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Australian adults with bronchiectasis: The first report from the Australian Bronchiectasis Registry

Open ArchivePublished:July 16, 2019DOI:https://doi.org/10.1016/j.rmed.2019.07.016

      Highlights

      • The Australian Bronchiectasis Registry reports its first data.
      • Most patients had a moderate or high severity of disease (per FACED & BSI scores).
      • One third had airflow obstruction; normal spirometry does not rule out “severe” bronchiectasis.
      • Increasing disease severity is associated with poorer quality of life (QoL-B).
      • Frequent exacerbators (≥3/year) have poorer quality of life and greater health-care utilisation.

      Abstract

      Background

      /objective: There are no large, multi-centre studies of Australians with bronchiectasis. The Australian Bronchiectasis Registry (ABR) was established in 2015 to create a longitudinal research platform. We aimed to describe the baseline characteristics of adult ABR participants and assess the impact of disease severity and exacerbation phenotype on quality of life (QoL).

      Methods

      The ABR is a centralised database of patients with radiologically confirmed bronchiectasis unrelated to cystic fibrosis. We analysed the baseline data of adult patients (≥18 years).

      Results

      From March 2016–August 2018, 799 adults were enrolled from 14 Australian sites. Baseline data were available for 589 adults predominantly from six tertiary centres (420 female, median age 71 years (interquartile range 64–77), 14% with chronic Pseudomonas aeruginosa infection). Most patients had moderate or severe disease based on the Bronchiectasis Severity Index (BSI) (84%) and FACED (59%) composite scores. Using Global Lung function Initiative-2012 reference equations, the majority of patients (48%) had normal spirometry; only 34% had airflow obstruction (FEV1/FVC < LLN). Disease severity scores (BSI and FACED) were negatively correlated with QoL-Bronchiectasis domain scores (rs between −0.09 and −0.58). The frequent exacerbator phenotype (≥3 in the preceding year) was identified in 23%; this group had lower scores in all QoL-B domains (p ≤ 0.001) and more hospitalisations (p < 0.001) than those with <3 exacerbations.

      Conclusions

      The largest cohort of Australian adults with bronchiectasis has been described. Using contemporary criteria, most patients with bronchiectasis did not have airflow obstruction. The frequent exacerbation trait connotes poorer QoL and greater health-care utilisation.

      Keywords

      List of abbreviations

      ABPA
      Allergic Bronchopulmonary Aspergillosis
      ABR
      Australian Bronchiectasis Registry
      BMI
      Body Mass Index (kg/m2)
      BSI
      Bronchiectasis Severity Index
      COPD
      Chronic Obstructive Airways Disease
      CT-chest
      Computed Tomography scan of the chest
      FACED
      FEV1, Age, Colonisation, Extension, Dyspnoea
      FEV1
      Forced Expiratory Volume in 1 s
      FEV1%pred
      Forced Expiratory Volume in 1 s as a percent of predicted (per Global Lung function Initiative-2012 reference equations)
      FVC
      Forced Vital Capacity
      FVC%pred
      Forced Vital Capacity as a percent of predicted (per Global Lung function Initiative-2012 reference equations)
      GLI
      Global Lung function Initiative
      GORD
      Gastro-oesophageal Reflux Disease
      IQR
      Interquartile range
      LLN
      Lower Limit of Normal defined by the Global Lung function Initiative-2012 reference equations
      MABSC
      M. abscessus complex
      MCID
      Minimal Clinically Important Difference
      mMRC
      modified Medical Research Council dyspnoea scale
      n
      number of participants
      NTM
      Nontuberculous mycobacteria
      PCD
      Primary Ciliary Dyskinesia
      QoL
      Quality of Life
      QoL-B
      Quality of Life Questionnaire-Bronchiectasis
      TB
      Tuberculosis

