Allergic bronchopulmonary aspergillosis and Aspergillus-related airway diseases in bronchiectasis: a narrative review

Introduction

Aspergillus species are ubiquitous environmental fungi that can cause a diverse spectrum of pulmonary disorders, largely determined by the host’s immune response. These disorders are broadly classified as invasive (e.g., acute and subacute invasive pulmonary aspergillosis or airway-invasive disease), noninvasive (such as chronic cavitary pulmonary aspergillosis, aspergilloma, and Aspergillus bronchitis), and hypersensitivity-related, most notably allergic bronchopulmonary aspergillosis (ABPA). Among these, ABPA is a complex and underrecognized entity caused by an exaggerated immune response to colonization with Aspergillus species, most frequently A. fumigatus. Traditionally, ABPA was thought to occur primarily in individuals with asthma or cystic fibrosis (CF); however, this paradigm is evolving (1).

Bronchiectasis, characterized by the irreversible dilatation of the subsegmental bronchi, is marked by impaired mucociliary clearance, chronic microbial colonization, persistent airway inflammation, and progressive airway destruction (2). Although ABPA has long been recognized in patients with bronchiectasis, it has been underreported in diagnostic frameworks, mainly due to the historical neglect of bronchiectasis as an important clinical entity. Notably, ABPA may develop in individuals with bronchiectasis, even in the absence of asthma or CF (3). Patients may present with unexplained exacerbations, hemoptysis, fleeting pulmonary infiltrates, or expectoration of thick mucus plugs, features that may be mistakenly attributed to the underlying bronchiectasis itself.

Crucially, ABPA exhibits a bidirectional pathogenic relationship with bronchiectasis; it can be both a cause and a consequence. Chronic eosinophilic inflammation and mucus plugging in ABPA can lead to the development of bronchiectasis. In contrast, in patients with pre-existing bronchiectasis of unrelated etiologies, Aspergillus colonization may trigger the hypersensitivity cascade that causes ABPA (4). This overlapping and often indistinct pathophysiology poses significant diagnostic and therapeutic challenges, particularly in patients lacking traditional risk factors such as asthma or CF.

Despite these complexities, ABPA remains a highly treatable form of bronchiectasis exacerbation and progression. Early recognition and appropriate treatment can markedly improve outcomes and potentially halt disease progression (5). In this review, we describe the epidemiology, immunopathogenesis, radiological features, diagnostic criteria, and treatment strategies for ABPA in the context of bronchiectasis. We also address the broader spectrum of Aspergillus-related airway diseases, including Aspergillus sensitization (AS) and chronic Aspergillus infection (CAI), which represent a continuum of disease with distinct clinical implications. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1548/rc).

Methods

We searched PubMed from inception to June 6, 2025. Keywords included ABPA OR allergic bronchopulmonary aspergillosis OR bronchiectasis. Our study is a narrative review and does not assess the quality or the risk of bias of the included literature. Inclusion criteria focused on studies involving ABPA and bronchiectasis, published in peer-reviewed journals and available in English. The search strategy is detailed in Table 1.

Spectrum of aspergillus-associated disease in bronchiectasis

Aspergillus-related airway disease in bronchiectasis spans a broad immunological and microbiological spectrum, ranging from asymptomatic colonization to overt ABPA (6). This spectrum reflects the complex interplay between Aspergillus species, structural lung abnormalities, and host immune predisposition (4). Based on serological and microbiological profiles, four principal phenotypes can be proposed:

• AS: defined by elevated A. fumigatus-specific immunoglobulin E (IgE) (typically ≥0.35 kUA/L) without fulfilling the diagnostic criteria for ABPA. AS is often regarded as an early stage or prerequisite in the evolution toward ABPA.
• Aspergillus bronchitis: diagnosed when Aspergillus species are cultured from respiratory samples on at least two occasions, 3–6 months apart, without fulfilling criteria for ABPA or chronic pulmonary aspergillosis (CPA) (7). Affected individuals may present with chronic cough and sputum production but typically lack the immunological [eosinophilia, elevated A. fumigatus-IgE/immunoglobulin G (IgG)] and radiological features of ABPA.
• CAI: characterized by elevated A. fumigatus-specific IgG levels, suggesting chronic antigenic exposure, likely due to persistent fungal colonization in structurally abnormal airways (3,8). CAI is particularly common in patients with post-tuberculosis bronchiectasis and cavitary disease. Unlike CPA, CAI does not require the clinical features or radiological evidence of fungal lesions (e.g., aspergilloma or cavitation) and represents a distinct entity defined primarily by serological criteria.
• ABPA: the classic hypersensitivity disorder defined by a constellation of immunological features, including elevated A. fumigatus-specific IgE and IgG, increased total IgE, and peripheral blood eosinophilia. The 2024 International Society for Human and Animal Mycology (ISHAM) ABPA Working Group (AWG) criteria now include bronchiectasis, independent of asthma or CF, as a predisposing condition for ABPA, reflecting a broader appreciation of its clinical spectrum (9). Allergic bronchopulmonary mycosis (ABPM) represents an ABPA-like syndrome that is driven by non-Aspergillus fungi (e.g., Bipolaris, Alternaria, Schizophyllum, and others).

Importantly, these phenotypes represent a continuum of fungal interactions with the diseased lung, rather than being mutually exclusive. Many patients may exhibit overlapping features, such as AS with concurrent IgG positivity or positive fungal cultures, supporting the concept of a fungal endotype of bronchiectasis. This spectrum highlights the need for comprehensive diagnostic approaches to accurately classify and manage Aspergillus-associated airway disease in bronchiectasis, as it likely represents treatable traits in bronchiectasis with distinct therapeutic implications.

