ORIGINAL ARTICLE

Aetiology of bronchiectasis in Guangzhou, southern China

WEI-JIE GUAN,1* YONG-HUA GAO,2* GANG XU,3 ZHI-YA LIN,1 YAN TANG,1 HUI-MIN LI,1 ZHI-MIN LIN,1

JIN-PING ZHENG,1 RONG-CHANG CHEN1 AND NAN-SHAN ZHONG1

1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, GuangzhouInstitute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, 3Department of Geriatrics

Medicine, Guangzhou First People’s Hospital, Guangzhou, Guangdong, and 2Department of Respiratory and Critical CareMedicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

ABSTRACT

Background and objective: Aetiologies of bronchiec-tasis in mainland China and their comparisons withthose in western countries are unknown. We aimed toinvestigate bronchiectasis aetiologies in Guangzhou,southern China, and to determine ethnic or geographicdifferences with reports from western countries.Methods: Consecutive patients with steady-statebronchiectasis were randomly recruited. Past historywas meticulously extracted. Patients underwent physi-cal examination, saccharine test, humoral immunityassays, gastroesophageal reflux scoring and sputumculture. Fiberoptic bronchoscopy, total immunoglobinE (IgE) and Aspergillus fumigatus-specific IgE meas-urement, 24-h gastroesophageal pH monitoring andmiscellaneous screening tests were performed, if indi-cated. This entailed comparisons on aetiologies withliterature reports.Results: We enrolled 148 patients (44.6 ± 13.8 years,92 females), most of whom had mild to moderate bron-chiectasis. Idiopathic (46.0%), post-infectious (27.0%)and immunodeficiency (8.8%) were the most commonaetiologies. Miscellaneous aetiologies consisted ofasthma (5.4%), gastroesophageal reflux (4.1%), asper-gillosis (2.7%), congenital lung malformation (2.0%),Kartagener syndrome (1.4%), rheumatoid arthritis(1.4%), chronic obstructive pulmonary disease (0.7%),Young’s syndrome (0.7%), yellow nail’s syndrome(0.7%), eosinophilic bronchiolitis (0.7%) and foreignbodies (0.7%). No notable differences in clinical char-acteristics between idiopathic and known aetiologieswere found. Ethnic or geographic variations of aetiolo-gies were overall unremarkable.

Conclusions: Idiopathic, post-infectious and immu-nodeficiency constitute major bronchiectasis aetiolo-gies in Guangzhou. Clinical characteristics of patientsbetween known aetiologies and idiopathic bronchiecta-sis were similar. Ethnicity and geography only accountfor limited differences in aetiologic spectra. These find-ings will offer rationales for early diagnosis and man-agement of bronchiectasis in future studies and clinicalpractice in China.

Key words: aetiology, bronchiectasis, clinical characteristic,diagnostic test, idiopathic.

Abbreviations: ABPA, allergic bronchopulmonary aspergillosis;COPD, chronic obstructive pulmonary disease; FEV1, forcedexpiratory volume in 1 s; FVC, forced vital capacity; GERD,gastroesophageal reflux disease; HRCT, high-resolution com-puted tomography; MMEF, maximal mid-expiratory flow.

INTRODUCTION

Bronchiectasis is a heterogeneous disease charac-terized by chronic cough, sputum production,haemoptysis and fever1–4 that results from variousaetiologies. Ethnic or geographic variations wereshown to contribute to different aetiologic spectraamong different studies, for instance, idiopathicbronchiectasis accounted for around 50% in westerncountries5–9 and 80% in Hong Kong, China.10

Symptoms, signs, disease severity and prognosisof bronchiectasis differ considerably with different

Correspondence: Rong-chang Chen, State Key Laboratory ofRespiratory Disease, National Clinical Research Center for Res-piratory Disease, Guangzhou Institute of Respiratory Disease,First Affiliated Hospital of Guangzhou Medical University, 151Yanjiang Road, Guangzhou, Guangdong, China. Email: chenrc@vip.163.com

*Wei-jie Guan and Yong-hua Gao share joint first authorship.Received 28 October 2014; invited to revise 13 December 2014

and 8 January 2015; revised 21 December 2014 and 13 January2015; accepted 19 January 2015 (Associate Editor: Chi ChiuLeung).

Article first published online: 26 March 2015

SUMMARY AT A GLANCE

This is the first report on bronchiectasis aetiologiesin mainland China. Idiopathic, post-infectious andimmunodeficiency were the most common aeti-ologies. No significant differences were found inethnicity or geography. Our findings will shed lighton early diagnosis and management of bronchiec-tasis in future studies and clinical practice inChina.

bs_bs_banner

© 2015 Asian Pacific Society of Respirology Respirology (2015) 20, 739–748doi: 10.1111/resp.12528

aetiologies. Pseudomonas aeruginosa infection elic-ited worsening of symptoms11 and rapid lung functiondecline2 in cystic fibrosis. Importantly, aetiologicassessment may shift treatment paradigms.6 Childrenwith bronchiectasis related to primary ciliary dyskine-sia, aspiration and immunodeficiency would benefitconsiderably from aetiology-targeted therapies.7

Global prevalence of bronchiectasis was estimatedto be 1.5∼17.8 per 10 000,12 and the morbidity increas-ing with age.13 China accounts for one fifth of world’spopulation, yet lacks epidemiologic profiles of bron-chiectasis. Comparatively poor hygiene andhealthcare conditions could lead to higher prevalenceof bronchiectasis and different aetiologic spectracompared with western countries. Guangzhou is amajor city in southern China, with a population ofover 10 million, with representative characteristics ofsoutheastern Asians. Investigation into bronchiecta-sis aetiology in this group is urgently indicated, andmight improve treatment outcomes and provideinsights into future clinical trials.

