Bronchiectasis is characterized by permanent, irreversible dilation of the bronchi due to inflammation and impaired mucus clearance and is associated with significant respiratory impairment. Bronchiectasis shares significant clinical characteristics with severe asthma, and they often coexist.1 Although classically thought of as neutrophilic-predominant inflammation, emerging evidence suggests that the inflammation in bronchiectasis is heterogeneous with a subset of patients having an eosinophil-predominant type 2 inflammatory response. 2 Based on this observation, biologics that target type 2 inflammation may be a consideration for patients with bronchiectasis and severe asthma. However, evidence for this is limited to two small case reports, and patients with bronchiectasis were excluded from phase 3 biologic asthma clinical trials.3,4 In this study, we report our real-world experience with an IL-4/IL-13 antagonist (dupilumab), anti-IgE (omalizumab) and extend the evidence for IL-5 (reslizumab)/ IL-5Rα antagonist (benralizumab) in patients with non-cystic fibrosis (CF) and non-allergic bronchopulmonary aspergillosis (ABPA) bronchiectasis.
This case series includes 12 patients with a radiographic diagnosis of bronchiectasis not due to cystic fibrosis (CF) or allergic bronchopulmonary aspergillosis (ABPA) who were treated with biologics targeting type 2 inflammation in an academic allergy-immunology clinic. All patients had chronic cough, sputum production, and a chest computed tomography (CT) scan documenting bronchiectasis. ABPA and CF diagnoses were excluded based on documentation by the treating allergist/immunologist/pulmonologist. We characterized patient demographics, asthma controller medications, lung function, laboratory data (IgE and absolute eosinophil count (AEC)) respiratory exacerbations, systemic corticosteroids, and antibiotic courses for respiratory infections for the 12 months prior to initiation of the biologics. Respiratory exacerbation was defined as respiratory symptoms requiring systemic corticosteroids, or any increase in baseline dose if on chronic corticosteroids for ≥3 days or urgent care/emergency department visit for worsening respiratory symptoms. Respiratory exacerbations were considered distinct episodes if the interval between start dates was ≥21 days. The overall efficacy of the biologics was assessed through global physician assessment by the treating physicians (scale ranged from 1–5, Table 1). Outcomes were assessed during the use of biologics and compared to the 12 months prior to initiation of biologics and included 1) number of respiratory exacerbations; 2) number of systemic corticosteroid courses; 3) number of antibiotic courses for respiratory infections; and 4) global physician assessment. For those receiving dual biologics, outcomes were assessed after the second biologic was initiated.
Table 1.
Patient Characteristics and Global Physician Assessment with Use of Type 2-Targeted Biologics
| ID# | Age | Sex | Race | Smoking history | Allergic rhinitis (allergen sensitization) | Asthma controller medications | CRS | Asthma | FEV1 baseline % predicted | lgE(kU/L) | AEC (K/uL) | Biologic | Duration on biologic (months) | Global physician assessment⇞ |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 73 | F | Asian | Never | Yes (tree, grass, dust mite, cockroach, fusarium) | ICS, LABA, LAMA | CRSwNP | Yes | 67 | 2622 | 1.1 | benralizumab | 27 | 5 |
| 2 | 47 | F | Black | Never | Yes (tree, grass, cockroach, cat, dog, fusarium, helminthosporium, epicoccum, aspergillus) | ICS, LABA, LAMA, LTRA | CRSwNP (AERD) | Yes | 49 | 345 | 0.1 | dupilumab | 11 | 5 |
| 3 | 76 | F | Black | Never | Yes (ragweed, dust mite, cockroach) | ICS, LABA, LAMA. LTRA | No | Yes | 28 | 12 | 0 | dupilumab | 1 | Excluded (<3months of biologic) |
| 4 | 51 | M | Caucasian | Never | Yes (tree, dust mite, cat, dog, alternaría, fusarium, helminthosporium, pénicillium, hormodendrum, aspergillus) | ICS, LABA | No | Yes | 57 | 357 | 0.05 | dupilumab | 7 | 4 |
| 5 | 58 | M | Declined | Former | Yes (tree, grass, ragweed, dust mite, cockroach, cat, dog, mouse, pénicillium, aspergillus) | ICS, LABA | CRSsNP | Yes | 23 | 1872 | 0.4 | benralizumab + omalizumab | 1* | Excluded (<3months of biologic) |
| 6 | 65 | F | Caucasian | Never | Not performed | ICS, LTRA | CRSsNP | Yes | 64 | 7.8 | 0.8 | dupilumab | 4 | 5 |
| 7 | 54 | F | Hispanic | Never | Yes (dust mite) | ICS, LABA LAMA. LTRA | No | Yes | 44 | 83 | 0.3 | benralizumab | 9 | 4 |
| 8 | 57 | F | Caucasian | Never | Yes (tree, grass, ragweed, dust mite, cat, dog, aspergillus) | ICS, LABA, LTRA | CRSsNP | Yes | 57 | 11.5 | 0 | benralizumab | 22 | 3 |
| 9 | 73 | F | Caucasian | Former | No (skin test negative) | ICS, LABA | No | Yes | 100 | 43.7 | 1.5 | reslizumab | 33 | 4 |
| 10 | 49 | F | Caucasian | Never | Yes (grass, ragweed, dust mite, cat, dog, alternaría, aspergillus) | ICS, LABA. LTRA | CRSwNP | Yes | 79 | 1144 | 0.8 | benralizumab + omalizumab | 23** | 4 |
| 11 | 57 | M | Declined | Former | Yes (aspergillus) | ICS, LABA, LTRA | CRSwNP (AERD) | Yes | 65 | 381 | 0.3 | reslizumab | 28 | 5 |
| 12 | 81 | M | Caucasian | Former | Yes (tree, ragweed, cat, dog, pénicillium, alternaría, helminthosporium, aspergillus) | ICS, LABA, LAMA | No | Yes | 51 | 43 | 0.1 | dupilumab + omalizumab | 6*** | 5 |
F: female, M: male
ICS: inhaled corticosteroid, LABA: long-acting beta-agonist, LAMA: long-acting muscarinic antagonist, LTRA: leukotriene receptor antagonists
CRS: chronic rhinosinusitis, CRSwNP: chronic rhinosinusitis with nasal polyps, CRSsNP: chronic rhinosinusitis without nasal polyps, AERD: aspirin exacerbated respiratory disease
FEV: forced expiratory volume, AEC: absolute eosinophil count
: 1= significantly worse, 2= somewhat worse, 3= same, 4= somewhat improved, 5= significantly improved
omalizumab: 26 months, benralizumab: 1 month,
omalizumab: 13.9 years, benralizumab: 23 months,
omalizumab: 4 years, dupilumab: 6 months
Descriptive and categorical variables were calculated and summarized. Wilcoxon signed-rank test was performed to test the difference between pre- and post- biologic initiation. All analyses were conducted in R 3.6.1 and SAS version 9.4 (The SAS Institute; Cary, NC). This study was approved by the Institutional Review Board.