Prevalence of Aspergillus-associated disease in bronchiectasis

Aspergillus-related airway disease, including AS, CAI, and ABPA, is increasingly recognized as a clinically relevant endotype in patients with bronchiectasis. However, the true burden remains poorly defined due to limited and inconsistent screening practices across cohorts and healthcare settings.

AS and CAI

One of the most robust datasets on Aspergillus-associated disease prevalence comes from the European EMBARC registry, which analyzed 9,953 patients with bronchiectasis from 28 countries (3). In this cohort, AS and CAI were identified in 5.7% and 8.1% of patients, respectively. In contrast, a single-center prospective study from India involving 258 well-characterized bronchiectasis patients (excluding those with ABPA) reported markedly higher rates, 29.5% for AS and 76% for CAI (8). These substantial differences likely reflect geographic variation in Aspergillus exposure (higher in tropical countries), differences in underlying bronchiectasis etiologies (post-tuberculosis bronchiectasis being more prevalent in developing countries versus idiopathic and other etiologies elsewhere), and variability in screening intensity (systematic versus symptom-triggered protocols).

ABPA

In asthma and CF, where systematic screening has been more consistently implemented, ABPA prevalence is well established at approximately 11% and 9%, respectively, based on meta-analyses (10,11). In contrast, the prevalence of ABPA in bronchiectasis remains inadequately characterized, largely due to underrecognition and inconsistent diagnostic practices.

To better quantify ABPA prevalence in bronchiectasis, we systematically reviewed multicenter studies reporting ABPA prevalence in unselected bronchiectasis populations. Across ten studies encompassing 67,669 individuals, reported prevalence ranged from 0.0% to 8.9% (Figure 1). We conducted a Bayesian proportional meta-analysis using the bayesmeta package in R, applying a normal prior centered at 5% (on the logit scale) with a weak prior (standard deviation of 2) to reflect moderate uncertainty. The pooled ABPA prevalence was 0.90% [posterior mean; 95% credible interval (CrI): 0.2–3.6%] (12-21). Notably, the 95% prediction interval, representing the range of prevalence rates expected in a future similar study, ranged from 0.01–62%. This substantial uncertainty reflects considerable heterogeneity across studies, primarily driven by the absence of systematic screening protocols in most cohorts (Table 2).

Figure 1 Forest plot depicting the prevalence of ABPA across ten multicenter studies encompassing 67,669 patients with bronchiectasis. The point estimate of each study is represented by a circle, with horizontal lines indicating the 95% credible intervals. Circle sizes are proportional to study weight in the meta-analysis. The pooled prevalence estimate, derived from Bayesian proportional meta-analysis, is 0.9% (95% credible interval: 0.2–3.6%), represented by the diamond. Substantial heterogeneity is evident (95% prediction interval: 0.01–62%), reflecting differences in geographic regions, underlying bronchiectasis etiologies, and absence of systematic screening protocols across cohorts (n, number of ABPA cases; N, total number of patients screened). ABPA, allergic bronchopulmonary aspergillosis; CI, credible interval.

Further supporting this, a recent analysis from the EMBARC registry reported that merely 53% of patients underwent any form of Aspergillus-specific serological testing, with country-level screening rates ranging from 7% to 96% (3). Indian registry data showed that only 17.7% of patients had been tested for ABPA at any point during their clinical course (14). One of the few studies that employed systematic screening was a retrospective analysis by Bonaiti et al., which identified ABPA in 4.9% (15/304) of screened bronchiectasis patients (22). However, even in this study, 21% (81/385) of the overall cohort could not be evaluated for ABPA, illustrating the logistical barriers to comprehensive evaluation in routine clinical practice.

Current international bronchiectasis guidelines recommend screening for ABPA at diagnosis and during episodes of unexplained clinical deterioration (23). However, studies that rely predominantly on symptom-driven or selective testing likely underestimate the true prevalence and may introduce ascertainment bias. Collectively, these data suggest that ABPA is substantially underrecognized in bronchiectasis populations, with the true prevalence likely exceeding reported estimates, particularly in settings without protocolized screening strategies.

Clinical significance of Aspergillus-related disease in bronchiectasis

Aspergillus-associated airway conditions, including AS, CAI, and ABPA, are increasingly recognized as clinically relevant and prognostically important entities in bronchiectasis patients (24,25). ABPA is well-established as a cause of recurrent exacerbations, progressive airway damage, and bronchiectasis (26-28). Early diagnosis and prompt initiation of therapy can significantly attenuate these risks and may prevent progression to end-stage lung disease.

Emerging evidence challenges the traditional view that AS represents a benign finding without clinical consequence. In a large analysis from the EMBARC registry, Pollock et al. showed that individuals with AS had significantly higher Bronchiectasis Severity Index (BSI) scores, worse health-related quality of life, and more frequent annual exacerbations compared with non-sensitized counterparts (3). These findings are consistent with observations from asthma cohorts, where fungal sensitization, even in the absence of overt allergic disease, is associated with poorer outcomes (29-32). A large UK bronchiectasis cohort reported that patients sensitized to fungal allergens, particularly Aspergillus, experience worse symptom burden, more frequent exacerbations, and more radiological involvement than those with non-fungal sensitization or no sensitization (25). Importantly, these effects were independent of ABPA diagnosis, suggesting that fungal sensitization itself represents a distinct, modifiable, and treatable phenotype. These data support broader implementation of screening for AS and consideration of interventions targeting type 2 inflammation, even in patients who do not meet full ABPA criteria.