We hypothesized that bronchiectasis aetiologies inmainland Chinese patients differed from those ofwestern countries, with a higher proportion of post-infectious bronchiectasis.

We sought to determine the aetiologies and clinicalcharacteristics of bronchiectasis in Guangzhou, andto compare with literature reports, thus unravelingethnic or geographic differences.

METHODS

Patients

Between September 2012 and November 2013, bron-chiectasis patients aged 18–75 years were consecu-tively recruited from outpatient respiratory clinics, forperforming serial studies on steady-state bronchiec-tasis (Guangzhou Bronchiectasis Study). Patients withbronchiectasis exacerbations upon physician’s refer-ral were scheduled for inclusion at least 4 weekspost-exacerbation. Bronchiectasis was diagnosedbased on chest high-resolution computed tomogra-phy (HRCT)2,5,6,10 and symptoms (chronic coughing,sputum production and/or haemoptysis). Patientswith asymptomatic bronchiectasis and malignancywere excluded.

This study was approved by Ethic Committee ofFirst Affiliated Hospital of Guangzhou Medical Uni-versity. Patients gave written informed consent.

Chest HRCT scoring

Chest HRCT at 2 mm collimation within 12 months,when clinically stable, was evaluated. A specialistradiologist with at least 10 years of experience ofHRCT review who was blinded to patient’s conditionsperformed systematic evaluation, including modi-fied Reiff score, predominantly middle lobe bronchi-ectasis, dyshomogeneity, atelectasis, aspergilloma,cystic bronchiectasis and pulmonary infiltration.Consultancy of a second radiologist was sought ifappropriate.

Lingular was deemed a separate lobe. For individ-ual lobes, bronchiectasis was scored: 0 for no, 1 for

tubular, 2 for varicose and 3 for cystic bronchiectasis.Maximal total score was 18 for six lobes.14 Diseaseseverity was assessed using Bronchiectasis SeverityIndex.15

Summarized methods for

determining aetiologies

Patients were meticulously questioned about theirpast and present medical history, followed by physicalexamination, chest (and nasal, if indicated) HRCT,spirometry, diffusing capacity measurement, venousblood sampling (blood routine test and immu-noglobins), sputum culture, saccharine test andsimplified reflux questionnaire interview. Patientssusceptible of having gastroesophageal reflux disease(GERD), aspergillosis, asthma or chronic obstructivepulmonary disease (COPD) underwent 24-h oesopha-geal pH monitoring, serum total and Aspergillusfumigatus-specific IgE test, and bronchial dilationtest, respectively. Hemagglutinin and auto-antibodieswere tested for susceptible diffuse panbronchiolitisand connective tissue diseases, respectively. Otherdiagnostic tests (i.e. bronchoscopy, gastroscopy)could be performed if appropriate (Table 1,Figure S1). See Supplementary Appendix S1 forhumoral immunity assessment, nasal saccharine test,sputum culture, diffusing capacity measurement andspirometry.

Serum total and A. fumigatus-specific IgE

These measurements were conducted in patientswith wheezing and/or brownish sputum, elevatedperipheral blood (>0.4 × 109/L) and (or) sputumeosinophil count (>2.5%), and predominantly centralairway bronchiectasis. IgE was assayed usingImmunoCAP microplate reader (Phadia AB, Uppsala,Sweden). Compatible history with serum total IgE>170 kU/L5 and aspergillus-specific IgE >0.35 kU/Lsuggested allergic bronchopulmonary aspergillosis(ABPA) as the aetiology of bronchiectasis.

Gastroesophageal reflux

GERD questionnaire was employed for screening(Table S1), with the total score of 12 or greater indi-cating high probability of GERD,17 which warranted24-h oesophageal pH monitoring (see SupplementaryAppendix S1).

History of reflux was meticulously extracted. Inpatients with confirmed history (gastroscopy, gastrec-tomy for physician-diagnosed reflux, oesophagealresistance tested positive), GERD was deemed theaetiology if onset of reflux-associated events werechronologically followed by chronic cough andsputum production. Otherwise, GERD was consid-ered as a mere concomitant disease.

Post-infectious bronchiectasis

During hospital visits, we meticulously inquiredpast histories of infectious diseases associated withbronchiectasis pathogenesis, including measles,

W Guan et al.740

© 2015 Asian Pacific Society of RespirologyRespirology (2015) 20, 739–748

pertussis, tuberculosis, childhood and adulthoodpneumonia. We meticulously determined thesequence of symptoms onset and bronchiectasis,prognosis and relevant treatments. To minimizerecall bias, we inquired patients regarding the char-acteristics of infectious diseases or any of their pasthistory, and verified this via detailed medical chartsand chest HRCT review. Patient’s replies were syste-matically recorded in medical records during inter-views. If bronchiectasis symptoms developed afterinfection,16,18 post-infectious bronchiectasis wasdeemed the aetiology. History of childhood infectionwas ascertained by detailed inquiry of patient’srelatives.

Diagnostic criteria of miscellaneous

aetiologies16

See Supplementary Appendix S1.

Statistical analysis

Statistical analysis was performed using SPSS 16.0version package (SPSS Inc., Chicago, IL, USA).Kolmogorov–Smirnov test was conducted to deter-mine normality of distribution for continuous vari-ables, which were expressed as mean ± standarddeviation or median (interquartile range) as appro-priate. Two-sided independent t-test was adopted fornormal distribution, otherwise non-parametric test.

