating appropriate colonies from culture plates and performing genetic analysis which can be possible only in specialized laboratories. To address these issues, the ABPA/ABPM Research Program has developed a simple, yet highly specific detection method based on hydrogen sulfide produced by S. commune.¹¹,¹² Furthermore, the S. commune-specific allergen component Sch c 1, a glucoamylase, was identified, and enzyme-linked immunosorbent assays for Sch c 1-specific IgE and IgG have been developed.¹³

The information on the clinical features of ABPM-Sc is still limited. The largest clinical case series study by Oguma et al.¹⁴ compared clinical presentation between 30 cases of ABPM-Sc and 46 cases of ABPA with positive of Aspergillus spp. culture in sputum or bronchial lavage fluids. Interestingly, two-thirds of ABPA-Sc cases were co-sensitized to A. fumigatus, although fungal culture only demonstrated S. commune, but not any of Aspergillus spp. Clinical features of ABPA and A. fumigatus-sensitized ABPM-Sc were indistinguishable except for serological tests for A. fumigatus, whereas ABPM-Sc cases not sensitized to A. fumigatus were less likely to exhibit asthma (30% vs. 70% in ABPA) and presented with lower levels of total IgE in serum (562 vs. 1,952 IU/mL in ABPA). Following development of new diagnostic modalities for fungal identification and serological tests for S. commune as mentioned before, a clinical study is currently underway to explore the epidemiology, clinical characteristics, treatment responses, and prognosis of ABPM-Sc.

MUCUS PLUGS, A KEY PATHOLOGICAL FEATURE OF ABPA/ABPM, AND EOSINOPHILIC EXTRACELLULAR TRAPS

From a pathological standpoint, the defining feature of ABPA/ABPM is the presence of highly viscous mucus plugs, enriched with eosinophils and containing fungal hyphae, impacted within the central bronchi.¹⁵,¹⁶ The radiological abnormalities emphasized in conventional diagnostic criteria, central bronchiectasis and migratory pulmonary infiltrates, are now understood to represent secondary consequences of mucus impaction.³,¹⁷ Central bronchiectasis arises from expanding mucus plugs that displace the airway wall outward, whereas pulmonary infiltrates reflect downstream lesions from intrabronchial mucus, such as eosinophilic pneumonia or atelectasis. Accordingly, elucidating the mechanisms that drive the formation of eosinophilic mucus plugs has been central to advancing our understanding of ABPA/ABPM pathophysiology.¹⁸

The eosinophilic mucus plugs observed in ABPA/ABPM are characteristically brownish, extremely tenacious, and often difficult to remove physically, even with bronchoscopy. These plugs frequently exhibit high density on chest computed tomography (CT) exceeding the density of skeletal muscles, a finding known as high attenuation mucus (HAM).¹⁹,²⁰ Intrabronchial HAM is highly characteristic of ABPA/ABPM, whereas similar lesions are observed in the paranasal sinuses of eosinophilic chronic rhinosinusitis or allergic fungal rhinosinusitis.²¹

The formation of these characteristic eosinophilic mucus plugs is driven by extracellular trap cell death (ETosis) of eosinophils, a process in which eosinophils activated by the contact with fungi release nuclear chromatin including DNA and histones as extracellular traps.²²,²³,²⁴ Aggregates of experimentally induced extracellular traps from activated eosinophils closely recapitulate the physical characteristics of mucus plugs in patients with ABPA/ABPM, exhibiting a brownish color, low water content, a peanut-butter-like viscoelasticity, and high CT attenuation.²⁵ This sharply contrasts with the white, hydrated gel-like aggregates formed by neutrophil-derived extracellular traps. Consistent with these findings, mucus plugs from patients with ABPA/ABPM contain abundant extracellular DNA and citrullinated histones, together with remnants of disintegrated eosinophils (Fig. 2), indicating that eosinophil-derived extracellular traps constitute a major structural component of the plugs.²⁴

Fig. 2. Presence of Aspergillus fumigatus and abundant extracellular trap cell death (ETosis) of eosinophils and extracellular traps in bronchial mucus plugs obtained from a patient with allergic bronchopulmonary aspergillosis. (A) Fungal hyphae in the mucus plug on Grocott-stained sections (scale bar: 20 μm). (B) Mucus plug stained for histone H1 (green) and DNA (blue, scale bar: 20 μm). The mesh-like eosinophil extracellular traps colocalized with histone H1 spread throughout the mucus. (C) Section of mucus plug immunostained for citrullinated histone H3 (citH3, green) and DNA (blue) on fluorescence imaging (ii, iv), and the same section was further stained with the HE method (i, iii). Lower panels (×100 objective, scale bar: 10 μm) are the boxed area in upper panels (×10 objective, scale bar: 100 μm) presented at a higher magnification. Lytic eosinophils with decondensed nuclei and extracellular traps (iii, arrows) were positive for citrullinated histone H3 (iv). Reproduced from Muniz et al.²⁴ with permission from Elsevier.