Perhaps most striking are the clinical outcomes associated with CAI. In the EMBARC analysis, patients with CAI but without ABPA exhibited the highest risk of severe exacerbations, paradoxically exceeding even those with ABPA itself (3). This counterintuitive finding likely reflects differences in disease recognition and treatment rather than inherent disease severity. Unlike ABPA, which is typically treated with systemic corticosteroids or antifungal therapy once diagnosed, CAI often remains unrecognized or untreated in routine clinical practice. Consequently, patients with CAI experience ongoing, unmodulated antigenic exposure and persistent low-grade airway inflammation without therapeutic intervention. In contrast, patients with diagnosed ABPA receive treatment that suppresses the hypersensitivity response and reduces fungal burden, potentially explaining the lower observed exacerbation rates despite ABPA being traditionally considered the more severe condition. This observation underscores CAI as an underrecognized and undertreated contributor to disease progression in bronchiectasis.

Geographic and etiological factors appear to influence the prevalence and impact of CAI. In a study from India, post-tuberculosis bronchiectasis emerged as the strongest independent predictor of AS and CAI (8), likely due to post-tuberculous airway remodeling and cavitary lung damage that provides a permissive niche for Aspergillus colonization. A related study in patients with post-tuberculosis chronic obstructive lung disease from Singapore found this phenotype associated with systemic inflammation and increased mortality, further highlighting its high-risk profile (33). Collectively, these data suggest that individuals with post-tuberculosis structural lung disease may be particularly susceptible to Aspergillus-related endotypes and should be prioritized for targeted surveillance and early intervention.

The clinical implications of Aspergillus bronchitis are less well-established. Although these patients typically report chronic cough and sputum production (34), it remains uncertain whether Aspergillus contributes to disease pathogenesis or merely reflects colonization in a structurally damaged airway. Longitudinal studies are needed to determine whether Aspergillus bronchitis predisposes to progression towards AS or ABPA, contributes to accelerated lung function decline or increased symptom burden, and whether antifungal therapy alters its natural course. Supporting its potential relevance, a recent study found that elevated chitotriosidase levels, a host chitinase secreted by epithelial or immune cells in response to fungal elements, are elevated in bronchiectasis patients colonized by Aspergillus, and this biomarker was associated with frequent exacerbations (35).

The bronchiectasis microbiome: bacterial-fungal interplay

The airway microbiome in bronchiectasis is complex and polymicrobial, with both bacterial and fungal components contributing critically to disease pathogenesis, progression, and clinical outcomes. The bacterial microbiome has been extensively characterized and remains central to understanding the pathophysiology of bronchiectasis (36).

The bacterial microbiome and clinical impact

Bacterial pathogens represent the dominant and most well-studied component of the bronchiectasis microbiome. Culture-based and next-generation sequencing studies consistently identify Pseudomonas aeruginosa, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Streptococcus pneumoniae, and Enterobacteriaceae as key organisms (14,18,37). These bacterial pathogens are established drivers of chronic inflammation, frequent exacerbations, accelerated lung function decline, and increased mortality risk, particularly P. aeruginosa and nontuberculous mycobacteria (NTM) (38,39). P. aeruginosa chronic infection affects 11–40% of bronchiectasis patients globally and independently predicts worse clinical outcomes, including higher exacerbation rates, more rapid lung function decline, increased disease severity scores, and elevated mortality (37). Similarly, NTM infection, particularly Mycobacterium avium complex and M. abscessus, represents an increasingly recognized sub-phenotype of bronchiectasis characterized by cavitary disease, distinct microbiome features including enrichment with oral commensals, and Th17-driven neutrophilic immune responses (40). Importantly, chronic bacterial colonisation drives aberrant neutrophilic inflammation marked by excessive neutrophil elastase activity, neutrophil extracellular trap (NET) formation, and elevated pro-inflammatory cytokines including IL-1β, IL-8, TNF-α, and leukotriene B4, all of which perpetuate the vicious cycle of infection, inflammation, and progressive airway damage (41,42). Microbiome studies reveal that patients with severe disease demonstrate dysbiotic profiles, which are often dominated by Pseudomonas, Haemophilus, or Streptococcus, with reduced alpha diversity strongly correlating with disease severity, exacerbation frequency, and poorer clinical outcomes (38,43).

The mycobiome and inter-kingdom interactions

Beyond this well-defined bacterial landscape, recent insights from next-generation sequencing and mycobiome profiling have revealed that Aspergillus and Candida species frequently dominate the airway fungal communities in bronchiectasis patients (24). These fungal community shifts, or mycobiome dysbiosis, are associated with increased airway inflammation, enhanced type 2 immune responses, and worse clinical outcomes independent of bacterial profiles (24,44).

Importantly, emerging evidence suggests complex inter-kingdom interactions between bacterial and fungal communities that influence disease phenotype and progression. Studies employing integrative multi-kingdom microbiome analysis demonstrate that microbial interaction networks, which capture crosstalk among bacteria, fungi, and viruses, more accurately predict exacerbation risk than single-kingdom compositional analyses (45). For instance, bacterial dominance by Pseudomonas may influence fungal colonization patterns and vice versa. The association between NTM infection and increased risk of A. fumigatus colonisation exemplifies clinically relevant inter-kingdom interactions (37).

Furthermore, analysis of the gut-lung microbiome axis reveals that dysregulated bacterial-fungal interactions across anatomical compartments are associated with distinct bronchiectasis phenotypes and clinical outcomes, with Pseudomonas dominance in the lung coupled with specific gut microbiome signatures predicting a worse prognosis (46).

Clinical implications and future directions

The recognition that both bacterial and fungal microbiome components contribute independently and interactively to disease progression underscores the need for comprehensive microbiological assessment in bronchiectasis management. While bacterial pathogens remain the primary focus of routine surveillance and antimicrobial therapy, airway fungal communities, particularly Aspergillus, represent an underappreciated yet potentially modifiable contributor to inflammation, type 2 immune activation, and clinical deterioration (25). Therapeutic strategies must therefore consider the entire microbial ecosystem rather than targeting pathogens in isolation. Future precision medicine approaches integrating multi-omics profiling with clinical, inflammatory, and immunological data hold promise for identifying treatable traits, predicting treatment response, and developing targeted interventions that address both bacterial and fungal dysbiosis while preserving beneficial commensal organisms (37,47).