Table 1 Summarized methods for determining the main aetiologies of bronchiectasis

Aetiology MethodsScreening ofall subjects References

Post-infectious History inquiry Yes 6,16

Immunodeficiency History inquirySerum immunoglobin titres assay

Yes 6,7,16

Gastroesophageal reflux disease History inquirySimplified reflux questionnaire24-h pH monitoring (if indicated)

Yes 16,17

Aspergillosis History inquirySymptomsChest HRCT charactersSerum IgE (if indicated)Aspergillosis fumigatus-specific IgE titres

(if indicated)

No 5,6,16

Kartagener syndrome Chest HRCTHistory inquiryPhysical examinationSaccharine test

Yes 6,16

Young’s syndrome Nasal CTPhysical examinationHistory inquirySperm examination (if indicated)

No 6,16

Yellow nail syndrome Chest HRCTPhysical examinationHistory inquiryConsultation of dermatologists (if indicated)

No 6,16

Connective tissue diseases Chest HRCTPhysical examinationHistory inquirySerum auto-immune antibodies

No 6,16

Asthma History inquiryPhysical examinationBronchial dilation/provocation testAspergillosis fumigatus-specific IgE titres for

exclusion of aspergillosis)

No 16

Chronic obstructivepulmonary disease

History inquiryPhysical examinationBronchial dilation test

No 16

Lung maldevelopment History inquiryPhysical examinationChest HRCT

Yes NA

Idiopathic Exclusion of all known aetiologies NA 5,6,16

CT, computed tomography; HRCT, high-resolution computed tomography; NA, not applicable.

Aetiology of bronchiectasis in Guangzhou 741

© 2015 Asian Pacific Society of Respirology Respirology (2015) 20, 739–748

Categorical data were expressed as number (percent-age) and analysed using chi-square tests. P < 0.05 wasdeemed statistically significant.

RESULTS

Subject recruitment and comparison of

clinical characteristics between male and

female patients

The recruitment process is outlined in Figure 1. Twopatients were twin sisters and five had family historyof bronchiectasis. Age of onset was normally distrib-uted (Figure S2) and culminated between 30 and 60years.

Most patients were females (62.2%), with a higherproportion of never-smokers compared with males(P < 0.01). Most patients had ventilatory dysfunction(obstructive, restrictive or mixed type). Gender differ-ences in the past history, bronchiectasis exacerba-tions, HRCT scores and concomitant medicationswere unremarkable (all P > 0.05) (Table 2).

Socioeconomic status

For a description of the information on the socioeco-nomic status of the study participants, see the Sup-plementary Appendix S1.

Sputum bacteriology

Four patients failed to produce sputum. Of 144patients, 57 (39.58%) isolated commensals. Of 97culture-positive patients, 44 (29.7%) isolated P.aeruginosa, 15 (10.1%) Haemophilus parain-fluenzae and 14 (9.5%) Haemophilus influenzae.Overall positive rate for non-tuberculosis Myco-bacteria was 3.5% (n = 5). Nine patients (sevenfemales) with predominantly middle/lingular lobebronchiectasis tested negative for non-tuberculosisMycobacteria (data not shown).

Aetiologic spectra

Aetiologic spectra are shown in Figure 2. Of knownaetiologies, post-infectious accounted for 27.0%(n = 40), of which post-measles (n = 14, 9.5%) andpost-tuberculous (n = 16, 10.8%) were most common,followed by immunodeficiency (n = 13, 8.8%) andasthma (n = 8, 5.4%). Miscellaneous known aetiolo-gies accounted for 8.8%. Patients with Kartagenersyndrome, lung maldevelopment, foreign body andYoung’s syndrome were comparatively younger uponenrolment. Patients with post-measles, aspergillosis,rheumatoid arthritis and diffuse panbronchiolitisharboured more bronchiectatic lobes leading tohigher HRCT scores. Idiopathic (48.91%), post-

Figure 1 Recruitment flowchart. *Saccharine tested positive denoted a nasal mucociliary clearance time being 60 min or greater. Sinuscomputed tomography (CT) was performed following saccharine test because sinus disease was considered the cause of prolongednasal mucociliary clearance time (NMCC) in a subgroup of patients. The male patient with Young’s syndrome was not tested for primaryciliary dyskinesia because of the unavailability of measuring tools. NTM, non-tuberculous mycobacteria; DPB, diffuse panbronchiolitis.

W Guan et al.742

© 2015 Asian Pacific Society of RespirologyRespirology (2015) 20, 739–748

Table 2 Clinical characteristics

ParameterAll patients

(n = 148)Male

(n = 56)Female(n = 92) P value*

Anthropometry Age (years) 44.6 ± 13.8 43.4 ± 13.0 44.6 ± 14.2 0.78Height (cm) 160.0 (10.0) 167.4 ± 5.8 157.1 ± 5.7 <0.01Weight (kg) 52.0 (10.5) 58.9 ± 9.3 49.5 ± 7.3 <0.01BMI (cm/kg2) 20.0 (3.9) 21.0 ± 3.2 20.1 ± 3.0 0.18Never-smoker (No., %) 131 (88.52) 40 (71.43) 91 (98.91) <0.01

Spirometry FVC (L) 2.58 ± 0.87 3.28 (1.17) 2.23 ± 0.68 <0.01FVC pred% 81.79 (26.34) 78.73 ± 19.03 78.49 ± 21.08 0.97FEV1 (L) 1.91 ± 0.75 2.26 ± 0.80 1.70 ± 0.64 <0.01FEV1 pred% 70.37 ± 23.76 68.68 ± 22.52 71.41 ± 24.56 0.55FEV1/FVC (%) 75.70 (16.40) 70.58 ± 13.40 76.65 (14.75) 0.05MMEF (L) 1.68 ± 0.98 1.88 ± 1.15 1.55 ± 0.85 0.14MMEF pred% 56.79 ± 30.53 55.53 ± 32.14 57.58 ± 29.65 0.79

