Corticosteroid-sparing effect of biologics in patients with allergic bronchopulmonary aspergillosis

Allergic Bronchopulmonary Aspergillosis (ABPA) is a disease characterized by asthmatic symptoms and recurrent exacerbations due to Aspergillus antigen hypersensitivity in patients with asthma or cystic fibrosis. Current guideline-directed treatment centers around oral corticosteroids (OCS), which have numerous side effects especially with chronic use.1 Biologic agents specifically targeting eosinophils, IgE, and related Type 2 cytokines have proven efficacy in related disorders such as severe asthma. Patients with ABPA on chronic OCSs represent a subgroup with high disease burden who are particularly situated to benefit from novel therapeutics. We designed a retrospective analysis examining biologic use in this population and association with change in OCS dose. A retrospective chart review was performed to identify patients with ABPA at a tertiary medical center treated with one or multiple biologics (i.e. benralizumab, dupilumab, mepolizumab, omalizumab, reslizumab, and tezepelumab) between 1/1/2012 and 7/11/2022. Individuals were classified as corticosteroid-dependent if they were prescribed a daily oral corticosteroid for at least 4 weeks prior to biologic initiation. The primary outcome was change in corticosteroid dose in prednisone equivalents. The OCS dose at biologic initiation and either discontinuation of biologic or end of study period was compared using a two-tailed paired t-test. Patients were excluded if they did not meet diagnostic criteria for ABPA, they never initiated biologic therapy, they were not corticosteroid-dependent, or OCS doses could not be determined. If a patient had been prescribed multiple biologics, each biologic trial was analyzed independently in terms of the primary outcome, treatment duration, and adverse effects, but each patient was counted once in the reporting of demographic information, medication use, comorbidities, and diagnostic testing. The electronic medical record query yielded 69 patients of which 20 patients with ABPA were identified that met inclusion criteria. There were 29 biologic trials (six benralizumab, three dupilumab, five mepolizumab, fifteen omalizumab) identified. Patient demographic information, comorbidities, medications, and diagnostic testing are summarized in Table 1. The median age of biologic initiation was 56 years. All patients had a chart diagnosis of asthma, and two patients had cystic fibrosis. All patients were on an inhaled corticosteroid at time of biologic initiation, and most patients had taken or were taking an antifungal agent and/or leukotriene receptor antagonist. Thirty-five percent of patients had tried two or more biologics. The order of biologics trialed was variable and influenced by various factors including availability (not all biologics were approved throughout the entire study period or covered by the patient's insurance) and provider and patient preference. The median peak IgE was 4,056 IU/mL and median absolute eosinophil count of 1,200/mm3. 85 percent had bronchiectasis noted on computed tomography.Table 1Patient Characteristics. Values are presented as median (interquartile range), mean ± standard deviation, or n (percentage). N is the number of patients with available data. *Positivity based on I-SHAM criteria.9 **Third quartile could not be determined definitively due to assay cutoffs. FEV1 forced expiratory volume, FVC forced vital capacity.Patient CharacteristicValueNDemographics Male8 (40%)20 Age (years)56 (43.75-66.25)20 Non-Hispanic White13 (65%)20 Hispanic or Latino6 (30%)20 Black or African American1 (5%)20Associated Conditions Cystic Fibrosis2 (10%)20 Asthma20 (100%)20Comorbidities Allergic Rhinitis18 (90%)20 Ever Smoked11 (55%)20# of Biologics Trialed One13 (65%)20 Two3 (15%)20 Three4 (20%)20Other Medications Inhaled Corticosteroid20 (100%)20 Antifungal Agent18 (90%)20 Leukotriene Receptor Antagonists19 (95%)20Markers of Aspergillus Sensitization* IgE Aspergillus (kU/L)39.1 (12.6-61.7)20 IgE Aspergillus Positive19 (95%)20 Aspergillus IgG Positive4 (36.36%)11 Aspergillus Precipitans Positive3 (33.34%)9 Skin Prick Positive6 (85.71%)7Other Laboratory Testing Peak IgE (IU/mL)4,056 (1,017-5,000)**20 Peak Absolute Eosinophils (1000/mm3)1.2 (0.96-2.1)20CT Characteristics Bronchiectasis17 (85%)20 Mucus plugging17 (85%)20Baseline Pulmonary Function Tests Percent FEV1 of Predicted (mean)66.8 ± 19.019 FEV1/FVC (mean)63.8 ± 10.218 Percent FEV1/FVC of Predicted (mean)77.96 ± 