Immunology and Biologics in the Treatment of Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis

Abstract

Allergic bronchopulmonary aspergillosis (ABPA) is mediated by hypersensitivity reactions to Aspergillus fumigatus, which is ubiquitous in the environment. People with Cystic Fibrosis (PwCF) are at an increased risk for developing ABPA, which can lead to frequent pulmonary exacerbations and progressive decline in lung function. In the age of highly effective modulator therapies (HEMT), PwCF have improved clinical outcomes and overall life expectancy, but they continue to suffer from comorbidities such as ABPA, which may be difficult to diagnose and treat. Establishing the diagnosis of ABPA in PwCF requires high clinical suspicion due to similarities in symptoms with the underlying disease. First-line treatment involves corticosteroids and anti-fungals, which have multiple side effects and drug interactions, especially with HEMT. Given this challenge, biologics have gained attention as potential agents directly targeting the Th-2 inflammatory pathway of ABPA with good tolerability and without significant drug interactions with HEMT. In this review, we discuss the diagnostic process and management of ABPA in PwCF, including a brief overview of the current literature on biologic agents.

1. Introduction

Clinical care for Cystic Fibrosis (CF)—a rare genetic disorder with multiple organ manifestations, predominantly affecting the lungs, but also significantly impacting the sinuses, pancreatic, gastrointestinal, liver, and reproductive systems—has evolved since the advent of highly effective modulator therapies (HEMTs) such as ivacaftor, elexacaftor-tezacaftor-ivacaftor (ETI), and vanzacaftor-tezacaftor-deutivacaftor [1]. These medications improve the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride ion transport channel across cell membranes that is impaired as a result of mutations in the CFTR gene [2]. Dysregulation of the CFTR protein in the lungs results in abnormal transport of chloride and sodium across respiratory epithelial cells, leading to mucous build up, impairment of ciliary function, inflammation, acquired infections, bronchiectasis, and eventually respiratory failure. HEMT is associated with reduced pulmonary exacerbations, improved lung function, body mass index, and symptom control [3]. Based on the 2024 CF Foundation (CFF) Patient Registry, the median age of survival for CF in the United States is 65 years of age for people with CF (PwCF) born between 2020 and 2024 [4]. While clinical outcomes are improving in PwCF, certain comorbidities and complications may become rarer, although not non-existent, and all the more challenging to manage, as there remains no cure for CF. Pathogens known to chronically colonize CF lungs, such as Pseudomonas aeruginosa and Staphylococcus aureus, are being isolated less over time, likely as a result of improved mucociliary clearance in the CF respiratory tract following use of HEMT [4,5].

Fungal exposure of the CF airways to Aspergillus fumigatus, the most common type of Aspergillus species, presents potentially long-term sequela, as it is ubiquitously present in the environment and isolated in the airways of PwCF in 27% to 57% of cultures [6]. The risk of colonization with A. fumigatus may vary depending on the environmental exposure and host susceptibility such as colonization with Pseudomonas aeruginosa or chronic antibiotic use [7,8]. Importantly, defective CFTR may alter the host’s innate and adaptive immune response to A. fumigatus, predisposing PwCF to developing hypersensitivity reactions. Allergic bronchopulmonary aspergillosis (ABPA) is a predominantly Type I hypersensitivity reaction to A. fumigatus, but Types III and IV may also be involved [9,10]. In addition to the decreased mucociliary clearance of pathogens, the dysfunctional CFTR protein has been associated with increased T-helper cell type 2 (Th2-type) response to A. fumigatus with subsequent elevated Ig-E levels, which is the primary mechanism involved in the development of ABPA [11]. Once the spores of A. fumigatus enter the respiratory tract, they remain attached to the epithelium, allowing for increased fungal antigen presentation and exaggerated Th2-type immunologic response involving the production of interleukin (IL)-4 and IL-13 with resultant Ig-E release and eosinophil attraction [12]; see Figure 1. This heightened immune response leads to airway hyperactivity and progressive lung damage.