Disease-related parameters Duration of symptoms (years) 10.0 (16.0) 10.0 (17.0) 10.0 (15.0) 0.54Duration of diagnosis (years) 3.0 (9.0) 3.0 (6.0) 3.0 (9.0) 0.73No. of acute exacerbations in 2 years 3.0 (4.0) 3.0 (3.0) 3.0 (3.0) 0.19No. of severe acute exacerbations in

2 years†

1.0 (3.0) 1.0 (2.0) 1.0 (3.0) 0.91

No. of hospitalizations in 2 years 0.0 (1.0) 0.0 (1.0) 0.0 (1.0) 0.47No. of bronchiectatic lobes 4.0 (2.0) 4.0 (2.0) 4.0 (3.0) 0.62HRCT total score 7.0 (5.0) 6.0 (6.0) 7.0 (4.0) 0.20Bronchiectasis Severity Index 6.0 (7.0) 5.6 ± 3.9 6.0 (6.0) 0.4124-h sputum volume (mL) 20.0 (25.0) 20.0 (25.0) 17.5 (26.0) 0.86

Concomitant medicationswithin 6 months

Inhaled corticosteroids (No., %) 30 (20.27) 12 (21.43) 18 (19.56) 0.78Mucolytics (No., %) 109 (73.65) 40 (71.43) 69 (75.00) 0.63Macrolides (No., %) 64 (43.24) 27 (48.21) 37 (40.22) 0.34Theophylline (No., %) 88 (59.46) 34 (60.71) 54 (58.70) 0.81

Continuous data were expressed as mean (standard deviation) for normal distribution or otherwise median (interquartile range).Categorical data were expressed as number (percentage).

*P value for the comparisons between both genders, comparisons of rates were conducted by using chi-square tests.†Severe acute exacerbations denoted the exacerbation requiring intravenous antibiotics, emergency visits or hospitalizations.BMI, body mass index; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; MMEF, maximal mid-expiratory flow.

Figure 2 Aetiologic spectra ofbronchiectasis.

Aetiology of bronchiectasis in Guangzhou 743

© 2015 Asian Pacific Society of Respirology Respirology (2015) 20, 739–748

infectious (28.26%) and GERD (4.35%) were morecommon among females. Furthermore, 145 patientshad single aetiology and three (two females) had dualaetiologies. No patient had inflammatory boweldisease.

Humoral immunity

Humoral immunodeficiency was found in 13 patients(8.8%), none of whom had selective IgA deficiency.Selective IgM deficiency (1.4%) and hypogammaglo-bulinemia (0.7%) was found in two patients and onepatient, respectively. IgG1, IgG2, IgG3 and IgG4 defi-ciency was identified in one (0.7%), two (1.4%), four(2.8%) and nine patients (6.1%), in conjunction withtwo patients who had combined variant immunodefi-ciency (1.4%), unanimously yielded normal Hib-IgGlevels (Table S3). See further details in SupplementaryAppendix S1.

GERD

Of 15 suspected GERD patients, 11 yielded a totalscore of 12 or greater for simplified reflux question-naire. Of these, six tested positive to oesophageal pHmonitoring but GERD was not deemed the aetiology.GERD was suspected in one patient who tested nega-tive to oesophageal pH monitoring and four patientswho declined measurement. Of six patients withGERD-associated bronchiectasis, three tested posi-tive to oesophageal pH monitoring (one patientyielded reflux score of 11 and was on regular anti-reflux medications), one had history of physician-diagnosed reflux but declined oesophageal pHmonitoring and the remaining two patients had refluxscore of 0 and were diagnosed as having bile reflux,and reflux plus erosive oesophagitis, that were ame-liorated by antacid therapy (Table S4).

Aspergillosis

Serum total and A. fumigatus-specific IgE levels aredisplayed in Table S5. IgE was not assayed in onepatient with aspergilloma, confirmed by broncho-scopic biopsy. Of 10 remaining patients, three yieldedincreased total and A. fumigatus-specific IgE, ofwhom massive aspergilloma was found in one patientand ABPA in two remaining patients.

Miscellaneous known aetiologies

Of eight asthmatic patients who achieved bettersymptom control following regular treatments, nonehad abnormal diffusing capacity.

Kartagener syndrome was diagnosed in twopatients with dextrocardia (excluding traction-induced situs inversus) and rhinosinusitis. Neitherpatient had reduced diffusing capacity, one withphysician-diagnosed infertility had prolonged nasalmucociliary clearance time (>60 min).

Rheumatoid arthritis was diagnosed in two patientswith extremity deformity, significantly increasedserum rheumatoid factor titres and prolonged history.Reduced diffusing capacity was found in one patient.No patient harboured other connective tissue dis-

eases (i.e. Sjogren’s disease) based on physical exami-nation and serum auto-immune antibodies (ifindicated).

Lung maldevelopment, evidenced by chest walldeformity, unilateral destroyed lung and stenosis ofmain bronchus, was noted in two patients, in whomchildhood post-pneumonic bronchiectasis had beenexcluded. Spirometry was markedly reduced (forcedvital capacity (FVC) < 1.0 L in one patient) but diffus-ing capacity remained normal in one patient.