Pathogenesis

The pathogenesis of ABPA is driven by two fundamental events: persistent airway colonization by A. fumigatus and a dysregulated type 2 immune response in individuals who are genetically predisposed (48). The temporal relationship between ABPA and bronchiectasis, however, differs depending on the underlying clinical context, resulting in two distinct pathogenic sequences.

Classical pathway, ABPA leading to bronchiectasis

In the classical setting of asthma or CF, ABPA arises as a primary immunologic disorder that subsequently causes bronchiectasis. Chronic exposure to A. fumigatus triggers eosinophilic inflammation, mucus plugging, and immune-mediated injury, ultimately leading to progressive bronchial wall destruction and bronchiectasis (49,50). In this pathway, the immunologic response precedes and directly causes the structural airway damage.

Reverse pathway, bronchiectasis predisposing to ABPA

In contrast, ABPA in patients with pre-existing bronchiectasis follows a reversed pathophysiological sequence. Here, bronchiectasis precedes and predisposes to ABPA development. The underlying bronchiectasis may stem from diverse etiologies, including post-infectious damage, primary ciliary dyskinesia, immunodeficiency, or idiopathic causes (51,52). The structurally abnormal airways, impaired mucociliary clearance, and chronic inflammatory milieu create a permissive environment for persistent A. fumigatus colonization. Over time, sustained antigenic exposure may trigger hypersensitivity responses in susceptible individuals, resulting in a syndrome clinically and serologically resembling classical ABPA.

Evidence supporting this reversed pathogenic sequence comes from studies of other chronic airway diseases. For instance, individuals with chronic obstructive pulmonary disease (COPD)-associated bronchiectasis demonstrate a higher prevalence and greater clinical severity of ABPA compared to those with COPD without bronchiectasis, suggesting that structurally damaged airways amplify the risk of persistent fungal colonization and subsequent development of allergic inflammation (44). Similarly, the strong association between post-tuberculosis bronchiectasis and both AS and CAI supports the concept that cavitary and bronchiectatic airways provide an anatomical substrate for fungal persistence and immune activation (8).

A key unresolved question, however, is whether ABPA arising in the context of pre-existing bronchiectasis represents true ABPA or constitutes an ABPA-like syndrome, a phenocopy that shares immunological and clinical features with classical ABPA but with distinct pathobiological underpinnings. Furthermore, it remains unclear whether ABPA actively drives bronchiectasis progression in these individuals or merely reflects an epiphenomenon in already damaged airways that does not substantially alter the disease trajectory.

Despite these uncertainties, both pathogenic pathways, whether classical or reversed, appear to converge on a common triad of fungal colonization, Th2-skewed immune activation, and chronic airway injury. This convergence suggests that, regardless of the initiating sequence, the downstream inflammatory cascade is similar; thus, therapeutic strategies targeting fungal burden and type 2 inflammation may be beneficial. This conceptual framework underscores the importance of early detection through systematic screening and timely institution of immunomodulatory and antifungal therapy to interrupt the cycle of inflammation, structural damage, and recurrent exacerbations that characterize ABPA in bronchiectasis.

Diagnosis

Diagnosing ABPA in the context of bronchiectasis presents unique challenges. Clinical and radiological features often overlap with other causes of bronchiectasis, and distinguishing simple fungal colonization from active hypersensitivity disease is not straightforward. However, a structured diagnostic approach incorporating immunologic markers, radiological features, and the updated 2024 ISHAM-AWG criteria provides a reliable framework for identifying ABPA in this population.

Key immunological investigations

A. fumigatus-specific IgE

Measurement of A. fumigatus-IgE is the cornerstone of ABPA diagnosis. At a threshold of ≥0.35 kUA/L, this assay exhibits near-perfect sensitivity (98–100%), making it an ideal screening tool (53-55). However, its specificity remains modest (approximately 70%) (32). A recent study identified an optimized A. fumigatus-IgE threshold (0.7 kUA/L) that improved specificity without sacrificing sensitivity (55). Thus, A. fumigatus-specific IgE should be interpreted in conjunction with other immunological and radiological findings (56).

Also, A. fumigatus-IgE alone reliably detects nearly all ABPA cases, even those triggered by other Aspergillus species (57). Neither multi-species IgE panel (e.g., mx4) nor additional species-specific IgE (e.g., A. flavus, A. niger, A. terreus) provides incremental diagnostic yield. This finding reinforces A. fumigatus-IgE as the preferred and sufficient serologic assay for ABPA screening, simplifying diagnostic algorithms and reducing unnecessary testing costs.

Serum total IgE

Serum total IgE is another important biomarker for ABPA, playing a dual role in both diagnosis and disease monitoring. While earlier criteria employed a threshold of ≥1,000 IU/mL (58), the 2024 ISHAM-AWG criteria adopt a lower cut-off of ≥500 IU/mL (9), thereby increasing sensitivity without significantly compromising specificity. Additionally, serial total IgE measurements are valuable for monitoring treatment response and detecting disease exacerbations, with increases of ≥50% from previous values typically indicating disease activity.

A. fumigatus-specific IgG

The presence of elevated A. fumigatus-IgG reflects chronic antigenic exposure and contributes to the diagnosis of ABPA, particularly in distinguishing it from simple AS, where IgG levels are typically lower or absent (59). A. fumigatus-specific IgG testing by enzyme immunoassays (EIA) has largely replaced older methods like serum precipitins due to its superior sensitivity, reproducibility, and standardization. Traditional double-diffusion methods detect precipitins in only 27% of ABPA patients, whereas EIA for IgG demonstrates sensitivity approaching 89% (59). A systematic review concluded that one additional case of ABPA is identified for every six patients tested using EIA rather than immunoprecipitation (60). Lateral flow assays for A. fumigatus-IgG now offer a practical alternative with reasonable performance (sensitivity 85%, specificity 83%), making them particularly valuable in low-resource or point-of-care settings (61).