The prevalence of ABPA is higher in PwCF than the general population, estimated to occur from 3 to 25% [13,14]. Patients usually present with pulmonary symptoms and decreased lung function unresponsive to antibiotics. The diagnosis of ABPA can often be delayed due to the significant overlap of symptoms with the underlying disease, but several diagnostic criteria have been established to guide the diagnostic process. Once the diagnosis is suspected or confirmed, the standard therapy for ABPA includes oral corticosteroids, and possibly anti-fungals, to reduce immunologic response and fungal burden [12]. However, some patients experience intolerable side effects, drug interactions, or refractory disease with recurrent exacerbations that necessitate alternative treatment. For these challenging cases, there is emerging evidence for the role of biologics targeting the Th-2 inflammatory pathway of the disease. Here, we review the diagnostic process and management of ABPA in CF, including an overview of the current evidence and a discussion of the utility of biologic agents.

2. Diagnosis

The diagnosis of ABPA in CF requires a comprehensive assessment of the patients’ clinical, serologic, microbiologic, and radiographic findings. Clinically, patients present with productive cough and wheezing related to airway hyperactivity [15]. On imaging, they may have pulmonary infiltrates, central bronchiectasis (varicose or cystic as opposed to cylindrical), high-attenuation mucus plugs, or pleural thickening [12,16,17,18]. Various serologic markers, including total serum IgE, A. fumigatus specific IgG, and precipitating antibodies, as well as cutaneous skin reaction, have been utilized to detect ABPA [19,20,21]. Diagnosing ABPA with these tests alone, however, may be limited, as many PwCF have evidence of sensitization to A. fumigatus early on in their life [22]. Similarly, sputum positivity with A. fumigatus, as well as decreased pulmonary function with imaging changes, may be found in PwCF with or without ABPA [23].

In the past, several diagnostic criteria have been established to standardize the diagnostic process of ABPA for the general population [24,25]. In the early 2000s, the CFF proposed diagnostic criteria for PwCF, which include the following: (1) acute or subacute clinical deterioration not attributable to another etiology, (2) total serum IgE concentration > 1000 IU/mL (or >500 IU/mL for minimal diagnostic criteria) not on any systemic corticosteroids, (3) immediate cutaneous reactivity or IgE antibody to A. fumigatus, (4) precipitating antibodies or IgG to A. fumigatus, and (5) new or recent abnormalities on chest imaging that have not cleared with antibiotics or chest physiotherapy [12]. For the full diagnostic criteria, the patient must meet all five requirements, whereas the minimal diagnostic criteria require all the first three major criteria mentioned above and one of the latter two criteria (i.e., precipitating antibodies or IgG to A. fumigatus; or radiographic evidence of disease). [12]. The CFF also recommends annual screening with serum IgE concentration, and to consider further testing for ABPA if >500 IU/mL or 200–500 IU/mL with adequate clinical suspicion. Using the diagnostic criteria as a guide, it is crucial that clinicians remain vigilant to screen and test for ABPA in PwCF who present with clinical deterioration (

Table 1. ABPA diagnostic criteria proposed by the CFF.

ABPA Diagnostic Criteria Proposed by the CFF
Clinical	Acute or subacute clinical respiratory deterioration not attributable to another etiology
Serologic	Total serum IgE concentration > 1000 IU/mL (or >500 IU/mL for minimal diagnostic criteria) off any systemic corticosteroids Precipitating antibodies to A. fumigatus or serum IgG antibody to A. fumigatus Immediate cutaneous reactivity to Aspergillus (prick skin test wheal > 3 mm in diameter with surrounding erythema) or IgE antibody to A. fumigatus
Radiographic	New or recent abnormalities on chest radiograph or CT that do not clear with antibiotics or chest physiotherapy

Minimal diagnostic criteria require either precipitating antibodies or IgG to A. fumigatus or radiographic evidence of disease [12].

).