COPD, lung sequestration, yellow nail syndrome,diffuse panbronchiolitis, eosinophilic bronchiolitis,Young’s syndrome and bronchial foreign body(pencil) were considered as bronchiectasis aetiologiesin seven remaining patients. Despite that airflow limi-tation was common, only one patient presented withreduced diffusing capacity (yellow nail syndrome)(Table S6).

Known aetiologies versus idiopathic

bronchiectasis

Apart from higher forced expiratory volume in 1 s(FEV1) and maximal mid-expiratory flow (MMEF) inidiopathic bronchiectasis (P < 0.05), there were nonotable differences in other clinical parameters(P > 0.05). FVC and FEV1/FVC were numerically butnot statistically higher in idiopathic bronchiectasis(Table 3).

DISCUSSION

This is the first study documenting bronchiec-tasis aetiologies in mainland China. Our cohortconsisted predominantly of females and had mild-to-moderate bronchiectasis. Idiopathic, post-infectiousand immunodeficiency were the most commonaetiologies. Differences in clinical characteristicsbetween idiopathic bronchiectasis and known aeti-ologies were unremarkable. No significant ethnic orgeographic differences in bronchiectasis aetiologieswere noted.

Consistent with literature, post-infectious bron-chiectasis remained common, which might haveresulted from poor hygiene conditions in 1960s∼1970s. Despite that neonatal vaccination programmehas dramatically curbed infectious diseases, impactsof infection should not be underestimated, particu-larly in developing countries.

Immunodeficiency accounted for 10% of aetiolo-gies and consisted of cellular immunodeficiency,antibody deficiency and defected antibody produc-tion.5,6,19 Demerits of costs and complexity have ren-dered cellular immunodeficiency impractical forroutine screening. Patients with normal or borderlinereduced immunoglobins might be defective in anti-body production.5 Unfortunately, the fact thatpatients declined vaccination rendered it impracticalto fully investigate antibody production deficiency,which might have underestimated the proportion ofimmunodeficiency.

Conventional screening of cystic fibrosis and α1anti-trypsin deficiency included sweat test, nasal

W Guan et al.744

© 2015 Asian Pacific Society of RespirologyRespirology (2015) 20, 739–748

potential test and serum anti-trypsin assay andgenotyping. Both diseases have been extremely scarcein Asian countries20; routine screening was not rec-ommended by British Thoracic Society guidelines.16

Potential underdiagnosis could be neglected.Notably, the complexity, time-consuming and

costly nature of comprehensive assessments mighthave resulted in overestimation of idiopathic bron-chiectasis. The fact that idiopathic bronchiectasismight have antibody production deficiency calledinto question the utility of currently availableapproaches.8,9 In contrast to literature,21 we foundunremarkable differences except for FEV1 and MMEFbetween known aetiologies and idiopathic bronchiec-tasis. However, the inclusion criteria and study designmight help interpret these disparities.

Apart from two reports focusing on childhoodbronchiectasis, most enrolled adults (mostly females)aged 44–60 years. Ethnicity mainly comprised Ameri-can, African, Hispanic and Hong Kong Chinese(Table 4). Consistently, idiopathic bronchiectasisconstituted 50% ∼ 80% in all but three articles.6,10,21 Ofknown aetiologies, post-infectious was the mostcommon (10% ∼ 32% vs 27% in Guangzhou). Immu-nodeficiency ranged from 0% to 17% in adults (8.8%in Guangzhou). Apart from three studies regardingadulthood6,10 and childhood bronchiectasis,7 primaryciliary dyskinesia accounted for 10% or less (1.4%in our study). However, ABPA was more common inwestern countries (7%, 8%, 4% and 4% vs 1.4% inGuangzhou).5,6,18,19 Similar with western countries(∼11%18), asthma was not uncommon in our study

Table 3 Comparison on clinical profiles between known aetiologies and idiopathic bronchiectasis

ParameterIdiopathic

(n = 68)

Knownaetiology(n = 80) P value

Anthropometry Age (years) 45.3 ± 13.9 44.0 ± 13.8 0.57Height (cm) 161.2 ± 7.6 160.0 (8.8) 0.68Weight (kg) 52.0 (9.8) 53.0 ± 10.3 0.57BMI (cm/kg2) 20.1 (3.8) 20.3 ± 3.1 0.93Current smoker (%) 1 (1.5) 4 (5.0) 0.37Ex-smoker (%) 4 (5.9) 9 (11.3) 0.74

Disease-related indices Age of onset (years) 31.8 ± 17.1 28.9 ± 16.6 0.34Duration of bronchiectasis (years) 10.0 (14.0) 10.0 (15.0) 0.45Duration of confirmed diagnosis (years) 3.0 (3.0) 2.0 (5.5) 0.48Acute exacerbations within 2 years 3.0 (4.0) 3.0 (4.0) 0.66Chronic rhinosinusitis (%) 17 (25.0) 19 (23.8) 0.86

Imaging and other clinicalcharacteristics

No. of bronchiectatic lobes 3.0 (3.0) 4.0 (3.0) 0.24HRCT score 6.0 (5.0) 7.0 (5.0) 0.74Bronchiectasis Severity Index 6.0 (7.0) 5.5 (6.0) 0.84Bilateral bronchiectasis (%) 55 (80.9) 66 (82.5) 0.80Predominantly middle/lower lobe bronchiectasis (%) 53 (77.9) 52 (65.0) 0.08Peripheral bronchiectasis (%) 25 (36.8) 27 (33.8) 0.70Central with peripheral bronchiectasis (%) 43 (63.2) 52 (65.0) 0.82Cystic bronchiectasis (%) 38 (55.9) 44 (55.0) 0.91