Peripheral blood eosinophil count (BEC)

A BEC ≥500 cells/µL serves as a supportive diagnostic marker in the diagnosis of ABPA, reflecting underlying type 2-driven inflammation (62). However, its diagnostic sensitivity is substantially reduced in patients receiving glucocorticoids. In such cases, historical eosinophil counts may be utilized. While nonspecific for ABPA, peripheral blood eosinophilia enhances diagnostic confidence when considered in conjunction with other immunological and radiological features. Moreover, higher baseline eosinophil counts may correlate with greater disease burden, increased mucus plugging, and higher relapse risk (63), suggesting potential prognostic value beyond diagnosis.

Radiological evaluation

Thin-section chest computed tomography (CT) is indispensable in diagnosing ABPA, providing critical anatomical confirmation of immune-mediated airway injury. The hallmark radiological finding of classical ABPA is bronchiectasis, typically central, with a predilection for the upper lobes (Figure 2). When present in the appropriate clinical and immunologic context, this distribution is considered highly suggestive of ABPA. A pathognomonic radiological sign is high-attenuation mucus (HAM), defined as mucoid impaction that exhibits greater radiodensity than adjacent paraspinal skeletal muscle (>70 Hounsfield units) on unenhanced CT imaging (64). Even in isolation, HAM is often sufficient to establish the diagnosis, even when other criteria are incompletely met (Figure 2) (65). The sensitivity of HAM for ABPA is limited (approximately 10–25%), but its specificity approaches 100%. Other characteristic features include mucus plugging, finger-in-glove opacities, lobar collapse, and fleeting pulmonary infiltrates, each reflecting airway inflammation and obstruction at various anatomical sites.

Figure 2 Thin-section chest computed tomography scan images from a patient with classical ABPA. Axial CT image (A) with mediastinal windowing demonstrates HAM within dilated central bronchi (white arrowhead), appearing denser than adjacent paraspinal muscle, a pathognomonic radiological finding for ABPA. Axial CT image with lung window (B) showing central bronchiectasis predominantly affecting the upper and middle lobes, with characteristic proximal bronchial dilatation and sparing of peripheral airways, the typical distribution pattern of classical ABPA. ABPA, allergic bronchopulmonary aspergillosis; CT, computed tomography; HAM, high-attenuation mucus.

In patients with pre-existing bronchiectasis from other etiologies, the radiological presentation of superimposed ABPA may differ substantially from classical patterns. Bronchiectasis in these cases predominantly involves the middle or lower lobes, or a more diffuse distribution, reflecting the underlying primary bronchiectasis etiology, and suggesting that ABPA has developed as a complication of underlying bronchiectasis rather than a primary cause (Figure 3). In this context, the development of ABPA may be heralded by new or worsening mucus plugging in previously involved or adjacent airways, the development of HAM in a patient with pre-existing bronchiectasis, the appearance of new fleeting infiltrates or areas of consolidation, or progressive bronchiectasis despite appropriate management of the underlying condition.

Figure 3 Thin-section chest computed tomography images of a patient with allergic bronchopulmonary aspergillosis complicating non-cystic fibrosis bronchiectasis. Bronchiectasis predominantly involves the middle and lower lobes, with sparing of the upper lobes. The patient exhibited elevated Aspergillus fumigatus-specific IgE and IgG, raised serum total IgE, and peripheral eosinophilia. Genetic testing revealed a homozygous NEK10 mutation, consistent with primary ciliary dyskinesia. IgE, immunoglobulin E; IgG, immunoglobulin G.

Recognizing these distinctions is crucial for accurate phenotyping, as they differentiate classical ABPA from ABPA complicating pre-existing bronchiectasis. Importantly, the absence of typical central or upper lobe predominance should not exclude ABPA in patients with established bronchiectasis, as the distribution reflects the underlying structural disease rather than ABPA itself.

Diagnostic criteria (2024 ISHAM-AWG)

The 2024 ISHAM-AWG criteria broaden the spectrum of recognized predisposing conditions beyond the traditional asthma and CF paradigm to explicitly include bronchiectasis and COPD (Table 3) (9). Moreover, in individuals without a clearly defined predisposing condition, ABPA may be suspected based on a compatible clinical and radiological profile, such as expectoration of mucus plugs, fleeting pulmonary opacities, finger-in-glove opacities, and lobar collapse on imaging (66). In these subgroups, a diagnosis of ABPA requires fulfilment of the following two essential immunological criteria, namely A. fumigatus-IgE ≥0.35 kUA/L and serum total IgE ≥500 IU/mL. Since these markers may also be elevated in patients with AS without overt ABPA, they are insufficient on their own to establish a definitive diagnosis. The essential criteria effectively identify patients with Aspergillus-driven type 2 inflammation but require additional supporting evidence to confirm that this represents true ABPA rather than simple sensitization. To establish a definitive diagnosis, at least two of the following three ancillary criteria must also be met, including peripheral BEC ≥500 cells/µL (either current or historical), elevated A. fumigatus-IgG (quantified by EIA or lateral flow assay), and radiological features consistent with ABPA (such as bronchiectasis, mucus plugging, HAM, or fleeting opacities).

