Clinical characteristics of the asthma bronchiectasis phenotype.

Bronchiectasis is defined as irreversible bronchial dilatation typically associated with characteristic radiologic and clinical features.1Hill AT Sullivan AL Chalmers JD De Soyza A Elborn SJ Floto AR et al.British Thoracic Society Guideline for bronchiectasis in adults.Thorax. 2019; 74: 1-69Crossref Scopus (233) Google Scholar Its prevalence in asthma varies but is generally accepted to be higher in patients with more severe disease (range 25%-68%), especially in the presence of allergic fungal sensitization.2Matsumoto H. Bronchiectasis in severe asthma and asthmatic components in bronchiectasis.Respir Investig. 2022; 60: 187-196Crossref PubMed Scopus (7) Google Scholar A previous analysis revealed that the asthma bronchiectasis (AB) phenotype is related to higher blood eosinophil counts.3Coman I Pola-Bibián B Barranco P Vila-Nadal G Dominguez-Ortega J Romero D et al.Bronchiectasis in severe asthma: clinical features and outcomes.Ann Allergy Asthma Immunol. 2018; 120: 409-413Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar However, the same study found no differences in spirometry compared with patients having asthma without bronchiectasis.3Coman I Pola-Bibián B Barranco P Vila-Nadal G Dominguez-Ortega J Romero D et al.Bronchiectasis in severe asthma: clinical features and outcomes.Ann Allergy Asthma Immunol. 2018; 120: 409-413Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Another large retrospective study4Kim NY Lee CH Jin KN Lee HW Heo EY Kim DK et al.Clinical deterioration and lung function change in patients with concomitant asthma and bronchiectasis.J Allergy Clin Immunol Pract. 2022; 10 (e4): 2607-2613Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar found that patients with AB had lower forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) coupled with a significantly greater history of tuberculosis and nontuberculous mycobacterial lung disease. Nevertheless, there is limited data regarding differences in clinical characteristics in patients having asthma with vs without bronchiectasis. Hence, in the present study, we aimed to compare clinical phenotypes in patients with AB vs asthma alone (AO). A total of 74 moderate-to-severe adult patients with asthma from our National Health Service clinic were included in this retrospective cohort study. This population comprised 37 patients with concomitant bronchiectasis and 37 controls matched for age, nasal polyps, and the dose of inhaled corticosteroid. Here, we sought to determine differences in demographics, spirometry, type 2 (T2) biomarkers, asthma control, exacerbation frequency, and mucus plug scores (MPS) between the 2 groups. The presence of bronchiectasis was identified on high-resolution computed tomography (HRCT) scans performed in volumetric mode on the basis of the following criteria: nontapering bronchus with an internal diameter of 110% or greater than the adjacent pulmonary artery or the presence of visible bronchi within 1 cm of the costal pleural surface or adjacent to the mediastinal pleural surface.1Hill AT Sullivan AL Chalmers JD De Soyza A Elborn SJ Floto AR et al.British Thoracic Society Guideline for bronchiectasis in adults.Thorax. 2019; 74: 1-69Crossref Scopus (233) Google Scholar The joint European Respiratory Society and American Thoracic Society guidelines were followed for spirometry (Micromedical, Chatham, United Kingdom). Peripheral blood eosinophil (PBE) counts were averaged over 1 year because of temporal variability.5Corren J Du E Gubbi A Vanlandingham R. Variability in blood eosinophil counts in patients with eosinophilic asthma.J Allergy Clin Immunol Pract. 2021; 9 (e9): 1224-1231Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Fractional exhaled nitric oxide (FeNO) was measured using Niox Vero (Circassia, Oxford, United Kingdom) according to the manufacturer's instructions and American Thoracic Society guidelines. Asthma control was obtained using the Asthma Control Questionnaire and the number of oral corticosteroid courses required for severe exacerbations over the past 12 months was retrieved from medical records. Mucus plugging was identified by an experienced thoracic radiologist using a previous protocol.6Dunican EM Elicker BM Gierada DS Nagle SK Schiebler ML Newell JD et al.Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction.J Clin Invest. 2018; 128: 997-1009Crossref PubMed Scopus (296) Google Scholar The radiologist was blinded to all clinical data except the information that patients had moderate-severe asthma. The HRCT scans were performed in volumetric mode with maximal inspiration, as per standard department protocol (128-slice computed tomography Revolution EVO, GE Healthcare). Computed tomography reconstruction was performed in the lung window with a slice thickness of 1 to 1.25 mm and no interval gap. Images were analyzed in an axial plane, with coronal and sagittal reconstruction used as necessary. The HRCT scans were performed within 1 year of pulmonary function testing, T2 inflammatory markers, and asthma control data. All measurements were taken before patients started biologic therapy. The Statistical Package for the Social Sciences version 27 was used to perform statistical analysis. Independent t or Mann-Whitney U tests were implemented to compare continuous variables according to patient group (AB and AO) using a 2-tailed alpha error set at 0.05. Values are presented as means (SEM) or median (interquartile range). Caldicott's approval was obtained before any data collection. Demographic data are presented in Table 1. Patients with AB had significantly higher PBE counts together with a higher mucus plug burden than patients with AO (Table 1). There were no differences in spirometry measurements, asthma control levels, frequency of exacerbations, FeNO levels, or total immunoglobulin E levels.Table 1Comparisons in Spirometry, Asthma Control, Exacerbations, Type 2 Inflammation, and Mucus Plug Scores in Patients With Asthma Bronchiectasis (AB) vs Asthma Only (AO)CharacteristicAO (n = 37)AB (n = 37)P valueAge (y)52 (2)56 (2).25ICS BDP (µg)1792 (62)1746 (69).62Nasal polyps (%)30%30%> .99White (%)100%100%> .99BMI (kg/m2)30.7 (0.8)28.7 (1.0).12Sex (F/M)20/1726/11.15FEV1 (L)2.23 (0.13)2.38 (0.15).45FEV1%80.8 (4.0)83.7 (4.2).62FEF25-75 (L/s)1.54 (0.17)1.65 (0.18).67FEF25-75%45.1 (4.6)48.2 (4.7).63FVC (L)3.36 (0.17)3.54 (0.17).46FVC%100.4 (3.2)101.8 (3.3).77FEV1/FVC66.1 (2.1)66.9 (2.3).80ACQ2.7 (0.2)2.3 (0.2).24OCS exacerbations4 (4)3 (3).65PBE (cells/µL)360 (333)440 (290).03aP value is less than .05.FeNO (ppb)25 (40)20 (41).59Total IgE (Ku/L)118 (338)170 (380).73A. fumigatus IgE (Ku/L)0.03 (0.16)0.07 (0.82).07A. fumigatus IgG (mg/L)16.80 (26.93)17.20 (25.65).80Mucus plug score0 (3)4 (7).002bP value is less than .01.Abbreviations: AB, asthma bronchiectasis; ACQ, asthma control questionnaire; AO, asthma only; BMI; body mass index; F, female; FEF25-75, forced expiratory flow rate between 25 and 75% of FVC; FeNO, Fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS BDP, inhaled corticosteroid beclomethasone diproprionate equivalent dose; IgE, immunoglobulin E; IgG, immunoglobulin G; IQR, interquartile range; M, male; OCS, oral corticosteroid; PBE, peripheral blood eosinophil; ppb, parts per billion; T2, type 2 inflammation.NOTE. Demographics, spirometry, and ACQ as means (SEM); OCS exacerbations, T2 biomarkers, and mucus plug scores as medians (IQR). Bold denotes significant P-value.a P value is less than .05.b P value is less than .01. Open table in a new tab Abbreviations: AB, asthma bronchiectasis; ACQ, asthma control questionnaire; AO, asthma only; BMI; body mass index; F, female; FEF25-75, forced expiratory flow rate between 25 and 75% of FVC; FeNO, Fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS BDP, inhaled corticosteroid beclomethasone diproprionate equivalent dose; IgE, immunoglobulin E; IgG, immunoglobulin G; IQR, interquartile range; M, male; OCS, oral corticosteroid; PBE, peripheral blood eosinophil; ppb, parts per billion; T2, type 2 inflammation. NOTE. Demographics, spirometry, and ACQ as means (SEM); OCS