3. Management

The treatment aim of ABPA is to minimize immunologic response to A. fumigatus and reduce fungal burden in the airways. To achieve this, systemic corticosteroids and anti-fungals, specifically azoles, have been studied and utilized [26,27,28,29]. The CFF recommends initial corticosteroid dose of 0.5–2 mg/kg/day of prednisone equivalent up to a maximum of 60 mg for 1–2 weeks, then tapering the dose to every other day and onwards based on their clinical response and tolerance of the drug [12]. Several systemic corticosteroids, including prednisone, prednisolone, and methylprednisolone, have shown efficacy in the treatment of ABPA [12,27,30]. Although there is evidence for favorable outcomes with oral corticosteroids, some patients may become chronically steroid-dependent due to low remission rates [31]. For these patients, or others who cannot tolerate systemic corticosteroids due to adverse effects, the clinician can consider adding an azole (e.g., itraconazole, voriconazole, posaconazole) to the regimen for a duration of 3–6 months [6,12]. Currently, there is no consensus on recommended duration of anti-fungals, and the treatment course can vary depending on the clinical response. Clinical trials by Stevens et al. and Wark et al. have demonstrated symptomatic and serum IgE level improvement in ABPA patients treated with 16 weeks of itraconazole, albeit in non-CF patients [28,32]. On the other hand, real-world data have shown that, despite 4–6 months of azole therapy, ABPA may remain refractory in a significant proportion of patients with high-risk features for difficult-to-treat disease, which include age ≤ 50 years at the onset of ABPA, serum A. fumigatus-specific IgE titer of ≥20 U_A/mL, positive culture for Aspergillus spp. in sputum/bronchial lavage, and high- attenuation mucus on CT [33]. Anti-fungal agents are used to reduce the fungal burden in the CF lungs and lessen antigenic stimulation of immune response. It is crucial that the drug levels are closely monitored to maintain therapeutic effects and avoid toxicity such as liver injury, skin rash, photosensitivity, and adrenal suppression [26]. The CFF recommends an initial dose of itraconazole to be 5 mg/kg/day, but not exceeding 400 mg/day [12]. Strong CYP3A inhibitors include itraconazole, posaconazole, and voriconazole [12]. HEMT is metabolized by CYP3A4, and thus concomitant use with these particular azoles would raise HEMT levels [1,4]. To address this, dosing of HEMT must be reduced appropriately to avoid the drug toxicity associated with HEMT, depending on the strength of CYP3A4 inhibition [34,35]. For instance, recommended ETI dose adjustment with concomitant use of a strong CYP3A inhibitor is two tablets of ETI in the morning twice a week, about 3–4 days apart, without evening dosing of ivacaftor [36]. On the other hand, the CFTR modulator lumacaftor/ivacaftor has been associated with subtherapeutic levels of azoles, emphasizing the varying degree of interaction azoles have with medications essential to PwCF [35,37]. Azoles may also raise the serum concentrations of certain corticosteroids such as methylprednisolone and fluticasone propionate, which may increase the risk of steroid-related adverse effects [36,38].

In addition to oral corticosteroids and anti-fungals, patients should be maintained on airway clearance therapy, consisting of mucolytics and chest physiotherapy, to decrease mucoid impaction. Despite these first-line treatments, however, some patients continue to experience relapse of symptoms and result in progressive lung function decline. In such refractory cases, biologic agents targeting the hypersensitivity pathway of ABPA may be reasonable to consider.

4. Immunology in Cystic Fibrosis

Managing chronic inflammation is a challenge in PwCF with or without ABPA. Chronic inflammation leads to progressive structural damage and lung function decline. Targeted therapies to reduce inflammation is an avenue of investigation, but there are only a few anti-inflammatory agents approved for CF. It is well known that the dysfunctional or absent CFTR protein in the respiratory epithelium leads to decreased mucociliary clearance of pathogens and persistent inflammation [39]. Over the past few decades, research has increased our understanding of immune dysregulation in PwCF resulting from the dysfunctional CFTR proteins that are present on other immune cells such as neutrophils and macrophages. Figure 1 illustrates immune dysregulation in CF. As part of the innate immune response, macrophages phagocytose and kill pathogens that are not cleared by the mucociliary pathway [40]. Many studies have now investigated the altered phagocytic abilities of CFTR deficient macrophages leading to defective bacterial killing and heightened inflammation through increased release of cytokines [41,42,43,44]. From this initial inflammatory cascade, neutrophils are actively recruited to the site and become the predominant immune cell population. Neutrophils in the CF lung, however, have also been found to display pathogenic phenotypes, such as increased exocytosis of inflammatory granules releasing serine protease neutrophil elastase that is destructive to the connective tissue in the lung, promoting increased mucus production and inflammation [45,46]. Emerging evidence on the altered immunologic function in PwCF has led to increased interest in targeted immunotherapies, but the advancement in this field is still lacking due to our incomplete understanding of the complex relationship between CFTR-deficient immune cells and various inflammatory mediators present in the microenvironment of CF lungs.