HE, hematoxylin-eosin.

Collectively, these insights establish a conceptual framework that redefines ABPA/ABPM not merely as an allergic disorder but as a disease fundamentally driven by eosinophil ETosis-mediated mucus plug formation and consequent airway remodeling. This concept is further supported by the results of a factor analysis conducted using data from a prospective cohort of 106 well-characterized ABPA patients recruited from 14 medical institutions in Japan between 2013 and 2023. The analysis identified the 3 distinct clinical components of ABPA: allergic, eosinophilic, and fungal (Fig. 3).²⁶ Peripheral blood eosinophil counts, the presence of mucus plugs, and HAM constituted the eosinophilic component—which was independent of the allergic component defined primarily by serum total and allergen-specific IgE levels. Notably, although factor scores for the allergic and fungal components varied among the 3 clinical phenotypes: ABPA sans asthma, ABPA with atopic asthma, and ABPA with non-atopic asthma, the eosinophilic component remained consistent across all phenotypes. These findings indicate that the eosinophilic component represents the cardinal and unifying feature of ABPA.

Fig. 3. Three major components characterized by clinical features of ABPA. Non-cystic fibrosis ABPA cases in Japan (n = 106) were analyzed by factor analysis.²⁶ .

ABPA, allergic bronchopulmonary aspergillosis; IgE, immunoglobulin E; HDM, house dust mite; IgG, immunoglobulin G.

Importantly, within these eosinophilic mucus plugs, eosinophil extracellular traps immobilize the causative fungi of ABPA/ABPM; however, they lack fungicidal activity, allowing airway inflammation to persist. Suppressing eosinophil migration and activation with corticosteroids or biologics facilitates the removal of these mucus plugs, which not only helps prevent airway remodeling but also contributes to eliminating the fungi that drive ABPA/ABPM. This also explains why combining antifungal agents with corticosteroids does not necessarily enhance therapeutic efficacy²⁷: corticosteroids alone can eliminate the fungi colonizing mucus plugs within the airways.

DIAGNOSTIC CRITERIA UPDATE

The classical diagnostic criteria for ABPA,⁵ proposed in 1977, do not adequately reflect advances in diagnostic modalities achieved in recent decades. In response to these limitations, the ISHAM working group for ABPA proposed new diagnostic criteria in 2013.¹ The diagnosis of ABPA using these criteria requires the fulfillment of both mandatory components—fungus-specific IgE positivity and an elevated total serum IgE (≥ 1,000 IU/mL) —in the presence of an underlying disease (asthma or cystic fibrosis), as well as at least 2 of the following 3 criteria: peripheral blood eosinophilia, fungus-specific IgG positivity, and characteristic radiological findings. A nationwide survey in Japan, however, revealed that approximately 20% of ABPA/ABPM cases exhibited neither asthma nor cystic fibrosis, and nearly 50% did not meet total serum IgE levels in the ISHAM criteria.²⁸ Diagnostic performance was especially suboptimal for ABPM caused by non-Aspergillus fungi.

To address these issues, the Japanese ABPA/ABPM Research Program proposed new diagnostic criteria in 2021.²⁹ The criteria comprise 10 items, which can be organized into 3 domains: allergic components (asthma, elevated total serum IgE, and type I hypersensitivity to fungi), eosinophilic components (peripheral blood eosinophilia, central bronchiectasis, mucus plugs in the central bronchi, and HAM); and fungal components (type III hypersensitivity to fungi, positive fungal culture from airway-derived specimens, and pathological detection of fungal hyphae within mucus plugs). A diagnosis of definite ABPA/ABPM is established when ≥ 6 items are fulfilled, whereas cases meeting five items are classified as probable ABPA/ABPM. Validation of the criteria was performed using two cohorts: pathological ABPA/ABPM diagnosed according to pathological criteria¹⁶ and physician-diagnosed disease clinically diagnosed by certified experts in respiratory medicine or allergology in Japan.²⁹ The sensitivity of the Japanese criteria was 94%–96%, outperforming the classical criteria (25%–49%) and the ISHAM criteria (77%–83%). Specificity was 99% for the classical criteria, 87%–91% for the ISHAM criteria, and 90%–97% for the Japanese criteria, when evaluated using 151 control cases (eosinophilic mucus plugs without fungi, chronic eosinophilic pneumonia, Aspergillus-sensitized asthma, and chronic pulmonary aspergillosis). Notably, sensitivity remained high (91%) even for ABPM caused by non-Aspergillus fungi (vs. 13% for classical criteria and 48% for ISHAM criteria), highlighting the robustness of the criteria. Although most cases can be diagnosed with non-invasive tests, such as laboratory and radiological tests, additional bronchoscopic examination accompanied by mycological and pathological evaluation of mucus plugs significantly improves the rate of definite diagnosis among suspected cases; from 80% to 92% in ABPA and from 36% to 61% in ABPM.⁹