exacerbations, T2 biomarkers, and mucus plug scores as medians (IQR). Bold denotes significant P-value. In a separate analysis of the AB group, a MPS cut point of 5 identified patients with worse airflow obstruction (Table 2).Table 2Comparisons in Spirometry, Asthma Control, Exacerbations and Type 2 Inflammation in Patients With Asthma Bronchiectasis According to Low (0 – 4) vs High Mucus Plug Scores (≥5)CharacteristicMPS <5 (n = 19)MPS ≥5 (n = 18)P valueFEV1 (L)2.57 (0.23)2.18 (0.17).19FEV1%90.0 (5.5)77.1 (6.1).13FEF25-75 (L/s)2.03 (0.27)1.25 (0.18).03aP value is less than .05.FEF25-75%58.5 (7.0)37.6 (5.3).02aP value is less than .05.FVC (L)3.56 (0.27)3.51 (0.19).88FVC%102.8 (4.2)100.7 (5.3).76FEV1/FVC71.6 (3.4)61.9 (2.7).03aP value is less than .05.ACQ2.6 (0.3)2.1 (0.4).31OCS exacerbations3 (3)4 (3).85PBE (cells/µL)400 (239)510 (480).16FeNO (ppb)15 (21)38 (73).09Total IgE (kU/L)91 (395)190 (293).71A. fumigatus IgE (kU/L)0.02 (0.28)0.19 (1.06).11A. fumigatus IgG (mg/L)12.47 (14.10)26.00 (34.70).03aP value is less than .05.Abbreviations: AB, asthma bronchiectasis; ACQ, asthma control questionnaire; AO, asthma only; BMI; body mass index; FEF25-75, forced expiratory flow rate between 25 and 75% of FVC; FeNO, Fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS BDP, inhaled corticosteroid beclomethasone dipropionate equivalent dose; IgE, immunoglobulin E; IgG, immunoglobulin G; IQR, interquartile range; MPS, mucus plug score; OCS, oral corticosteroid; PBE, peripheral blood eosinophil; ppb, parts per billion; T2, type 2 inflammation.NOTE. Spirometry and ACQ as means (SEM); OCS exacerbations and T2 biomarkers as medians (IQR). Bold denotes significant comparison.a P value is less than .05. Open table in a new tab Abbreviations: AB, asthma bronchiectasis; ACQ, asthma control questionnaire; AO, asthma only; BMI; body mass index; FEF25-75, forced expiratory flow rate between 25 and 75% of FVC; FeNO, Fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS BDP, inhaled corticosteroid beclomethasone dipropionate equivalent dose; IgE, immunoglobulin E; IgG, immunoglobulin G; IQR, interquartile range; MPS, mucus plug score; OCS, oral corticosteroid; PBE, peripheral blood eosinophil; ppb, parts per billion; T2, type 2 inflammation. NOTE. Spirometry and ACQ as means (SEM); OCS exacerbations and T2 biomarkers as medians (IQR). Bold denotes significant comparison. Our findings are in keeping with a previous study3Coman I Pola-Bibián B Barranco P Vila-Nadal G Dominguez-Ortega J Romero D et al.Bronchiectasis in severe asthma: clinical features and outcomes.Ann Allergy Asthma Immunol. 2018; 120: 409-413Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar reporting that patients having asthma with bronchiectasis exhibit higher PBE counts than those without bronchiectasis. In the same study,3Coman I Pola-Bibián B Barranco P Vila-Nadal G Dominguez-Ortega J Romero D et al.Bronchiectasis in severe asthma: clinical features and outcomes.Ann Allergy Asthma Immunol. 2018; 120: 409-413Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar the authors noted more frequent hospitalization for asthma exacerbations in patients with AB; although, in keeping with our study, there were no differences in overall exacerbation occurrence. Higher PBE counts are associated with greater reductions in exacerbation frequency with anti–interleukin 5 therapy,7Pavord ID Korn S Howarth P Bleecker ER Buhl R Keene ON et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.Lancet. 2012; 380: 651-659Abstract Full Text Full Text PDF PubMed Scopus (1709) Google Scholar with a previous study reporting improvements in mucus plugging and ventilation heterogeneity in patients with eosinophilic asthma treated with the anti–interleukin 5Rα biologic benralizumab.8McIntosh MJ Kooner HK Eddy RL Jeimy S Licskai C Mackenzie CA et al.Asthma control, airway mucus, and 129Xe MRI ventilation after a single benralizumab dose.Chest. 