This tiered diagnostic framework enhances diagnostic accuracy by striking a balance between sensitivity and specificity. The stepwise approach, which first establishes Aspergillus-associated type 2 inflammation through essential criteria and then confirms ABPA through ancillary features, reduces both false-positive diagnoses (by requiring additional supportive evidence beyond sensitization) and false-negative diagnoses (by allowing flexibility in meeting ancillary criteria).

Treatment of ABPA

The management of ABPA targets two central pathophysiological mechanisms: the exaggerated type 2 immune response and persistent airway colonization by A. fumigatus. The primary therapeutic goals are to suppress airway inflammation, prevent acute exacerbations, halt or slow the progression of bronchiectasis, and improve quality of life. Treatment modalities are broadly categorized as anti-inflammatory or antifungal, with the choice and sequence of therapies determined by disease severity, frequency of exacerbations, and patient-specific factors such as comorbidities and medication tolerance.

Systemic glucocorticoids

Systemic glucocorticoids remain the most widely used agents for treating ABPA. Oral prednisolone is typically initiated at a dose of 0.5 mg/kg/day for 4 weeks, followed by sequential tapering to 0.25 and 0.125 mg/kg/day, each maintained for 4 weeks. The dose is decreased by 5 mg weekly to complete the therapy in approximately 16 weeks (67-70). This regimen balances the anti-inflammatory activity required for disease control while minimizing glucocorticoid-associated adverse effects such as hyperglycemia, osteoporosis, weight gain, and susceptibility to infections. Patients should be closely monitored during therapy for glucocorticoid-related complications. Prophylactic measures, such as calcium and vitamin D supplementation, bone density monitoring, and gastric protection, should be considered for prolonged courses.

Antifungal triazoles

Antifungal triazoles reduce the Aspergillus burden in the airways, thereby limiting ongoing antigenic stimulation and dampening the downstream type 2 immune cascade. These agents are effective both as monotherapy and as adjuncts to systemic glucocorticoids. Further, they can be used both during acute exacerbations and for maintenance therapy. Itraconazole is the most widely used agent, typically administered at 200 mg twice daily (conventional capsule formulation) or 65 mg twice daily when using the supra-bioavailable super bioavailable (SUBA)-itraconazole formulation for at least 4 months (69).

Therapeutic drug monitoring is crucial to ensure adequate serum levels (target range, 0.5–2 µg/mL) and minimize potential toxicity. Routine liver function monitoring is also recommended during treatment. Additionally, itraconazole has significant drug-drug interactions, particularly with medications metabolized via cytochrome P450 3A4 (like methylprednisolone and azithromycin), necessitating careful medication review. In patients with itraconazole intolerance, significant drug-drug interactions, inadequate serum levels despite appropriate dosing, or treatment failure, second-line triazoles such as voriconazole, posaconazole, or isavuconazole may be considered (71).

Combination therapy

Routine upfront combination therapy with glucocorticoids and antifungal triazoles is not recommended in newly diagnosed ABPA but may be warranted in select patients with more aggressive disease phenotypes. Specifically, combination treatment is reserved for individuals who have experienced two or more ABPA exacerbations within the previous 1–2 years, have extensive bronchiectasis (involving ≥10 segments), or marked eosinophilia (≥1,000 cells/µL) (70). While concomitant therapy may improve clinical outcomes, the added risk of cumulative toxicity and drug interactions necessitates careful monitoring.

Inhaled antifungal therapy

Inhaled antifungal therapy offers the theoretical benefit of delivering high local drug concentrations directly to the airways while minimizing systemic exposure and associated side effects (72). Nebulized amphotericin B (NAB) is the most studied agent in this context.

In a pilot randomized trial, NAB significantly reduced the frequency of ABPA exacerbations over one year compared to nebulized budesonide (73). However, in the NEBULAMB trial, a larger, multicenter, double-blind, placebo-controlled study, liposomal NAB did not significantly reduce cumulative exacerbation rates over two years compared with placebo (74). Nevertheless, the time to first exacerbation was significantly prolonged in the NAB arm, suggesting a role in extending periods of clinical stability and delaying disease progression (74). Based on current evidence, NAB may be considered as an adjunctive or steroid-sparing therapy, particularly in patients intolerant to systemic glucocorticoids or antifungals, or those who experience frequent relapses despite conventional treatment, or individuals seeking to minimize systemic medication burden (75). The typical regimen involves nebulized liposomal amphotericin B 25–50 mg 2–3 times weekly. Further studies are warranted to establish its optimal dosing, duration of use, and patient selection criteria.

Beyond amphotericin B, novel inhaled triazole formulations represent a particularly promising advancement in ABPA therapeutics. In a phase 1 trial, inhaled itraconazole (PUR1900) achieved 70-fold higher sputum concentrations compared to oral formulations while maintaining lower systemic exposure (76). A recent phase 2 clinical trial of PUR1900 in ABPA patients reported significant clinical benefits, including improved asthma control, increased forced expiratory volume in the first second (FEV₁), and reduced total IgE levels (77). Additionally, inhaled voriconazole and opelconazole formulations have demonstrated favorable safety and tolerability profiles in early-phase studies (78,79). If ongoing phase 3 trials confirm the efficacy and safety signals observed in phase 2 studies, inhaled triazoles could fundamentally transform the management of ABPA.

Biological therapies

Biologic agents targeting type 2 inflammatory pathways have emerged as promising treatment options for patients with ABPA (80), particularly those with steroid dependence, coexisting severe asthma, or recurrent exacerbations despite optimal conventional therapy. Currently available biologics with potential utility in ABPA include omalizumab (anti-IgE), mepolizumab (anti-IL-5), benralizumab (anti-IL-5R), dupilumab (anti-IL-4Rα), and tezepelumab (anti-thymic stromal lymphopoietin).