In 2024, the ISHAM criteria were revised to broaden the definition of underlying conditions, lower the cutoff value for total serum IgE from 1,000 IU/mL to 500 IU/mL, and permit a diagnosis of ABPA/ABPM based solely on the presence of HAM in the bronchi.²

STANDARD TREATMENT OF ACUTE ABPA/ABPM AND DIFFICULT-TO-TREAT ABPA/ABPM

The standard treatment for acute ABPA/ABPM, either at the onset or exacerbation of the disease, consists of oral corticosteroids initiated at a moderate dose or oral azole antifungal agents.² Both approaches yield high rates (88%–100%) of treatment response, defined by clinical/radiographic improvement and decrease in serum IgE levels by 20% or more at 6–8 weeks after treatment initiation.³⁰,³¹,³² Oral corticosteroids are generally preferred in symptomatic patients because of their rapid onset of action. Both oral itraconazole and voriconazole are effective against the causative fungi of ABPA/ABPM, such as Aspergillus spp. and S. commune. Because these agents suppress immune responses indirectly by eliminating the fungi, their onset of action is somewhat slower than that of corticosteroids. Consequently, the early treatment response at 6 weeks is slightly lower with antifungal therapy (88%) than with corticosteroids (100%).³¹,³² Furthermore, corticosteroids alone can eliminate the fungi colonizing the airways by removing the mucus plugs as we previously discussed, combining antifungal agents with corticosteroids does not enhance therapeutic efficacy in most cases.²⁷ However, antifungal agents are recommended as first-line therapy for individuals in whom corticosteroids are difficult to use, such as those with poorly controlled diabetes mellitus or chronic infections (Fig. 4). Therapeutic intervention should be considered even in patients with minimal symptoms when bronchial mucus plugging is present, to prevent irreversible bronchiectasis.²

Fig. 4. Treatment algorithm for ABPA/ABPM, including corticosteroids, antifungals, and biologics.

ABPA/ABPM, allergic bronchopulmonary aspergillosis/mycosis.

The recommended treatment duration for both corticosteroids and antifungal agents is 4 months, with discontinuation within at most 6 months. Prolonged or repeated courses of corticosteroids or antifungal agents, necessitated by treatment failure or recurrent exacerbations, inevitably lead to cumulative adverse effects. In addition to the well-recognized systemic complications associated with corticosteroids, long-term use of these agents in patients with pre-existing bronchiectasis due to ABPA/ABPM increases the risk of chronic airway infection with Pseudomonas aeruginosa or non-tuberculous mycobacteria.³³ Extended administration of azole antifungals beyond 6 months may also promote the emergence of antifungal resistance.³⁴

Clinical remission is defined as sustained stability of clinical symptoms, radiological findings, and total serum IgE levels for at least 6 months after cessation of corticosteroids.² In contrast, worsening clinical symptoms or radiological abnormalities accompanied by a ≥ 50% increase in total serum IgE, after excluding exacerbations of asthma or bronchiectasis, is considered an exacerbation (relapse) of ABPA/ABPM and warrants re-treatment.²

An analysis of ABPA cases from a nationwide survey in Japan, who received standard therapy after initial diagnosis, revealed that almost half of them (49%) failed to achieve clinical remission with standard treatment within the initial 6 months.³⁵ Multivariable logistic regression analysis identified four factors associated with poor outcomes: age at onset of ABPA ≤ 50 years, serum A. fumigatus-specific IgE levels ≥ 20 kU_A/L, positive culture for Aspergillus spp. in the sputum/bronchial lavage fluid, and the presence of HAM on CT (Table). These variables were incorporated into the difficult-to-treat ABPA score, and patients with scores ≥ 2 (approximately 60% of cases) exhibited significantly higher rates of treatment failure across two independent cohorts.³⁵

Table. Determinants of difficult-to-treat ABPA.