Sputum culture (isolation)* Pseudomonas aeruginosa (%) 24 (35.3) 21 (26.3) 0.23Haemophilus influenzae (%) 6 (8.8) 8 (10.0) 0.81Haemophilus parainfluenzae (%) 4 (5.9) 11 (13.8) 0.19Other potentially pathogenic bacteria (%) 5 (7.4) 9 (11.3) 0.42Commensals (%) 29 (42.6) 32 (40.0) 0.74

Sputum culture (colonization)* Pseudomonas aeruginosa (%) 21 (30.9) 18 (22.5) 0.25Other potentially pathogenic bacteria (%) 4 (5.9) 6 (7.5) 0.95No (%) 43 (63.2) 56 (70.0) 0.49

Lung function FVC pred% 83.4 ± 19.8 81.1 (26.5) 0.07FEV1 pred% 79.6 (32.7) 66.9 ± 20.3 0.01

FEV1/FVC (%) 75.7 ± 12.1 71.5 ± 12.9 0.07MMEF pred% 65.8 ± 34.1 51.0 ± 25.0 <0.01

DLCO pred% 89.9 ± 17.6 89.7 (18.1) 0.55DLCO/VA pred% 103.6 ± 13.5 103.6 (17.7) 0.65

Continuous data were expressed as mean (standard deviation) for normal distribution or otherwise median (interquartile range).Categorical data were expressed as number (percentage). Bold face indicated the comparisons with statistical significance.

*Isolation denoted sputum culture positive for once within 1 year; colonization denoted sputum culture positive for an identicalbacteria for at least twice within 1 year. Sputum culture was missing in four subjects, of whom three cases did not yield sufficientsputum volume and the remaining patient declined sputum induction.

BMI, body mass index; DLCO, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forcedvital capacity; HRCT, high-resolution computed tomography; MMEF, maximal mid-expiratory flow.

Aetiology of bronchiectasis in Guangzhou 745

© 2015 Asian Pacific Society of Respirology Respirology (2015) 20, 739–748

Tab

le4

Co

mp

aris

on

on

bro

nch

iect

asis

aeti

olo

gie

sw

ith

pu

blis

hed

liter

atu

rere

po

rts

Lite

ratu

reN

atio

n

Maj

or

aeti

olo

gie

sLe

ssco

mm

on

aeti

olo

gie

s

Idio

pat

hic

Po

st-i

nfe

ctio

us

Imm

un

od

efici

ency

AB

PAG

ER

DP

CD

Asp

irat

ion

Ast

hm

aM

isce

llan

eou

s

Eva

ns

etal

.22U

nit

edK

ing

do

m35

(71%

)6

(12%

)2

(4%

)0

(0%

)6

(4%

)0

(0%

)0

(0%

)0

(0%

)C

on

nec

tive

tiss

ue

dis

ease

:6

(6%

)P

aste

ur

etal

.5U

nit

edK

ing

do

m80

(53%

)44

(29%

)12

(8%

)11

(7%

)6

(4%

)3

(1.5

%)

0(0

%)

0(0

%)

RA

:4

(3%

)U

C:

2(<

1%)

You

ng

’ssy

nd

rom

e:5

(3%

)C

F:4

(3%

)D

PB

:1

(<1%

)C

on

gen

ital

:1

(<1%

)M

cSh

ane

etal

.21U

nit

edS

tate

s7

(7%

)20

(19%

18(1

7%)

1(1

%)

0(0

%)

3(3

%)

12(1

1%)

0(0

%)

Au

toim

mu

ne

dis

ease

:33

(31%

)H

emat

olo

gic

mal

ign

ancy

:15

(14%

)A

nti

α1-t

ryp

sin

defi

cien

cy:

12(1

1%)

Mo

un

ier-

Ku

hn

syn

dro

me:

1(1

%)

Am

ylo

ido

sis:

1(1

%)

Sm

oki

ng

inh

alat

ion

:1

(1%

)B

ron

chia

lo

bst

ruct

ion

:1

(1%

)K

ing

etal

.19A

ust

ralia

76(7

4%)

10(1

0%)

9(9

%)

4(4

%)

0(0

%)

1(1

%)

0(0

%)

11(1

1%)

RA

:2

(2%

)Yo

un

g’s

syn

dro

me:

1(1

%)

CO

PD

:3

(3%

)S

ho

emar

ket

al.6

Un

ited

Kin

gd

om

43(2

6%)

52(3

2%)

11(7

%)

13(8

%)

0(0

%)

17(1

0%)

2(1

%)

0(0

%)

UC

:5

(3%

)Yo

un

g’s

syn

dro

me:

5(3

%)

DP

B:

4(2

%)

Yello

wn

ail

syn

dro

me:

4(2

%)

NT

Min

fect

ion

:4

(2%

)R

A:

3(2

%)

CF:

2(1

%)

An

war

etal

.16U

nit

edK

ing

do

m82

(43%

)46

(24%

)2

(1%

)7

(4%

)2

(1%

)2

(1%

)0

(0%

)6

(3%

)R

A:

9(5

%)

UC

:5

(2%

)C

OP

D:

23(1

2%)

An

tiα1

-try

psi

nd

efici

ency

:2

(1%

)Yo

un

g’s

dis

ease

:1

(<1%

)P

ink’

sd

isea

se:

1(<

1%)

Cys

tic

fib

rosi

s:1

(<1%

)Li

etal

.7U

nit

edK

ing

do

m35

(26%

)5

(4%

)46

(34%

)0

(0%

)0

(0%

)20

(15%

)25

(18%

)0

(0%

)C

on

gen

ital

:5

(4%

)Tw

iss

etal

.12N

ewZ

eala

nd

35(5

4%)

14(2

2%4

(6%

)0

(0%

)0

(0%

)0

(0%

)4

(6%

)0

(0%

)P

ost

-on

colo

gy:

8(1

1%)

Gu

anet

al.