      1. Introduction

      Bronchiectasis, a chronic lung disease defined radiologically by abnormal bronchial dilatation, is characterised clinically by chronic cough, sputum production and recurrent pulmonary exacerbations [
      • Polverino E.
      • Goeminne P.C.
      • McDonnell M.J.
      • Aliberti S.
      • Marshall S.E.
      • Loebinger M.R.
      • et al.
      European Respiratory Society guidelines for the management of adult bronchiectasis.
      ]. Patients with bronchiectasis are markedly heterogeneous with a diverse disease aetiology [
      • Polverino E.
      • Dimakou K.
      • Hurst J.
      • Martinez-Garcia M.-A.
      • Miravitlles M.
      • Paggiaro P.
      • et al.
      The overlap between bronchiectasis and chronic airway diseases: state of the art and future directions.
      ].
      The reported prevalence of bronchiectasis is increasing worldwide [
      • Seitz A.E.
      • Olivier K.N.
      • Adjemian J.
      • Holland S.M.
      • Prevots R.
      Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007.
      ,
      • Quint J.K.
      • Millett E.R.C.
      • Joshi M.
      • Navaratnam V.
      • Thomas S.L.
      • Hurst J.R.
      • et al.
      Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study.
      ,
      • Ringshausen F.C.
      • de Roux A.
      • Pletz M.W.
      • Hämäläinen N.
      • Welte T.
      • Rademacher J.
      Bronchiectasis-associated hospitalizations in Germany, 2005-2011: a population-based study of disease burden and trends.
      ]. Recent United Kingdom data estimates a prevalence of 566/100,000 women and 485/100,000 men [
      • Quint J.K.
      • Millett E.R.C.
      • Joshi M.
      • Navaratnam V.
      • Thomas S.L.
      • Hurst J.R.
      • et al.
      Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study.
      ], although significant geographic diversity exists [
      • Chandrasekaran R.
      • Mac Aogáin M.
      • Chalmers J.D.
      • Elborn S.J.
      • Chotirmall S.H.
      Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis.
      ]. Females, the elderly [
      • Seitz A.E.
      • Olivier K.N.
      • Adjemian J.
      • Holland S.M.
      • Prevots R.
      Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007.
      ,
      • Quint J.K.
      • Millett E.R.C.
      • Joshi M.
      • Navaratnam V.
      • Thomas S.L.
      • Hurst J.R.
      • et al.
      Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study.
      ,
      • Ringshausen F.C.
      • de Roux A.
      • Pletz M.W.
      • Hämäläinen N.
      • Welte T.
      • Rademacher J.
      Bronchiectasis-associated hospitalizations in Germany, 2005-2011: a population-based study of disease burden and trends.
      ] and indigenous populations [
      • Singleton R.J.
      • Valery P.C.
      • Morris P.
      • Byrnes C.A.
      • Grimwood K.
      • Redding G.
      • et al.
      Indigenous children from three countries with non‐cystic fibrosis chronic suppurative lung disease/bronchiectasis.
      ] are more commonly affected; notably, Indigenous children in Australia's Northern Territory have the highest reported disease prevalence of 1470/100,000 children [
      • Chang A.B.
      • Grimwood K.
      • Mulholland E.K.
      • Torzillo P.J.
      Working group on indigenous paediatric respiratory H. Bronchiectasis in indigenous children in remote Australian communities.
      ]. Nevertheless, no large multi-centre study has been conducted to examine the prevalence or characteristics of bronchiectasis in an Australian setting.
      The Australian Bronchiectasis Registry (ABR) is a nationwide collaboration established in 2015 with the aims of evaluating the clinical phenotypes of Australians with bronchiectasis and providing a platform for ongoing collaborative research. Documenting the varying characteristics of bronchiectasis among cohorts, countries and settings is important for patient management and for planning the delivery of health service [
      • Chandrasekaran R.
      • Mac Aogáin M.
      • Chalmers J.D.
      • Elborn S.J.
      • Chotirmall S.H.
      Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis.
      ]. Furthermore, in a heterogeneous condition for which licensed therapies are non-existent and recent clinical trials have not met their primary endpoints, defining targetable phenotypes is important to ensure trials meet their endpoints and to progress towards precision management for patients [
      • Haworth C.S.
      • Bilton D.
      • Chalmers J.D.
      • Davis A.M.
      • Froehlich J.
      • Gonda I.
      • et al.
      Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials.
      ,
      • Chalmers J.D.
      • Aliberti S.
      • Filonenko A.
      • Shteinberg M.
      • Goeminne P.C.
      • Hill A.T.
      • et al.
      Characterization of the "frequent exacerbator phenotype" in bronchiectasis.
      ,
      • Chalmers J.D.
      • Chotirmall S.H.
      Bronchiectasis: new therapies and new perspectives.
      ,
      • Grimwood A.B., K.C.
      A new dawn: inhaled antibiotics for patients with bronchiectasis.
      ]. We report the baseline characteristics of the ABR adult cohort, and assess the influence of disease severity and exacerbation phenotype on patient quality of life (QoL) and health-care utilisation.

      2. Methods

      2.1 The Australian Bronchiectasis Registry

      The ABR is a secure online database of Australian adults and children with bronchiectasis. Sites recruiting to the ABR are predominantly tertiary centres located across Australia. Eligible patients are those with a physician diagnosis of bronchiectasis with abnormal bronchial dilatation demonstrated on computed tomography chest scan (CT-chest) [
      • Webb W.R.
      ]. Patients with known cystic fibrosis are excluded. National ethical approval was obtained (Protocol No X16-0382, Project no HREC/15/CRGH/225), with local research governance approval subsequently granted at investigating sites. Further information is available in Appendix S1.