Figure 1. Immune dysregulation in Cystic Fibrosis. A. The periciliary layer of the Cystic Fibrosis airway is dehydrated leading to poor mucociliary clearance as a result of dysfunctional CFTR protein that is normally expressed in airway epithelial cells [47,48]. B. Mucus plugging and biofilm buildup becomes a nidus for inhaled pathogens or allergens such as Aspergillus spp. C. Macrophages with impaired CFTR kill pathogens less efficiently and increase secretion of pro-inflammatory cytokines such as IL-6, IL-4, IL-13, and TNF-α [44,49]. D. CFTR deficient airway epithelial cells lead to increased IL-33 when exposed to allergens, resulting in higher expression of Th2 cell with increased release of IL-5, increased eosinophils, and IL-4 and IL-13, stimulating IgE expression by B cells [50,51]. E. Neutrophils, the predominant type of cell in CF airways, have reduced phagocytosis and can release toxic granule contents (e.g., serine and metalloproteases, oxidants) that can cause tissue damage over time. Neutrophils are known to release neutrophil extracellular traps (NETs), which are DNA fibers that immobilize and kill bacterial and fungal pathogens such as Pseudomonas aeruginosa and Aspergillus fumigatus, respectively. Abundant NET formations may attribute to common colonization of such pathogens in people with CF and reduced lung function; recombinant DNase (e.g., inhaled dornase alfa) improves mucociliary clearance by clearing the NET-DNA meshwork [49,51,52].

Figure 1. Immune dysregulation in Cystic Fibrosis. A. The periciliary layer of the Cystic Fibrosis airway is dehydrated leading to poor mucociliary clearance as a result of dysfunctional CFTR protein that is normally expressed in airway epithelial cells [47,48]. B. Mucus plugging and biofilm buildup becomes a nidus for inhaled pathogens or allergens such as Aspergillus spp. C. Macrophages with impaired CFTR kill pathogens less efficiently and increase secretion of pro-inflammatory cytokines such as IL-6, IL-4, IL-13, and TNF-α [44,49]. D. CFTR deficient airway epithelial cells lead to increased IL-33 when exposed to allergens, resulting in higher expression of Th2 cell with increased release of IL-5, increased eosinophils, and IL-4 and IL-13, stimulating IgE expression by B cells [50,51]. E. Neutrophils, the predominant type of cell in CF airways, have reduced phagocytosis and can release toxic granule contents (e.g., serine and metalloproteases, oxidants) that can cause tissue damage over time. Neutrophils are known to release neutrophil extracellular traps (NETs), which are DNA fibers that immobilize and kill bacterial and fungal pathogens such as Pseudomonas aeruginosa and Aspergillus fumigatus, respectively. Abundant NET formations may attribute to common colonization of such pathogens in people with CF and reduced lung function; recombinant DNase (e.g., inhaled dornase alfa) improves mucociliary clearance by clearing the NET-DNA meshwork [49,51,52].

Although other immune cells, such as eosinophils and mast cells, are not central to the development of CF lung disease, they play a more prominent role in the pathogenesis of ABPA. At baseline, PwCF without ABPA may have increased activation of eosinophils [53]. After exposure to A. fumigatus, eosinophils are actively recruited to the airways via multiple cytokines, including IL-5, as part of the Th-2 hypersensitivity reaction and participate in the allergic inflammatory response [54]. Eosinophilia, although not included in the diagnostic criteria, is a common laboratory finding associated with ABPA. Once recruited, they are cross-linked by different antibodies including A. fumigatus specific IgE, which leads to degranulation and inflammation [55]. Similarly, mast cells become cross-linked by IgE antibodies and release inflammatory mediators such as histamine, leukotrienes, platelet-activating factors, and prostaglandins (e.g., PgD2) that induce vascular permeability [56,57]. The IgE levels that activate these effector cells are significantly elevated in ABPA from IL-4 assisted B and T cell interaction as well as B cell IgE isotype switching [58]. The B cells in patients with ABPA have also been found to be more sensitive to IL-4 stimulation, emphasizing the close interplay between these mediators and effector cells to augment the Th-2 hypersensitivity response to the fungal pathogen [59].

Given the multiple immunologic mediators involved in PwCF with ABPA, their identification and modulation of activity may be essential to disease treatment, especially for cases that are refractory or intolerant to the standard therapy. Targeting the immunologic pathway may also be useful to distinguish an allergic response to A. fumigatus from a pulmonary exacerbation due to bacterial infections, both of which have similar presentations and pose a diagnostic challenge. In the next section, we review the current literature on the available biologic therapies for ABPA.