1518 Open table in a new tab We observed a statistically significant mean reduction in prednisone equivalent dose of 6.82 mg (P=0.0033, CI 2.48-11.18). The mean OCS dose at biologic initiation was 14.2 mg prednisone equivalents versus 7.38 mg at discontinuation or end of study period. In 52 percent of trials (15/29), patients achieved a 50% or greater reduction in OCS dose. In 34 percent of trials (10/29), patients were able to discontinue OCS completely. A reduction was still observed if we included only the initial biologic trial of each patient (n = 20, 8.24 mg, P=0.0056). The mean absolute eosinophil count (AEC) at prior to biologic initiation was 530 cells per microliter compared to 280 during treatment (medians of 400 and 200). The median reduction of AEC was 100 cells per microliter (IQR -350 to +130). There was not a statistically significant change in percent predicted FEV1 (-3%, P=0.49, n=13) with biologic treatment. We were unable to reliably analyze exacerbation rates or radiographic changes from the available data. The median duration of biologic trial was 244 days (IQR 93-683 days). Reasons for discontinuation included adverse reaction (n = 1), cost or insurance reasons (n=5), initiation of alternative biologic (n=5), unable to determine (n=1), or lack of benefit (n=2). Trial end date was based on date that patient was lost to follow-up (n=4) or end of study period (n=10) for the remaining patients. Potential adverse effects were reported for six biologic trials with one mepolizumab trial stopped prematurely due to adverse reaction requiring hospitalization (tachycardia, shortness of breath, severe injection site pain). Possible adverse effects were also reported for four omalizumab trials (hives, injection site reaction, increased respiratory infections, nausea, syncope) and one dupilumab trial (injection site reaction). Our population has similar characteristics to many prior studies of biologics in asthmatic patients with ABPA with respect to median age, high prevalence of bronchiectasis on imaging, maximization of other potential therapies including antifungal agents and inhaled corticosteroids, and serologic biomarkers. Thirty percent of patients self-identified as Hispanic or Latino, a group not clearly represented in the literature. The patients in this analysis may be more generalizable to the population seen in US tertiary centers, as prior retrospective and prospective studies have largely been based on non-US data.2-5 We believe our primary outcome is clinically meaningful as OCS dose provides a quantitative measure that correlates with symptom control. Eighteen patients (90%) had adverse effects attributed to OCS use including mood changes, adrenal insufficiency, osteoporosis/osteopenia, weight gain, and hyperglycemia, highlighting the potential additional benefit of mitigating adverse effects. Limitations of the study include the small sample size, retrospective data, single center design, and insufficient power to compare biologic agents to one another. Additionally, analyzing only two time points may provide an incomplete picture of overall symptom control in patients with other pulmonary comorbidities and in a disease process like ABPA that is influenced by environmental factors and characterized by exacerbations. Although not designed to directly compare biologic agents, subgroup analyses of individual biologic agents were performed. Subgroup analysis looking at omalizumab revealed a statistically significant reduction in OCS dose (P=0.014, paired t-test). Our work adds to mounting evidence, including a small randomized controlled trial, supporting omalizumab use in ABPA, despite initial concerns about dosing given the degree of IgE elevation in this population.6-7 The OCS dose was also significantly reduced in the subgroup analysis of patients on anti-IL-5 (benralizumab and mepolizumab) therapy (P=0.026, paired-t test). These results are concordant with a retrospective analysis of Japanese patients with mepolizumab and benralizumab.4 While some research has showed promising reductions in OCS dosing with dupilumab, none of the patients in our study were able to reduce their OCS with dupilumab use (0/3).3,8 Although no biologic agents are FDA-approved for use in ABPA, many patients meet criteria based on presence of asthma and the elevated IgE and eosinophilia associated with the disease. Biologic agents represent a promising OCS-sparing option in carefully selected patients with ABPA. 1. 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