      2.2 Data collection and definitions

      At enrolment, participants’ baseline data were collected from the patient and by searching all available hospital and outpatient records, including electronic medical records. Baseline data were collected at times of clinical stability.
      The likely aetiology of bronchiectasis was determined by the treating physician and obtained from patient records.
      Spirometry results measured closest to the date of enrolment were collected. Global Lung function Initiative (GLI)-2012 reference equations were used to determine the upper/lower limits of normal (LLN) and percent of predicted forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) based on age, sex, height and ethnicity [
      • Quanjer P.
      • Stanojevic S.
      • Cole T.
      • Baur X.
      • Hall G.L.
      • Culver B.
      • et al.
      Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.
      ]. Airflow obstruction was defined as FEV1/FVC < lower limit of normal (LLN), normal spirometry as FEV1, FVC, and FEV1/FVC > LLN, and restrictive pattern spirometry as FEV1/FVC > LLN and FVC < LLN [
      • Culver B.H.
      • Graham B.L.
      • Coates A.L.
      • Wanger J.
      • Berry C.E.
      • Clarke P.K.
      • et al.
      Recommendations for a standardized pulmonary function report. An official American thoracic society technical statement.
      ].
      Details of CT chest performed closest to the date of enrolment were extracted from radiology reports, including the location of bronchiectasis and presence of cystic dilatation.
      Airway culture results were obtained for the period two years prior to, and three months after enrolment. Chronic infection was pragmatically defined as two or more positive cultures for the same organism during this period [
      • Finch S.
      • McDonnell M.J.
      • Abo-Leyah H.
      • Aliberti S.
      • Chalmers J.D.
      A comprehensive analysis of the impact of pseudomonas aeruginosa colonization on prognosis in adult bronchiectasis.
      ].
      Pulmonary exacerbations, defined by the treating physician, in the year preceding enrolment, were obtained from the patient and/or records.
      The Quality of Life Questionnaire-Bronchiectasis (QoL-B) [
      • Quittner A.L.
      • O'Donnell A.E.
      • Salathe M.A.
      • Lewis S.A.
      • Li X.
      • Montgomery A.B.
      • et al.
      Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and determination of minimal important difference scores.
      ] was completed by participants at enrolment.
      Bronchiectasis severity was quantified as “mild”, “moderate” or “severe” using validated, disease-specific composite scales – the Bronchiectasis Severity Index (BSI) [
      • Chalmers J.D.
      • Goeminne P.
      • Aliberti S.
      • McDonnell M.J.
      • Lonni S.
      • Davidson J.
      • et al.
      The bronchiectasis severity index an international derivation and validation study.
      ] and the FACED (FEV1, Age, Colonisation, Extension, Dyspnoea) [
      • Martínez-García M.Á.
      • de Gracia J.
      • Vendrell Relat M.
      • Girón R.-M.
      • Máiz Carro L.
      • de la Rosa Carrillo D.
      • et al.
      Multidimensional approach to non-cystic fibrosis bronchiectasis: the FACED score.
      ] score.

      2.3 Statistical analysis

      Patients <18yrs and those lacking the results of both CT-chest and spirometry were excluded (Fig. 1).
      Data are not normally distributed; results are presented as median and interquartile range (IQR). Descriptive statistics were used to characterise the demographics and disease features of the cohort.
      Analysis of patient characteristics by spirometric pattern (normal, obstructed, restricted) was performed using a Kruskal-Wallis (for continuous or ordinal dependent variables) or Chi-square test (for categorical dependent variables) to compare independent groups. The relationship between FEV1/FVC and disease severity (BSI and FACED scores) was assessed using Spearman's correlation (rs).
      Sub-group analysis of patient characteristics by cultured organism (P. aeruginosa, H. influenzae, nil organisms) was performed using a Kruskal-Wallis or Chi-square test. For this microbiological analysis, patients without airway culture results, those who cultured both H. influenzae and P. aeruginosa, and those with nontuberculous mycobacteria were excluded.
      Cohen's kappa coefficient (κ) was used to measure agreement between BSI and FACED-determined severity categories (mild, moderate, severe). The relationship between severity scores - BSI score (0-26) and FACED score (0–7) - and QoL-B domain scores (0–100) were explored with scatterplots. Subsequently, Spearman's correlation was performed between the BSI/FACED scores and QoL-B domain scores.
      The characteristics of patients with frequent (≥3 exacerbations in the preceding year) (10) versus non-frequent exacerbations were compared using a Mann-Whitney (for continuous or ordinal dependent variables) or Chi-square test (for categorical variables). Data were analysed in StataSE Version 15.1.621.