Study (first author and reference)	Tanaka et al.35	Qian et al.36	Ping’an et al.37
Definition of poor prognosis	Treatment failure	ABPA exacerbation	Treatment escalation
Factor(s) associated with poor prognosis
Young age at onset of ABPA	•
Female gender		•
High Aspergillus fumigatus-specific IgE titer	•	•	•
High peripheral blood eosinophil counts			•
Low diffusing capacity of the lungs			•
Positive fungal culture	•
Bronchiectasis		•
High attenuation mucus	•		•

ABPA, allergic bronchopulmonary aspergillosis; IgE, immunoglobulin E.

Similar results are reported in two studies from China; one study reported that female sex, A. fumigatus-specific IgE levels of at least 9.88 kU_A/L, and the presence of bronchiectasis were significant predictors of ABPA relapse within one year after discontinuing combination therapy.³⁶ A second single-center study proposed the HEID score based on A. fumigatus-specific IgE > 3.5 kU_A/L, peripheral eosinophil counts > 1,000/µL, HAM, and a diffusing capacity for carbon monoxide < 60% of predicted as a marker associated with the need for treatment escalation during the first year (Table).³⁷ Findings from a Japanese cohort study align with these observations: among the three identified components (allergic, eosinophilic, and fungal), the allergic component showed the strongest relationship with post-treatment outcomes.²⁶ Taken together, these four studies possibly suggest highlight heightened A. fumigatus-specific sensitization as a key determinant of early clinical trajectories following standard therapy for ABPA.

APPROACHES FOR DIFFICULT-TO-TREAT ACUTE ABPA/ABPM

Combination therapy with corticosteroids and antifungal agents is generally recommended when the initial treatment response is inadequate. However, a randomized controlled trial comparing corticosteroid monotherapy with corticosteroid–antifungal combination therapy in patients with ABPA demonstrated no significant differences in treatment response or recurrence rates within one year.²⁷

Another strategy is to prevent exacerbations through maintenance therapy following initial treatment. A randomized controlled trial of nebulized liposomal L-amphotericin B was conducted in France.³⁸ In this study, patients with acute ABPA (n = 136) received 8 weeks of oral corticosteroids and 4 months of itraconazole, and were subsequently randomized to receive either nebulized L-amphotericin B or placebo for 6 months. Although the time to first severe clinical exacerbation was longer in the maintenance-therapy group, it was mostly attributed to the suppression of asthma exacerbations, and no significant differences were observed in ABPA exacerbation rates at either 6 or 24 months. A meta-analysis of three observational studies and two randomized controlled trials likewise failed to confirm the efficacy of nebulized amphotericin B in reducing the proportion of patients experiencing ABPA exacerbations one year after treatment.³⁹ Collectively, these findings highlight the need for more effective strategies for both induction and maintenance therapy.

Biologic agents targeting type 2 immune responses have been used in patients with severe asthma complicated by ABPA.⁴⁰,⁴¹ Omalizumab, an anti-IgE antibody and the first biologic approved for severe asthma, has been investigated as a potential treatment for ABPA. A meta-analysis of 14 reports including 186 cases of asthma- or cystic fibrosis–associated ABPA treated with omalizumab demonstrated reductions in exacerbations from 1.75–4.25/year to 0.20–1.00/year, with oral corticosteroids reduced in 65% and discontinued in 53% of patients.⁴² However, several caveats must be considered when interpreting these findings and applying omalizumab in difficult-to-treat ABPA. First, most studies did not distinguish between asthma and ABPA exacerbations. Second, improvements in imaging findings, particularly mucus plug resolution, have rarely been documented. Third, many patients with acute ABPA require omalizumab doses that exceed the approved upper dosing limit.

Several retrospective analyses have evaluated the real-world efficacy and safety of biologics targeting interleukin (IL)-5 or its receptor, including mepolizumab and benralizumab.⁴³,⁴⁴,⁴⁵ These studies have reported reductions in Asthma Control Questionnaire scores, exacerbation rates, and maintenance oral corticosteroid doses. Notably, one study demonstrated a high rate of mucus plug resolution, particularly with benralizumab.⁴⁴ Targeting eosinophils with biologics is biologically rational, as mucus plugs composed of eosinophilic extracellular traps provide a scaffold for fungal growth in the bronchi and contribute to irreversible structural damage (Fig. 5A).