(th

isst

ud

y)M

ain

lan

dC

hin

a68

(46%

)40

(27%

)13

(8.8

%)

2(1

.4%

)6

(4%

)N

A0

(0%

)8

(5%

)K

arta

gen

ersy

nd

rom

e:2

(1.4

%)

Rh

eum

ato

idar

thri

tis:

2(1

.4%

)Yo

un

g’s

syn

dro

me:

1(0

.7%

)C

OP

D:

1(0

.7%

)Ye

llow

nai

lsy

nd

rom

e:1

(0.7

%)

Lun

gm

alfo

rmat

ion

:3

(2.0

%)

Eo

sin

op

hili

cb

ron

chio

litis

:1

(0.7

%)

Fore

ign

bo

dy:

1(0

.7%

)

AB

PA,a

llerg

icb

ron

cho

pu

lmo

nar

yas

per

gill

osi

s;D

PB

,dif

fuse

pan

bro

nch

iolit

is;G

ER

D,g

astr

oes

op

hag

ealr

eflu

xd

isea

se;N

TM

,no

n-t

ub

ercu

lou

sM

yco

bac

teri

um

;PC

D,p

rim

ary

cilia

ryd

yski

nes

ia;R

A,r

heu

mat

oid

arth

riti

s;U

C,

ulc

erat

ive

colit

is.

W Guan et al.746

© 2015 Asian Pacific Society of RespirologyRespirology (2015) 20, 739–748

(5%). These overall similarities could be reflected byrapid urbanization in southern China, where grossdomestic product steadily increased. In other ruralareas of China, post-infectious, immunodeficiencyor ABPA might be more common. Multicentre studiesinvestigating bronchiectasis aetiologies in otherregions of China are urgently indicated.

Pseudomonas aeruginosa (10% ∼ 30%) andH. influenzae (∼39%7) were predominant pathogens.In contrast, H. influenzae accounted for 8% in ourcohort. Commensals isolation has been commonexcept for one study22 (Table 5). The high preva-lence of P. aeruginosa (30%) and low prevalence ofH. influenzae (8%) merit comments. The disparitymight be associated with extensive application of anti-biotics in China, growing prevalence of multidrug-resistant P. aeruginosa, ethnicity, meteorology and theseverity of bronchiectasis. Consistent with Tsanget al.’s studies,2,23 P. aeruginosa has been the predomi-nant pathogen in Hong Kong, China.

In concert with our findings, most studies docu-mented ventilatory dysfunction (moderate decline inFEV1), suggesting that lung function impairment wasnot uncommon in milder forms of bronchiectasis andwarranted intensive follow-up management.

Our research protocol and principal findings havesignificantly updated the current Chinese expert con-sensus24 regarding bronchiectasis aetiology composi-tions, distribution and characteristics, and will offerblueprints for establishing standard diagnostic flow-charts for future clinical trials and healthcare practicein mainland China. Our findings also highlight theimportance of identifying aetiologies that might beassociated with prognosis and guide personalizedtherapy.

Some limitations deserve comments: (i) Ourpatient referral pattern might have overestimated‘severe’ bronchiectasis. However, under Chinesehealthcare framework, patients directly sought con-sultation in tertiary hospitals; our cohort was unlikelyto have selection bias of socioeconomic status(Table S7), confirming representativeness of localpopulation. (ii) Patients with asymptomatic bronchi-ectasis or other concomitant airway diseases (i.e.asthma, COPD) characterized by major symptomsother than bronchiectasis would have been excluded.

However, our principal goal was to characterizetypical bronchiectasis, but not mild (or even subtle)bronchiectasis with atypical symptoms secondary toother chronic respiratory diseases. (iii) COPD mighthave been underestimated. Twenty-nine per centof COPD patients reportedly had, in communitysettings, concomitant bronchiectasis.25 However,patients with emphysema had fewer never-smokersthan those without (65% vs 92%, P < 0.01). Differencesin median smoking pack-year numbers were alsoinsignificant (22.5 vs 12.5 pack-years, P = 0.30). (iv)Immunodeficiency and primary ciliary dyskinesiamight have been underscored. (v) Diagnosis of GERDremained challenging without assessment of aspira-tion. (vi) Recall bias was inevitable for diagnosingpost-infectious bronchiectasis.

In conclusion, idiopathic, post-infectious andimmunodeficiency are the most common bronchiec-tasis aetiologies in Guangzhou, China. No notable dif-ferences in aetiologic spectra are found in terms ofethnicity or geography. These may add new evidenceto current Chinese expert consensus and will guidefuture clinical practice in mainland China.

AcknowledgementsWe wholeheartedly thank Professor Kenneth Wah-Tak Tsang andJune Sun (LKS Faculty of Medicine, Hong Kong SAR, China) andWei Luo (Cough laboratory, State Key Laboratory of RespiratoryDisease, National Clinical Research Center for RespiratoryDisease, First Affiliated Hospital of Guangzhou Medical Univer-sity), Dan-hong Su (Department of microbiology, State KeyLaboratory of Respiratory Disease, National Clinical ResearchCenter for Respiratory Disease, First Affiliated Hospital of Guang-zhou Medical University) for their assistance and recommenda-tions. We would also wish to thank Wen-ming Liu (Biorad Inc.(Guangzhou branch)) for his technical support.