      3. Results

      Between March 2016 and August 2018, 14 sites across the Australian mainland recruited a total of 1053 patients to the ABR: 799 (76%) adults (42 Indigenous) and 254 (24%) paediatric participants (130 Indigenous). Of these, 589 adults, predominantly from six centres across the states of New South Wales (303 patients) and Queensland (272 patients) met the inclusion criteria for this study (Fig. 1). The demographics and clinical characteristics of the cohort are presented in Table 1, Table 2. Patients were predominantly Caucasian (86%) and female (71%), with a median age of 71 years (IQR 64–77). Physician-reported disease aetiology (Fig. 2) was mostly idiopathic (32.5%) or post-infective (28%).
      Table 1Demographics of adult registry participants.
      Resultn
      Age, years71 (64–77)589
      Gender589
       Female420 (71%)
       Male169 (29%)
      Ethnicity450
       Caucasian386 (86%)
       Asian48 (11%)
       Indigenous1 (0.2%)
       Other15 (3%)
      Body Mass Index, kg/m225 (22–29)499
      Smoking Status581
       Never451 (78%)
       Former123 (21%)
       Current7 (1%)
      Values are median (interquartile range) or proportions.
      n – number of participants for whom variable data was available.
      Table 2Baseline characteristics of the Australian adult bronchiectasis cohort.
      Resultn
      Spirometric Indices
       FEV1 %pred75 (57–91)499
       FVC %pred84 (71–97)498
      Normal Spirometry
      FEV1/FVC, FEV1, FVC > LLN.
      239 (48%)498
      Airflow Obstruction509
       FEV1/FVC < LLN168 (34%)498
       FEV1/FVC < 0.7252 (50%)
      Restrictive Pattern
      FEV1/FVC > LLN & FVC < LLN; ∧ Defined as 2 + airway cultures positive for the same pathogen.
      72 (15%)
      Radiology563
       Number of lobes affected3 (2–5)
       Cystic bronchiectasis81 (14%)
      Microbiology
       Airway culture available345
       AFB culture available169
      EverChronic
      P. aeruginosa119 (35%)49 (14%)345
      H. influenzae60 (17%)15 (4%)345
       Nontuberculous mycobacteria40 (24%)15 (9%)169
      Exacerbations in the last 12 months
       Total1 (0–2)557
       Number of respiratory hospitalisations0 (0–1)580
       Respiratory hospitalisation (Y)166 (29%)580
      Symptoms
       mMRC1 (0–2)570
       Limited exercise tolerance (mMRC>0)393 (69%)570
       Daily cough with sputum416 (71%)589
      Disease severity scores
       BSI10 (6–13)290
       FACED3 (2–4)310
      QoL-B Scores
      Out of a total of 100 possible points for each domain.
       Respiratory Symptoms67 (48–78)414
       Physical Functioning83 (67–100)414
       Vitality56 (33–67)414
       Role Functioning73 (47–87)414
       Health Perceptions60 (27–87)414
       Emotional Functioning83 (67–100)414
       Social Functioning58 (42–83)414
       Treatment Burden78 (56–89)414
      Values are median (interquartile range) or proportions.
      n - number of participants for whom variable data was available; FEV1 %pred – forced expiratory volume in 1 s, percent of predicted (GLI-2012); FVC – forced viral capacity; LLN - lower limit of normal (per GLI-2012); AFB – acid-fast bacillus; mMRC - modified Medical Research Council dyspnoea scale; BSI – Bronchiectasis Severity Index; FACED - FEV1, Age, Colonisation, Extension, Dyspnoea; QoL-B – Quality of Life Questionnaire-Bronchiectasis.
      # respiratory-related hospitalisations in the year preceding enrollment.
      a FEV1/FVC, FEV1, FVC > LLN.
      b FEV1/FVC > LLN & FVC < LLN; Defined as 2 + airway cultures positive for the same pathogen.
      c Out of a total of 100 possible points for each domain.
      Fig. 2
      Fig. 2Physician-reported aetiology of bronchiectasis in the Australian adult cohort (n = 566). NTM – nontuberculous mycobacteria; ABPA – allergic bronchopulmonary aspergillosis; PCD – primary ciliary dyskinesia; COPD – chronic obstructive lung disease; GORD – gastro-oesophageal reflux disease; TB- tuberculosis; CTD – connective tissue disease.

      3.1 Spirometry

      Airflow obstruction was present in 168 (34%) patients using the lower-limit of normal definition (FEV1/FVC < LLN) (15) versus 50% of the population when defined by the Global initiative for Chronic Obstructive Lung Disease criteria of FEV1/FVC<0.7 (20). Restrictive pattern spirometry was observed in 72 (15%) patients.
      The spirometric ratio (FEV1/FVC) was negatively correlated with bronchiectasis severity, measured by the FACED score (rs = −0.43, p < 0.001) and the BSI score (rs = −0.34, p < 0.001). Airflow obstruction was the predominant pattern in patients with severe disease; present in 40% of patients with BSI-severe disease and 60% of those with FACED-severe disease. Nevertheless, 36% of those with BSI-severe disease and 19% of those with FACED-severe disease had normal spirometry (Fig. 3).
      Fig. 3
      Fig. 3Severity of disease and spirometry.
      BSI; Bronchiectasis Severity Index; FACED; FEV1, Age, Colonisation, Extension, Dyspnoea; n - number of participants for whom all included variables were available for score calculation.
      Normal spirometry = 
      Forced Expiratory Volume in 1 s
      (FEV1), Forced Vital Capacity (FVC), and FEV1/FVC all > lower limit of normal per GLI-2012.
      Airflow Obstruction = 
      FEV1/FVC < LLN.
      Restrictive Pattern = 
      FEV1/FVC > LLN & FVC < LLN.
      Table 3 displays patient characteristics and QoL stratified by spirometric pattern. Compared to patients with normal spirometry, those with restrictive patterns and those with obstruction had more lobes involved, more exacerbations, were more likely to have been hospitalised in the preceding year, and had lower QoL-B scores (p < 0.05 for all comparisons).
      Table 3Analysis of baseline clinical characteristics and quality of life by spirometric pattern.
      Normal SpirometryAirflow ObstructionRestrictive Patternp-value
      n = 489239 (49%)168 (34%)72 (15%)
      Age (yrs)71 (63–78)69 (62–75)72 (63–78)0.05
      Ever smoked (Y)46 (19%)47 (29%)13 (18%)0.06
      Lobes affected3 (2–4)4 (2–6)4 (2–6)0.02
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      P. aeruginosa
      Isolation of P. aeruginosa on ≥1 sample.
      (Y)
      39 (16%)43 (26%)26 (36%)0.001
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      BSI8 (5–11)12 (8–15)11 (7–13)<0.001
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      FACED score2 (1–4)4 (3–5)3 (2–4)<0.001
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      Respiratory hospitalisation
      Within the year preceding enrollment.
      44 (18%)65 (39%)27 (38%)<0.001
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      No. of Exacerbations
      Within the year preceding enrollment.
      1 (0–2)2 (1–3)2 (0–3)0.001
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      QoL-B Domains
      Out of a total of 100 possible points for each domain.
      Respiratory Symptoms70 (58–82)56 (41–70)67 (41–78)<0.001
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      Physical Functioning73 (40–93)40 (13–73)40 (17–73)<0.001
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      Vitality56 (33–67)44 (33–56)44 (22–67)0.01
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      Role Perceptions80 (60–93)67 (33–83)53 (27–87)<0.001
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      Health Perceptions50 (33–67)42 (25–58)42 (22–58)<0.001
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      Emotional Functioning83 (67–100)83 (67–100)67 (58–92)0.049
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      Social Functioning67 (50–83)57 (33–78)66 (33–75)0.004
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      Treatment Burden77 (67–100)67 (57–89)67 (44–89)<0.001
      Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      Results are presented as median (interquartile range) or proportions.
      Normal spirometry = Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), and FEV1/FVC all > lower limit of normal per GLI-2012; Airflow Obstruction = FEV1/FVC < LLN; Restrictive Pattern = FEV1/FVC > LLN & FVC < LLN; n - number of participants for whom variable data was available; BSI - Bronchiectasis Severity Index; FACED - FEV1, Age, Colonisation, Extension, Dyspnoea; QoL-B – Quality of Life Questionnaire-Bronchiectasis.
      a Significant differences (α < 0.05) between independent groups on Kruskal-Wallis (for continuous/ordinal variables) or Chi-square test (for categorical variables).
      b Isolation of P. aeruginosa on ≥1 sample.
      c Within the year preceding enrollment.
      d Out of a total of 100 possible points for each domain.