The choice of a biological agent is generally guided by the clinical phenotype, biomarker profile (e.g., IgE levels, eosinophil counts), and the overlapping asthma. Omalizumab has the most extensive experience in ABPA, particularly in the context of coexisting allergic asthma (81). Anti-IL-5/IL-5R agents may be more suitable in eosinophil-predominant disease or steroid-refractory ABPA. Despite their growing use in clinical practice, high-quality evidence for the efficacy of biologics in ABPA is limited to observational studies and case series (82). To date, only a single randomized controlled trial (RCT) has evaluated a biologic (omalizumab) specifically for ABPA (83). Nevertheless, accumulating real-world clinical experience suggests that biologics can reduce exacerbation frequency, improve asthma control, and lower glucocorticoid requirements in selected patients with refractory disease (84). Notably, the LIBERTY-ABPA-AIRED study, reported in abstract form, demonstrated clinical improvement with dupilumab in patients with ABPA, underscoring its potential role in enhancing disease management (85). Future head-to-head trials and phenotype-stratified studies are needed to delineate the optimal use of biologics in ABPA across different patient populations.

Special considerations in bronchiectasis: balancing efficacy and infection risk

The use of systemic glucocorticoids in ABPA complicating bronchiectasis raises important safety concerns that require careful consideration and, in many cases, alternative treatment approaches. Unlike classical ABPA in asthma, where the primary underlying pathology is reversible airway inflammation, patients with pre-existing bronchiectasis have structurally damaged airways with impaired mucociliary clearance and established or potential bacterial colonization, which substantially increases the risk of infection during corticosteroid therapy. Systemic glucocorticoids also increase the risk of NTM infection (40,86), which is associated with significantly worse clinical outcomes, including increased mortality. Furthermore, glucocorticoids disrupt the bacterial microbiome and may facilitate the acquisition or overgrowth of potentially pathogenic bacteria, including P. aeruginosa, which independently predicts worse long-term outcomes (18,38,39). Finally, immunosuppression from glucocorticoids may compromise neutrophil function in bronchiectasis, potentially increasing the frequency of exacerbations and bacterial burden despite treating ABPA-related inflammation. Given these substantial concerns, we propose a risk-stratified approach to ABPA treatment in bronchiectasis.

Established NTM or chronic P. aeruginosa colonization

In patients with documented NTM infection or chronic P. aeruginosa colonization, systemic glucocorticoids should be avoided entirely or used only as a last resort with extreme caution. Alternative therapeutic approaches should be prioritized, including oral itraconazole monotherapy as a first-line treatment and NAB (either as monotherapy or in combination with oral itraconazole) or targeted biological agents as second-line therapies. Oral itraconazole plus biologic therapy may be combined for cases requiring intensive treatment. If glucocorticoids are necessary, we suggest using the minimum effective dose (≤0.25 mg/kg/day) for the shortest possible duration (≤2 weeks), in combination with microbiological surveillance and antimicrobial coverage if indicated.

Extensive bronchiectasis without established colonization

In patients with extensive bronchiectasis (≥3 lobes involved, BSI >9) but without documented NTM or chronic P. aeruginosa colonization, oral itraconazole is again preferred. Low-intensity, short-duration glucocorticoid regimens may also be used. One suggested regimen is 0.25 mg/kg/day for 2–4 weeks, followed by rapid reduction over 8–12 weeks total (rather than 16–20 weeks). Microbiological surveillance with frequent sputum cultures, including NTM cultures, are suggested. For patients requiring prolonged therapy or experiencing relapses during tapering, early transition to oral triazoles or biologic agents is suggested, rather than continuing or escalating glucocorticoids.

Mild bronchiectasis without bacterial colonization

In patients with limited bronchiectasis (<3 lobes, BSI ≤9) and no bacterial colonization, standard glucocorticoid regimens may be used. However, it may be prudent to consider a shortened duration (12–16 weeks total, rather than 16–20 weeks, if an excellent clinical response is achieved). Oral itraconazole must be considered if any bacterial colonization is detected or if tapering proves difficult.

Notably, these recommendations represent expert opinion based on the known risks of glucocorticoid therapy in structurally damaged lungs and the established adverse outcomes associated with NTM and P. aeruginosa in bronchiectasis. However, there is a complete absence of RCT data specifically addressing these questions. Urgent research priorities in bronchiectasis-associated ABPA include prospective studies comparing standard-duration versus abbreviated glucocorticoid regimens, antifungal monotherapy versus glucocorticoid-based therapy, and efficacy of anti-IL-5, anti-IL-4Rα, and anti-IgE agents as first-line steroid-sparing therapy.

Monitoring treatment response and detecting exacerbations

Given the chronic, relapsing nature of ABPA and its propensity for frequent exacerbations, systematic monitoring is essential to optimize treatment efficacy, guide medication tapering, detect early relapse, and prevent both overtreatment and disease progression (87). A structured follow-up protocol ensures objective assessment of disease activity and facilitates timely therapeutic adjustments, ultimately improving long-term outcomes and minimizing cumulative medication toxicity.

Assessment of treatment response

Patients should be re-evaluated every 8–12 weeks during the initial treatment phase (first 4 months) and every 16–24 weeks thereafter. We recommend a multimodal assessment, incorporating clinical evaluation (assessment of dyspnea, cough, sputum production, hemoptysis, and fatigue), chest radiographs (to evaluate changes in infiltrates or mucus plugging), and serum total IgE (which remains the most reliable marker for assessing immunological activity).

A satisfactory treatment response is defined by a ≥50% improvement in symptoms and either a ≥20% decline in serum total IgE from baseline or major (≥50% reduction in infiltrates or mucus plugging) radiological improvement, after 8 weeks of treatment (26). Importantly, normalization of serum total IgE is not required and should not be considered a treatment target (88). Likewise, A. fumigatus-IgE/IgG is not helpful for monitoring, as it typically remains elevated and does not correlate with disease activity or treatment response (59,89).