4.1. Omalizumab

Omalizumab is approved by the U.S. Food and Drug Administration (FDA) for allergic asthma and chronic urticaria, but is used off-label for ABPA. It is a humanized monoclonal IgE antibody that binds to free IgE at the Cε3 domain of the IgE heavy chain typically found on basophils and mast cells, thereby preventing allergic response [60,61]. It also reduces the number of receptors for IgE [60]. It is administered subcutaneously every 2–4 weeks and is dosed based on the patient’s weight and total serum IgE levels. The drug has a good safety profile and is generally well tolerated [61].

The data on omalizumab for ABPA treatment is limited to case reports/series and retrospective studies, with more focus on the pediatric and asthmatic populations. A randomized, double-blind, placebo-controlled trial assessing the efficacy of different doses of omalizumab in PwCF with ABPA was attempted in 2009, but was discontinued prematurely due to difficulty enrolling patients [62]. From the available observational studies, the results on the efficacy of omalizumab for ABPA treatment in PwCF are mixed. In 2015, Emiralioglu and colleagues conducted a retrospective study on six adult PwCF who received omalizumab after a lack of response to or adverse effect from corticosteroids [63]. Within the first 3 months of treatment, they were successful in tapering or discontinuing steroids in half of their patients, but no significant differences were ultimately found in their pulmonary functions after at least a year of therapy, especially in those with severe baseline lung disease [63]. Similarly, a larger retrospective study with 32 patients, 21 of whom were adults, reported that the doses of corticosteroids were able to be lowered in most of the patients after 6–12 months of treatment without significant improvement in pulmonary function [64]. Interestingly, two studies—a case series on three patients and a retrospective study on nine patients, both of which included pediatric patients—reported improved forced expiratory volume in 1 s (FEV₁) in some patients in addition to the steroid-sparing effect [65,66]. In contrast, Ashkenazi et al. evaluated nine adult PwCF from 3 European CF centers and found no differences in their lung function or steroid doses post-treatment [67]. Another retrospective study with eleven PwCF with ABPA failed to show meaningful changes, although four patients were able to reduce their corticosteroid doses [68].

Based on the results of these studies, no definitive conclusions can be drawn on the utility of omalizumab in the treatment of ABPA. Most patients were trialed on omalizumab after failing or not tolerating first-line therapy, and many were able to reduce their corticosteroid doses. Given this, it may be reasonable to trial omalizumab for cases unresponsive to first-line treatments for its steroid-sparing effects (

Table 2. Summary of biologic agents used off-label for ABPA treatment in PwCF.

Agent	Mechanism of Action	Indications	Dose/Route of Administration	Adverse Effects	Clinical Benefits in PwCF with ABPA
Omalizumab	Humanized antibody that binds free IgE at the Cε3 domain of heavy chain	Allergic asthma, chronic urticaria, chronic rhinosinusitis with nasal polyps, Ig-E mediated food allergy	Subcutaneous injection every 2 to 4 weeks	Arthralgia, pain, fatigue, dizziness, dermatitis, injection site reaction	Possible corticosteroid sparing effect and reduced pulmonary exacerbations related to ABPA
Dupilumab	IL-4 receptor alpha antagonist, inhibits downstream effectors IL-4 and IL-13	Atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, prurigo nodularis, eosinophilic phenotype COPD, chronic spontaneous urticaria, bullous pemphigoid	Subcutaneous injection every 2 to 4 weeks	Injection site reaction, conjunctivitis, eosinophilia, upper respiratory tract infections, HSV infection, arthralgia, dizziness, headache	Limited data on PwCF, possible corticosteroid sparing effect, reduced pulmonary exacerbations and function in asthmatic patients
Mepolizumab	Monoclonal antibody that binds IL-5 receptor α	Add on therapy for severe eosinophilic asthma or chronic rhinosinusitis with nasal polyposis, eosinophilic phenotype COPD, EGPA, hypereosinophilic syndrome	Subcutaneous injection every 4 weeks	Headache, injection site reaction, back pain, fatigue, diarrhea, cough, oropharyngeal pain	Possible corticosteroid sparing effect, reduced Ig-E level, and improved eosinophilia
Benralizumab	IL-5 receptor alpha directed cytolytic monoclonal antibody	Add on therapy for severe eosinophilic asthma, EGPA	Subcutaneous injection every 4 weeks for first 3 doses followed by once every 8 weeks	Headache, pharyngitis	Limited data on PwCF, possible corticosteroid sparing effect and clinical improvement in asthmatic patients

COPD = chronic obstructive pulmonary disease; EGPA = eosinophilic granulomatosis with polyangiitis; HSV = Herpes Simplex Virus; IL = interleukin.