      3.2 Microbiology

      Standard airway culture results were available for 345 (59%) patients. P. aeruginosa was the most commonly isolated organism (at least once in 35% of patients; 14% had chronic infection). H. influenzae was the second most common bacterium isolated (at least once in 17% of patients; 4% had chronic infection). S. aureus was cultured in 17 (5%) patients, was methicillin-sensitive in 16, and was chronic in 4 patients. No other single microorganism was isolated in ≥5% of the tested cohort.
      Results of mycobacterial testing were available in 169 (29%) patients. Of these, 40 patients (24%) had one or more positive results, which were predominantly M. intracellulare (23/40) and M. avium (11/40). M. abscessus complex (MABSC) was found in 6/40 patients and was chronic in 4/40.
      Of the 356 (60%) patients for whom any culture (standard and/or mycobacterial) was available, 117 (33%) had no microorganisms isolated. More than one organism was found in 49 (14%) patients in either the same or subsequent samples, however only four patients cultured both H. influenzae and P. aeruginosa.
      Patients with P. aeruginosa were older, with lower FEV1%pred, more frequent exacerbations and more hospitalisations than those with H. influenzae or no organisms cultured on testing. Patients with no organisms cultured had significantly higher FEV1%pred and FEV1/FVC, and fewer lobes affected than those with either P. aeruginosa or H. influenzae. Notably, QoL-B domain scores were similar across groups, with the exception of lower scores in the Treatment Burden domain in patients with P. aeruginosa (p < 0.05 for all stated comparisons, Table S1).

      3.3 Disease severity

      Fig. 3 displays the disease severity of the cohort, as defined by the BSI (18) and FACED (19) score. According to BSI, 58% of our cohort has severe disease, whereas 17% have FACED-defined severe disease. Weak agreement was found between the FACED and BSI severity categories (κ = 0.2, SE 0.03, p < 0.001).