2022; 162: 520-533Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Bronchiectasis in asthma can manifest itself as eosinophilic or chronic infectious bronchiectasis, with targeted biologic therapy evidenced to be more effective in the former.2Matsumoto H. Bronchiectasis in severe asthma and asthmatic components in bronchiectasis.Respir Investig. 2022; 60: 187-196Crossref PubMed Scopus (7) Google Scholar In the present study, there were no detectable differences in FeNO between the 2 groups (Table 1), perhaps, in part, because of the high daily dose of inhaled corticosteroids. Notably, it was important to account for the presence of nasal polyps as the latter has been associated with greater PBE counts and FeNO levels.9Chan R Lipworth B Impact of nasal polyps on endotype and phenotype in patients with moderate to severe asthma.Ann Allergy Asthma Immunol. 2021; 127: 548-552Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar A recent large retrospective study4Kim NY Lee CH Jin KN Lee HW Heo EY Kim DK et al.Clinical deterioration and lung function change in patients with concomitant asthma and bronchiectasis.J Allergy Clin Immunol Pract. 2022; 10 (e4): 2607-2613Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar reported that, compared with the AO group, patients with AB had significantly lower FEV1 and FVC, although bronchiectasis was associated with higher exacerbation rates. In this regard, it has previously been found that asthma exacerbations are closely associated with lung function decline,10Soremekun S, Heaney LG, Skinner D, Bulathsinhala L, Carter V, Chaudhry I, et al. Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study [e-pub ahead of print]. Thorax. doi:10.1136/thorax-2021-217032. Accessed November 22, 2022.Google Scholar potentially adding a confounding variable to the analysis.4Kim NY Lee CH Jin KN Lee HW Heo EY Kim DK et al.Clinical deterioration and lung function change in patients with concomitant asthma and bronchiectasis.J Allergy Clin Immunol Pract. 2022; 10 (e4): 2607-2613Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar In contrast, patients with AO in our study were matched for disease severity and demographics and there were no differences in asthma control or exacerbations. The MPS scores were significantly higher in the AB group in keeping with previous data.6Dunican EM Elicker BM Gierada DS Nagle SK Schiebler ML Newell JD et al.Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction.J Clin Invest. 2018; 128: 997-1009Crossref PubMed Scopus (296) Google Scholar Here, we found that FEV1/FVC and the forced expiratory flow rate between 25 and 75% of FVC were significantly more impaired in patients with AB having MPS of greater than or equal to 5 compared with those having MPS less than 5, with the latter amounting to a difference of 20.9%, which is likely to be clinically relevant. The MPS cut point of 5 was arbitrarily used here to allow for relatively equal numbers of patients in both comparison groups. Moreover, patients with MPS 5 and higher also exhibited significantly higher levels of Aspergillus fumigatus specific immunoglobulin G, indicating greater previous exposure. When the analysis was repeated with the median MPS cut point of 4, results were similar albeit with less balanced numbers. We recognize the potential limitations of this study, including its retrospective nature and results coming from a single center. All the patients in this study were White and, therefore, the results can potentially only be extrapolated to this population. There was also data trend toward higher body mass indices, which can confer worse spirometry in patients with asthma.11Farah CS Kermode JA Downie SR Brown NJ Hardaker KM Berend N et al.Obesity is a determinant of asthma control independent of inflammation and lung mechanics.Chest. 2011; 140: 659-666Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar However, in this regard, there were no ethnic or body mass index differences between the 2 comparison groups. Future studies may wish to use these results for a longitudinal study with larger numbers, perhaps including the effect of biologic therapy to definitively characterize the effect of mucus plug severity in the AB phenotype.