Fig. 5. Therapeutic targeting profiles in less-difficult-to-treat and difficult-to-treat ABPA. The diagram maps the principal clinical components of ABPA (allergic, eosinophilic, and fungal) as the therapeutic targets of available biologic agents, maintenance antifungals, and/or environmental interventions. For less-difficult-to-treat ABPA in which eosinophilic component is dominant, mepolizumab or benralizumab may be appropriate, however, for difficult-to-treat ABPA, treatment strategies that target both allergic and eosinophilic components, such as dupilumab or tezepelumab would be preferred. Maintenance antifungals and/or environmental interventions can be considered for both (A) less-difficult-to-treat and (B) difficult-to-treat ABPA.

ABPA, allergic bronchopulmonary aspergillosis.

Nevertheless, several case reports and case series have suggested that dupilumab, an anti-IL-4 receptor α antibody, may offer additional benefit over mepolizumab and benralizumab, particularly through concurrent targeting of the allergic component.⁴⁶,⁴⁷,⁴⁸,⁴⁹ This is not unexpected, given the central role of heightened A. fumigatus–specific sensitization in difficult-to-treat ABPA, in which targeting both eosinophilic and allergic components may be essential (Fig. 5B).⁵⁰ A randomized controlled trial evaluating dupilumab in patients with severe asthma and ABPA (LIBERTY ABPA AIRED study, identifier: NCT04442269) has been conducted, and preliminary analyses are now available on the ClinicalTrials.gov website. According to these results, dupilumab significantly improved pulmonary function and quality of life, and reduced the annualized rate of severe respiratory exacerbations, suggesting potential clinical benefit in patients with asthma complicated by ABPA. However, the trial did not enroll patients with acute ABPA, and no ABPA exacerbations occurred in either treatment group during the study period. Consequently, whether dupilumab can improve the prognosis of acute ABPA remains unknown. Further prospective studies specifically targeting acute-phase ABPA are needed to clarify the therapeutic role of dupilumab in disease control and prevention of exacerbation. Tezepelumab, an anti-thymic stromal lymphopoietin antibody that more broadly suppresses type 2 inflammation, may also be effective in difficult-to-treat ABPA, although evidence remains limited.

ENVIRONMENTAL INTERVENTIONS TO PREVENT EXACERBATIONS

Failure to prevent the recurrent exacerbations of ABPA/ABPM through maintenance therapy using inhaled L-amphotericin B raises the possibility that persistent or repeated exposure to environmental fungi contributes to disease activity.⁵¹,⁵²,⁵³ Supporting this notion, a significantly higher prevalence of ABPA has been reported among individuals with cystic fibrosis living in environments with indoor mold exposure.⁵⁴ Although fungal exposure occurs both indoors and outdoors, the predominance of older patients with ABPA/ABPM in Japan, who typically spend extended periods at home, suggests that optimizing the residential environment may represent an important component of disease management.

It is well established that fungus-related allergic diseases are more common in homes affected by water leakage or dampness.⁵⁵ In addition, global warming and the widespread implementation of high-airtightness housing as part of the transition to a carbon-neutral society have increased reliance on air conditioners, which can serve as reservoirs for fungal growth owing to condensation formed during cooling. Indeed, a moldy odor has been reported for 37.1% of air conditioners in more than 1,000 Japanese residences.⁵⁶ Not only fungal allergens but also viable fungi, including Aspergillus species, are frequently isolated from their internal components.⁵⁷,⁵⁸,⁵⁹ In a randomized controlled trial conducted by the ABPA/ABPM Research Group (identifier: UMIN000048857), an integrated environmental intervention consisting of air-conditioner cleaning and the installation of an air purifier led to a significant reduction in total serum IgE levels among patients with ABPA (unpublished data). Collectively, these findings suggest that, in addition to patient-directed pharmacologic therapy, targeted interventions to improve the residential environment may help prevent exacerbations and mitigate disease progression.

CONCLUSION

The establishment of the ISHAM working group guidelines (2013, revised 2024), grounded in a deeper understanding of disease pathophysiology, the development and validation of updated diagnostic criteria, and randomized clinical trials defining standard therapeutic approaches, has substantially enhanced the early recognition and clinical management of ABPA/ABPM. Despite these advances, the persistently low remission rates and the high incidence rates of exacerbations under current standard therapy underscore the imperative to further refine treatment strategies in a severity-stratified manner. In particular, the systematic integration of biologic agents and maintenance therapy with pharmacological and environmental approaches into evidence-based therapeutic algorithms will be essential for improving long-term disease control and patient outcomes.