      3.4 Quality of life

      Most patients expectorated sputum every day (71%) and experienced limited effort tolerance (69%) (modified Medical Research Council dyspnoea scale score ≥1). In the 12 months preceding enrolment, 29% of patients had been hospitalised for bronchiectasis. QoL-B scores were impaired in all domains.
      Negative linear associations between disease severity (BSI and FACED scores) and QoL (QoL-B domain scores) were seen on scatterplots. QoL and disease severity were most strongly correlated in the Physical (BSI rs = −0.47, FACED rs = −0.58) and Role Functioning domains (BSI rs = −0.42, FACED rs = −0.44) (p < 0.001 for all stated) – see Table S2.
      Table 4 displays the characteristics of disease according to exacerbation phenotype (10). Frequent exacerbators (≥3 in preceding year) had significantly lower QoL-B scores compared to those with <3 exacerbations, with differences exceeding the MCID for each domain. Frequent exacerbators had more respiratory hospitalisations, lower FEV1%pred, lower FEV1/FVC, and were more likely to have chronic P. aeruginosa infection, produce sputum daily, and have limited exercise tolerance (p < 0.05 for all comparisons).
      Table 4Characteristics of disease according to “Frequent Exacerbator” phenotype.
      <3 exacerbations/year
      Refers to number of pulmonary exacerbations in the year preceding enrolment.
      ≥3 exacerbations/year
      Refers to number of pulmonary exacerbations in the year preceding enrolment.
      Data Availablep-value
      n429 (77%)128 (23%)557
      Female308 (72%)92 (72%)5571.0
      Age, yrs71 (64–77)71.5 (64–77)5570.9
      BMI kg/m225 (22–29)26 (21–29)4710.7
      FEV1 %pred78 (62–92)67 (51–86)471<0.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      FEV1/FVC0.72 (0.64–0.79)0.66 (0.58–0.76)4820.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      P. aeruginosa (ever)73 (31%)41 (42%)3290.06
      P. aeruginosa (chronic)
      Defined as ≥2 airway cultures positive for the same pathogen.
      19 (8%)28 (29%)329<0.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      H. influenzae (ever)47 (20%)10 (10%)3290.03
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      H. influenzae (chronic)
      Defined as ≥2 airway cultures positive for the same pathogen.
      10 (4%)5 (5%)3290.7
      Limited exercise tolerance278 (66%)101 (82%)5460.002
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      Daily sputum285 (67%)105 (82%)5570.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      No. of hospitalisations
      Respiratory-related hospitalisations in the year preceding enrolment.
      0 (0–0)1(0–2)557<0.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      QoL-B Domains
      Out of a total of 100 possible points.
      Respiratory Symptoms70(52–78)54(33–67)393<0.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      Physical Functioning67 (33–87)33(10–67)393<0.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      Vitality56 (33–67)44 (22–56)3930.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      Role Functioning80(53–93)53(27–80)393<0.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      Health Perception50(33–67)33 (22–50)393<0.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      Emotional Functioning83(67–100)75(58–92)3930.005
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      Social Functioning67(42–83)50(25–75)393<0.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      Treatment Burden78(67–100)67(44–89)3930.001
      Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      Values are median (interquartile range) or proportions.
      n – number of participants; BMI – Body Mass Index; FEV1%pred – forced expiratory volume in 1 s, percent of predicted (per GLI-2012); FVC – forced vital capacity; QoL-B – Quality of Life Bronchiectasis.
      a Refers to number of pulmonary exacerbations in the year preceding enrolment.
      b Significant differences (α < 0.05) between independent groups on Mann-Whitney (for continuous variables) or Chi-square test (for categorical variables).
      c Defined as ≥2 airway cultures positive for the same pathogen.
      d Respiratory-related hospitalisations in the year preceding enrolment.
      e Out of a total of 100 possible points.