Detection of exacerbations

An ABPA exacerbation is defined as clinical worsening lasting ≥14 days or radiological deterioration, accompanied by a ≥50% increase in total IgE from the most recent stable value. Differentiating ABPA exacerbations from infective bronchiectasis flares is essential as the therapeutic approach differs substantially in both treatment modality and duration. Infective exacerbations are typically treated with a 14-day antibiotic course targeted to the identified or suspected pathogen, while ABPA exacerbations require prolonged treatment with oral prednisolone or itraconazole, each given for at least 4 months. Infective flares are typically associated with increased sputum purulence and volume, isolation of bacterial pathogens in sputum cultures, stable IgE levels, and absence of radiological changes consistent with ABPA. In bronchiectasis, ABPA exacerbations may present more subtly, sometimes lacking typical features such as eosinophilia or visible mucus plugging. A high index of suspicion, supported by serial IgE measurements, sputum cultures, and repeat imaging, remains key to accurate differentiation and appropriate management.

Discussion

Despite growing recognition of ABPA as a treatable endotype in bronchiectasis, several challenges remain in its identification and management.

Underrecognition and inadequate screening

ABPA remains substantially underdiagnosed in bronchiectasis populations. While the European Respiratory Society and British Thoracic Society recommend routine screening for ABPA in all patients with bronchiectasis at the time of diagnosis (23,90,91), real-world data from multiple international registries show alarmingly low testing rates (14,18,21). This underrecognition leads to diagnostic delays, missed therapeutic opportunities, preventable exacerbations, and progression of irreversible lung damage. Given the high sensitivity and relative simplicity of A. fumigatus-IgE testing, routine serologic screening should become standard practice for all patients with bronchiectasis at diagnosis and during episodes of unexplained clinical deterioration, regardless of the underlying etiology or presence of asthma.

Phenotypic heterogeneity and atypical presentations

Unlike classical ABPA, ABPA complicating pre-existing bronchiectasis often exhibits atypical features. These include diffuse or lower lobe predominant disease, milder or absent eosinophilia (particularly in patients on inhaled corticosteroids), lower total IgE elevations (500–1,000 IU/mL range), and subtle or absent radiological signs such as HAM or fleeting infiltrates. Additionally, clinical presentation may be dominated by features of the underlying bronchiectasis rather than classic ABPA manifestations. These atypical presentations can be mistaken for other bronchiectasis endotypes. Clinicians must recognize this phenotypic heterogeneity and maintain a high index of suspicion for ABPA even when classical features are absent. The 2024 ISHAM-AWG criteria, with their lowered IgE threshold and recognition of bronchiectasis as a predisposing condition, help capture these atypical presentations, but clinical awareness remains paramount.

Limited phenotype-specific treatment data

While systemic corticosteroids and triazoles remain the cornerstone of therapy in ABPA in asthma, their specific efficacy, optimal dosing, and duration in ABPA complicating bronchiectasis remain poorly defined. Similarly, the role of biologics and inhaled antifungals also remains unclear in this subgroup. Future clinical trials should stratify patients by bronchiectasis phenotype to assess differential treatment responses and guide personalized care.

Pathophysiological ambiguity

The relationship between ABPA in bronchiectasis and classical ABPA remains unresolved, with debate over whether it represents a true hypersensitivity disorder or an epiphenomenon of fungal colonization in structurally damaged airways. Many patients lack classical type 2 features, raising the possibility of a distinct immunopathogenic mechanism. Focused studies using immunophenotyping, genetic analysis, and host-pathogen models are needed to clarify the underlying biology.

Conclusions

ABPA is an underrecognized yet highly treatable endotype in bronchiectasis. Once considered exclusive to asthma or CF, its occurrence in bronchiectasis, regardless of classical risk factors, is now well established. The 2024 ISHAM-AWG criteria reflect this expanded understanding, enabling broader diagnostic inclusion. Importantly, ABPA lies along a spectrum of Aspergillus-associated airway diseases, including AS and CAI. These are not merely immunological signatures but are clinically significant phenotypes associated with worse clinical outcomes.

Routine screening for Aspergillus-related endotypes should become standard in bronchiectasis care. At a minimum, this should include A. fumigatus-specific IgE testing at diagnosis, with reflex testing for total IgE, A. fumigatus-specific IgG, and a peripheral BEC when sensitization is detected. This is followed by an appropriate radiological evaluation to establish or exclude ABPA. Early recognition and targeted therapy can alter the disease course, reduce morbidity, and improve outcomes. Future research should aim to refine diagnostic strategies, explore the immunopathogenesis of ABPA, and develop phenotype-driven treatment algorithms to personalize care in this neglected domain of bronchiectasis.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease for the series “Frontiers in Bronchiectasis Management: Translational Science and Practice”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1548/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1548/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1548/coif). The series “Frontiers in Bronchiectasis Management: Translational Science and Practice” was commissioned by the editorial office without any funding or sponsorship. J.D.C. served as the unpaid Guest Editor of the series. R.A has received institutional grants from Cipla Pharmaceuticals, India, to conduct research in ABPA. S.H.C reports grants from the Singapore Ministry of Education and Singapore Ministry of Health’s National Medical Research Council, with payments made to the institution; consultancy fees from Boehringer Ingelheim, CSL Behring, Pneumagen Ltd., Sanofi and Zaccha Pte Ltd.; lecture fees from AstraZeneca, Boehringer-Ingelheim and Chiesi Farmaceutici; and participation on a data safety monitoring board for Inovio Pharmaceuticals Inc. and Imam Abdulrahman Bin Faisal University. J.D.C. has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed, and Trudell; and consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell, and Zambon. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Written informed consent was obtained from the patients for publication.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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