All patients had comorbid asthma. Clinical characteristics and global physician assessment during biologic treatment are described in Table 1. The etiology of bronchiectasis was post-infectious in three (25%), a combination of post-infectious and immunodeficiency in one (8%), and idiopathic in eight (67%). The average IgE (±SD) prior to biologic initiation was 576.83±856 kU/L, and AEC (±SD) was 479±470 K/uL. Based on chest CT scans, eight of the 12 patients had bronchiectasis that predominated in the lower lobes. The remainder had: upper lobe predominant (1/12), right middle lobe (2/12), and central bronchiectasis (1/12). High attenuated mucus was seen in one of the 12 patients. Nodules were seen in the majority of the scans (8/12), whereas tree-in-bud pattern was seen in 1/12.
Use of biologics decreased median (IQR) monthly respiratory exacerbations (pre: 0.13[0–0.29] vs post: 0.0[0–0.11], P=0.02) and corticosteroid courses (pre: 0.17[0.04–0.29] vs post: 0.0[0.0–0.11], P=0.008). Systemic antibiotic courses for respiratory infections also were decreased, although it was not statistically significant (pre: 0.17[0.08–0.23] vs. post: 0.04[0.0–0.16], P=0.13). FEV1 (L) pre- vs post-biologic was not different (1.42[1.08–2.23] vs 1.75[1.05–2.19], P=0.2). On overall global physician assessment, eight patients (80%) had somewhat or significant improvement, and two (20%) were unchanged. Two patients on therapy less than 3 months were excluded from the evaluation.
Previous studies have reported that an allergic (i.e. allergic rhinitis, elevated IgE) and/or eosinophilic (i.e. CRS) phenotype may predispose to bronchiectasis, a relationship also observed in this study.5,6 In this case series, biologics were effective for treating patients with non-CF and non-ABPA bronchiectasis with an eosinophilic phenotype and/or coexisting allergic diseases. Our results add to the two reports from Europe, which observed benefit with mepolizumab and benralizumab in a small number of bronchiectasis patients with severe asthma.3,4 Our study demonstrates that this is more likely a general class effect of anti-type 2 biologics as our series included patients treated with dupilumab and omalizumab in addition to anti-IL-5 agents.
This study has several limitations. It is a single-center retrospective case series, and our study population may not be generalizable. Second, bronchiectasis is recognized as a heterogeneous disease, and the etiology of bronchiectasis was not uniform in this study. There was significant referral bias in our cohort as patients with bronchiectasis and type 2 comorbid diseases were specifically referred to our clinic for consideration of biologic therapy. Finally, asthma and bronchiectasis are both obstructive lung diseases and have considerable overlap. In our cohort of patients with bronchiectasis and concomitant asthma, it cannot be precisely determined how much of the observed effect from the biologic was due to the treatment of asthma versus bronchiectasis. This is an important group to analyze, and imaging with a high-resolution chest CT scan should be considered integral in the work-up of severe asthma as bronchiectasis is associated with significant morbidity and is increasingly recognized in patients with severe asthma. 1,7,8
Bronchiectasis guidelines highlight the heterogeneous nature of bronchiectasis, and experts suggest an endotype-targeted approach for the treatment of bronchiectasis.9 This case series is one of the first to show that treatment with biologics targeting type 2 inflammation leads to clinical improvement including reduction in corticosteroid courses, respiratory exacerbations, and systemic antibiotic courses in a subset of patients with bronchiectasis. While additional studies are needed to further elucidate the role of biologics in patients with bronchiectasis, this study suggests that biologics are a potential treatment option for the subgroup of patients with type 2 bronchiectasis not controlled with standard of care therapy.
Acknowledgments
Funding Sources: Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine; Chronic Rhinosinusitis Integrative Studies Program (NIH P01AI145818); NIH T32AI083216; Ernest Bazley Foundation.
Footnotes
Disclosures:
A. T. Peters is a consultant for Sanofi-Regeneron; consultant and receives research support from AstraZeneca and Optinose.
The remaining authors have no disclosures.
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