      4. Discussion

      In this report on the largest cohort (n = 589) of Australian adults with bronchiectasis, we describe important findings about bronchiectasis in the Australian context that have broader relevance.
      Although traditionally classified as an obstructive airways disease, it is recognised that patients with bronchiectasis can exhibit normal, restrictive, or mixed spirometric pattern [
      • Polverino E.
      • Goeminne P.C.
      • McDonnell M.J.
      • Aliberti S.
      • Marshall S.E.
      • Loebinger M.R.
      • et al.
      European Respiratory Society guidelines for the management of adult bronchiectasis.
      ]. American and European registries report airflow obstruction in approximately 50% of each cohort [
      • Chalmers J.D.
      • Goeminne P.
      • Aliberti S.
      • McDonnell M.J.
      • Lonni S.
      • Davidson J.
      • et al.
      The bronchiectasis severity index an international derivation and validation study.
      ,
      • Aksamit T.R.
      • O'Donnell A.E.
      • Barker A.
      • Olivier K.N.
      • Winthrop K.L.
      • Daniels M.L.A.
      • et al.
      Adult patients with bronchiectasis: a first look at the US bronchiectasis research registry.
      ] using the former diagnostic criteria of FEV1/FVC <0.70 [
      • Vestbo J.
      • Hurd S.S.
      • Agustí A.G.
      • Jones P.W.
      • Vogelmeier C.
      • Anzueto A.
      • et al.
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
      ]. Using this criterion, 50% of our cohort also had obstruction. In contrast, using the current definition [
      • Culver B.H.
      • Graham B.L.
      • Coates A.L.
      • Wanger J.
      • Berry C.E.
      • Clarke P.K.
      • et al.
      Recommendations for a standardized pulmonary function report. An official American thoracic society technical statement.
      ] of abnormality (below the lower limit of normal as determined by GLI-2012 reference equations [
      • Quanjer P.
      • Stanojevic S.
      • Cole T.
      • Baur X.
      • Hall G.L.
      • Culver B.
      • et al.
      Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.
      ]), we showed that the largest proportion (48%) of our patients had normal spirometry. Airflow obstruction (FEV1/FVC < LLN) was present in only one-third of patients. We found a moderate negative correlation between spirometric ratio and disease severity as measured by FACED and BSI. Nevertheless, a large proportion of those classified as having severe disease did not demonstrate obstruction (60% of BSI-severe, 40% of FACED-severe).
      To our knowledge, this is the largest bronchiectasis study to examine spirometric pattern using the current LLN criteria. It demonstrates that even patients with “severe” bronchiectasis, as defined by validated composite scores that incorporate radiology and predict mortality [
      • Chalmers J.D.
      • Goeminne P.
      • Aliberti S.
      • McDonnell M.J.
      • Lonni S.
      • Davidson J.
      • et al.
      The bronchiectasis severity index an international derivation and validation study.
      ,
      • Martínez-García M.Á.
      • de Gracia J.
      • Vendrell Relat M.
      • Girón R.-M.
      • Máiz Carro L.
      • de la Rosa Carrillo D.
      • et al.
      Multidimensional approach to non-cystic fibrosis bronchiectasis: the FACED score.
      ], often do not meet the current diagnostic criterion for airflow obstruction and may have normal spirometry. We also showed that both obstructive and restrictive patterns are associated with poorer QoL and increased exacerbations and hospitalisations. As reporting of spirometry based on LLN per GLI becomes more widespread, it is important to recognise that normal results do not exclude clinically significant or even “severe” bronchiectasis and its attendant morbidity and mortality [
      • Chalmers J.D.
      • Goeminne P.
      • Aliberti S.
      • McDonnell M.J.
      • Lonni S.
      • Davidson J.
      • et al.
      The bronchiectasis severity index an international derivation and validation study.
      ,
      • Martínez-García M.Á.
      • de Gracia J.
      • Vendrell Relat M.
      • Girón R.-M.
      • Máiz Carro L.
      • de la Rosa Carrillo D.
      • et al.
      Multidimensional approach to non-cystic fibrosis bronchiectasis: the FACED score.
      ].
      Most of the Australian cohort had moderate or severe bronchiectasis (84% according to the BSI, 59% according to the FACED score). The weak agreement between severity scores and the tendency for the BSI to assign patients a higher severity grade than FACED is consistent with recent literature [
      • McDonnell M.
      • Aliberti S.
      • Goeminne P.
      • Dimakou K.
      • Zucchetti S.
      • Davidson J.
      • et al.
      Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts.
      ]. While both scores predict mortality, BSI has also been shown to predict exacerbations and QoL (per St George Respiratory Questionnaire) [
      • McDonnell M.
      • Aliberti S.
      • Goeminne P.
      • Dimakou K.
      • Zucchetti S.
      • Davidson J.
      • et al.
      Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts.
      ]. In our cohort, weak to moderate negative correlations were seen between severity scores (BSI and FACED) and QoL-B domain scores; the strongest negative correlations were seen with the Physical and Role Functioning domains. These findings highlight the difficulty of comprehensively appreciating QoL with existing tools in a complex condition such as bronchiectasis [
      • Dudgeon E.K.
      • Crichton M.
      • Chalmers J.D.
      The missing ingredient": the patient perspective of health related quality of life in bronchiectasis: a qualitative study.
      ,
      • Olveira C.
      • Martínez-García M.A.
      Health-related quality of life questionnaires in bronchiectasis: the simplest way to quantify complexity.
      ], but also suggest that there are clinical factors impacting QoL which are not captured in severity scores. Additionally, local prospective studies are required to determine the validity of the Qol-B and the BSI and FACED severity scores in Australian patients, especially in Indigenous Australians. As an example, a recent study found that Aboriginal Australians with bronchiectasis had lower FACED scores (due to younger age and less P. aeruginosa) but higher 5-year respiratory-related mortality than non-indigenous patients, and suggested that recalibration of age scoring may be required for Indigenous patients [
      • Blackall S.R.
      • Hong J.B.
      • King P.
      • Wong C.
      • Einsiedel L.
      • Rémond M.G.
      • et al.
      Bronchiectasis in indigenous and non‐indigenous residents of Australia and New Zealand.
      ].
      Most patients within our cohort have a daily productive cough, making sputum collection feasible. However, only 29% had mycobacterial culture results available, of which 24% had NTM isolated and 9% had chronic NTM. These were predominantly M. avium and M intracellulare, however M. abscessus complex (MABSC) was cultured in 6 patients, and was chronic in 4 patients. NTM have long been recognised as a cause or complication of bronchiectasis, however the increasing prevalence of NTM in bronchiectasis patients is now appreciated [