).

4.2. Dupilumab

Dupilumab is a human monoclonal antibody against IL-4 receptor subunit α and inhibits the downstream effectors IL-4 and IL-13 [69]. It is approved by the FDA for several conditions including moderate-to-severe atopic dermatitis, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis [69]. Dupilumab has often been used off-label for ABPA due to its effect on the Th-2 hypersensitivity pathway. It is administered subcutaneously and is rarely associated with adverse effects such as injection-site reactions.

Similarly to omalizumab, research on dupilumab is lacking. Observational studies supporting the utility of dupilumab for treatment-resistant ABPA are limited to asthmatic populations, and no studies to date report dupilumab use in PwCF. From the available data, favorable outcomes have been reported in the ability to taper corticosteroids, reduce exacerbations, and improve pulmonary functions, especially for cases resistant to initial treatment [70,71,72]. Interestingly, positive response to dupilumab has been published for asthmatics who did not respond to omalizumab or mepolizumab, possibly through dupilumab’s dual inhibitory effects on IL-4 and IL-13 [73,74,75]. Dupilumab has promising therapeutic effects, maybe even more-so compared to other biologics; however, further research is needed to determine its efficacy in PwCF.

4.3. Mepolizumab

Mepolizumab is an anti-IL-5 monoclonal antibody used to treat a wide range of eosinophilic disorders including eosinophilic asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic chronic obstructive pulmonary disease [76]. It is generally tolerated well without major adverse effects [77]. Although many clinical trials have supported the use of mepolizumab for conditions such as eosinophilic asthma, no randomized controlled trials exist for its use in PwCF with ABPA. In 2020, Zhang and colleagues published a case series on three PwCF with eosinophilic inflammation who were trialed on mepolizumab for ABPA refractory to first-line treatments [78]. They reported positive outcomes with tapering corticosteroids and lowering serum Ig-E and eosinophilic counts, but no changes were seen on the frequency of pulmonary exacerbations or lung functions after several months of follow-up [78]. Similarly, a case report on a patient with CF and asthma diagnosed with ABPA experienced a successful tapering of corticosteroids along with improved eosinophilia and symptoms after mepolizumab initiation [79]. Mepolizumab has also been used for ABPA in asthmatics with similar efficacy, and may be a reasonable alternative in PwCF who have evidence of eosinophilia or other allergic conditions [80].

4.4. Benralizumab

Benralizumab is a humanized recombinant monoclonal antibody against IL-5 that specifically binds the alpha chain of the IL-5 receptor present on eosinophils and basophils [81]. It is indicated for use as an add-on therapy for patients with severe eosinophilic asthma who are inadequately controlled on the standard regimen. Because of its effect on the Th-2 hypersensitivity pathway, benralizumab has also been used for ABPA treatment. Although data is limited to observational studies, it has shown favorable outcomes on steroid-tapering, clinical symptoms, and pulmonary function especially in asthmatic patients [82,83,84]. One report on benralizumab use for ABPA in a patient with CF showed similar success with improving symptoms, including oxygen requirement [85].

5. Conclusions

ABPA is a Th-2 hypersensitivity reaction to A. fumigatus and shares similarities to other allergic conditions involving immune mediators. PwCF are not only more susceptible to ABPA development, but also treatment resistance due to pre-existing abnormalities in their lung structure and difficulty clearing the fungal pathogen. Diagnostic challenges in PwCF due to similarities in ABPA and underlying CF manifestations may delay diagnosis and treatment. Decades of research have shown various immunologic dysfunctions perpetuating the inflammatory state in CF lungs. While clinical trial evidence for targeted immunomodulatory therapies is lacking, the use of biologics has demonstrated some benefit in the treatment of ABPA through observational studies and case series. An update in ABPA management guidelines in CF will be beneficial to account for the potential utility of biologic therapies. Given the pre-existing immunologic dysfunction and the complex microenvironment of CF lungs, treatment of ABPA in PwCF may require specialized attention on targeting immunologic pathways. Avoiding drug interactions between the traditional ABPA first-line treatment and HEMT is also a priority to be considered, as a majority of PwCF are on HEMT. Further research is needed to explore the efficacy of the available biologic agents in the treatment of ABPA in PwCF.