      • Haworth C.S.
      • Banks J.
      • Capstick T.
      • Fisher A.J.
      • Gorsuch T.
      • Laurenson I.F.
      • et al.
      British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).
      ]. Of particular concern are MABSC; multidrug-resistant NTM with the potential for person-to-person spread and a contraindication to lung transplant in many centres [
      • Bryant J.M.
      • Grogono D.M.
      • Rodriguez-Rincon D.
      • Everall I.
      • Brown K.P.
      • Moreno P.
      • et al.
      Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium.
      ]. In patients with bronchiectasis, mycobacterial cultures are recommended at diagnosis, periodically for surveillance in stable spontaneously expectorating patients, during times of clinical or radiological deterioration, and prior to and during long-term macrolide therapy [
      • Haworth C.S.
      • Banks J.
      • Capstick T.
      • Fisher A.J.
      • Gorsuch T.
      • Laurenson I.F.
      • et al.
      British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).
      ,
      • Floto R.A.
      • Olivier K.N.
      • Saiman L.
      • Daley C.L.
      • Herrmann J.-L.
      • Nick J.A.
      • et al.
      US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.
      ,
      • Chang A.B.
      • Bell S.C.
      • Byrnes C.A.
      • Grimwood K.
      • Holmes P.W.
      • King P.T.
      • et al.
      Chronic suppurative lung disease and bronchiectasis in children and adults in Australia and New Zealand.
      ]. Therefore, these ABR data serve as a useful guide as to where simple tests should be utilised more frequently to improve diagnostic yield and optimise infection control and treatment.
      Clinical phenotyping has been advocated as a strategy to minimise patient heterogeneity within bronchiectasis clinical trials and facilitate delivery of precision medicine [
      • Chalmers J.D.
      • Aliberti S.
      • Filonenko A.
      • Shteinberg M.
      • Goeminne P.C.
      • Hill A.T.
      • et al.
      Characterization of the "frequent exacerbator phenotype" in bronchiectasis.
      ,
      • Grimwood A.B., K.C.
      A new dawn: inhaled antibiotics for patients with bronchiectasis.
      ,
      • Aksamit T.
      • De Soyza A.
      • Bandel T.J.
      • Criollo M.
      • Elborn J.S.
      • Operschall E.
      • et al.
      RESPIRE 2: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis.
      ,
      • Aliberti S.
      • Lonni S.
      • Dore S.
      • McDonnell M.J.
      • Goeminne P.C.
      • Dimakou K.
      • et al.
      Clinical phenotypes in adult patients with bronchiectasis.
      ]. The recently identified “frequent exacerbator” phenotype (≥3 exacerbations/year) is associated with an increased 5-year mortality [
      • Chalmers J.D.
      • Aliberti S.
      • Filonenko A.
      • Shteinberg M.
      • Goeminne P.C.
      • Hill A.T.
      • et al.
      Characterization of the "frequent exacerbator phenotype" in bronchiectasis.
      ], and in recent clinical trials frequent exacerbators experienced greater benefit from inhaled ciprofloxacin than non-frequent exacerbators [
      • Haworth C.S.
      • Bilton D.
      • Chalmers J.D.
      • Davis A.M.
      • Froehlich J.
      • Gonda I.
      • et al.
      Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials.
      ]. In the present study, frequent exacerbators comprised 23% of the cohort, experienced more hospitalisations, higher symptom burden and poorer QoL, representing a group that may benefit from more intensive treatment and monitoring. Further, the higher prevalence of P. aeruginosa in frequent exacerbators in our study argues for surveillance and directed treatment of this organism [
      • Bell S.C.
      • Elborn J.S.
      • Byrnes C.A.
      Bronchiectasis: treatment decisions for pulmonary exacerbations and their prevention: pulmonary exacerbations in bronchiectasis.
      ].
      This study has a number of limitations. The ABR currently recruits patients attending tertiary centres with an interest in bronchiectasis, and potentially selects patients with prominent symptoms, more severe disease, and/or a higher prevalence of NTM. Data completeness limits the number of participants who can be evaluated; consequently this analysis predominantly represents non-indigenous patients from six sites on the East Coast of Australia. Patients with missing variable data were removed from the denominator of each variable; this may introduce some bias into our estimates. Furthermore, at this early point in registry operations, only cress-sectional data are available. Presently, the registry does not have an electronic repository of CT images. The use of the term “physician-reported aetiology” throughout the paper reflects the characteristics of an observational registry, where the degree to which aetiology is investigated is physician-dependant and historical aetiological test results are not always available. “Exacerbations” are currently defined by the treating physician, due to the lack of a validated consensus definition of pulmonary exacerbations in non-cystic fibrosis bronchiectasis. The ABR plans to improve data collection and completeness and recruit from a broader range of health providers and sites in the future. Finally, this study aimed to describe the adult cohort comprehensively, however the ABR also recruits children. These paediatric data will be presented in time as the cohort increases.
      The establishment of the ABR has allowed description of the characteristics of the largest cohort of Australian adults with bronchiectasis within 3 years of inception. These data reveal that many patients with bronchiectasis have normal spirometry, even in the presence of “severe” disease as defined by current composite severity scores. This study highlights the opportunity for improved sputum collection in Australian patients, particularly for mycobacterial testing. It demonstrates the negative influence of frequent exacerbations on QoL and health-care utilisation, and highlights a clinical phenotype that could be targeted in a treatable traits approach to bronchiectasis management. Longitudinal studies, including validation of widely used severity scores and the QoL-B questionnaire, are required in Australian patients with bronchiectasis.

      5. Declarations of interest

      None.

      Declaration of interests

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

      Acknowledgements

      We would like to acknowledge the late A/Prof David Serisier for his crucial role in the design and establishment of the Australian Bronchiectasis Registry.
      The ABR is an initiative of Lung Foundation Australia and was established with the generous support of sponsors Aradigm, Bayer HealthCare, Insmed and philanthropic donations. These sponsors had no input to the interpretation of data or preparation of the manuscript. We thank all the participants as well as all clinicians, volunteers and support staff.
      ABC is funded by a National Health and Medical Research Council (NHMRC) practitioner fellowship (grant 1154302) and SKV by a NHMRC postgraduate scholarship (grant 1134081).

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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