This study was funded by the Changjiang Scholars and Inno-vative Research Team in University ITR0961, the National KeyTechnology R&D Program of the 12th National Five-year Devel-opment Plan 2012BAI05B01 and National Key Scientific & Tech-nology Support Program: Collaborative Innovation of ClinicalResearch for Chronic Obstructive Pulmonary Disease and LungCancer No. 2013BAI09B09 (NZ and RC), National Natural ScienceFoundation No. 81400010 and 2014 Scientific Research Projectsfor Medical Doctors and Researchers from Overseas, GuangzhouMedical University No. 2014C21 (WG).

Table 5 Comparison on sputum bacteriology with published literature reports

Literature NationPseudomonas

aeruginosa (No., %)Haemophilus

influenzae (No., %)Commensals

(No., %)

Evans et al.22 United Kingdom 12 (12%) 22 (22%) 9 (9%)Pasteur et al.5 United Kingdom 46 (31%) 52 (35%) 34 (23%)McShane et al.21 United States 49 (46%) NA NAKing et al.19 Australia 7 (7%) 34 (36%) 36 (38%)Shoemark et al.6 United Kingdom 31 (19%) NA NAAnwar et al.16 United Kingdom 57 (30%) NA NALi et al.7 United Kingdom 15 (11%) 53 (39%) NATwiss et al.12 New Zealand NA NA NAGuan et al. (this study) Mainland China 44 (30%) 12 (8.1%) 60 (41%)

NA, not applicable.

Aetiology of bronchiectasis in Guangzhou 747

© 2015 Asian Pacific Society of Respirology Respirology (2015) 20, 739–748

REFERENCES

1 Laennec RTH. A Treatise on The Disease of The Chest. New York,NY: Library of the New York Academy of Medicine, Hafner Pub-lishing, 1962; 78.

2 Tsang KW, Tan KC, Ho PL, Ooi GC, Ho JC, Mak J, Tipoe GL, Ko C,Yan C, Lam WK, Chan-Yeung M. Inhaled fluticasone in bronchi-ectasis: a 12 month study. Thorax 2005; 60: 239–43.

3 Loebinger MR, Wells AU, Hansell DM, Chinyanganya N, DevarajA, Meister M, Wilson R. Mortality in bronchiectasis: a long-termstudy assessing the factors influencing survival. Eur. Respir. J.2009; 34: 843–9.

4 Baker AF. Bronchiectasis. N. Engl. J. Med. 2002; 346: 1383–93.5 Pasteur MC, Helliwell SM, Houghton SJ, Webb SC, Foweraker JE,

Coulden RA, Flower CD, Bilton D, Keogan MT. An investigationinto causative factors in patients with bronchiectasis. Am. J.Respir. Crit. Care Med. 2000; 162: 1277–84.

6 Shoemark A, Ozerovitch L, Wilson R. Aetiology in adult patientswith bronchiectasis. Respir. Med. 2007; 101: 1163–70.

7 Li AM, Sonnappa S, Lex C, Wong E, Zacharasiewicz A, Bush A,Jaffe A. Non-CF bronchiectasis: does knowing the aetiology leadto changes in management? Eur. Respir. J. 2005; 26: 8–14.

8 Vendrell M, Gracia JD, Rodrigo MJ, Cruz MJ, Alvarez A, Garcia M,Miravitlles M. Antibody production deficiency with normal IgGlevels in bronchiectasis of unknown etiology. Chest 2005; 127:197–204.

9 Kessel DA, Velzen-Blad H, Bosch JMM, Rijkers GT. Impairedpneumococcal antibody response in bronchiectasis of unknownaetiology. Eur. Respir. J. 2005; 25: 482–9.

10 Tsang KW, Lam SK, Lam WK, Karlberg J, Wong BC, Hu WH, YewWW, Ip MS. High seroprevalence of Helicobacter pylori in activebronchiectasis. Am. J. Respir. Crit. Care Med. 1998; 158: 1047–51.

11 Davies G, Wells AU, Doffman S, Watanabe S, Wilson R. The effectof Pseudomonas aeruginosa on pulmonary function in patientswith bronchiectasis. Eur. Respir. J. 2006; 28: 974–9.

12 Twiss J, Metcalfe R, Edwards E, Byrnes C. New Zealand nationalincidence of bronchiectasis ‘too high’ for a developed country.Arch. Dis. Child. 2005; 90: 737–40.

13 Weycker D, Edelsberg J, Oster G, Gregory T. Prevalence and eco-nomic burden of bronchiectasis. Clin. Pulm. Med. 2005; 12:205–9.

14 Reiff DB, Wells AU, Carr DH, Cole PJ, Hansell DM. CT findings inbronchiectasis: limited value in distinguishing between idi-opathic and specific types. Am. J. Roentgen. 1995; 165: 261–7.

15 Chalmers JD, Goeminne P, Aliberti S, McDonnell MJ, Lonni S,Davidson J, Poppelwell L, Salih W, Pesci A, Dupont LJ, Fardon TC,De Soyza A, Hill AT. The bronchiectasis severity index: an inter-national derivation and validation study. Am. J. Respir. Crit. CareMed. 2014; 189: 576–85.

16 Pasteur MC, Bilton D, Hill AT, on behalf of the British ThoracicSociety Bronchiectasis (non-CF) Guideline Group. British Tho-racic Society guidelines for non-CF bronchiectasis. Thorax 2010;65: i1–58.

17 Chinese GERD study group. Value of reflux diagnostic question-naire in the diagnosis of gastroesophageal reflux disease. Chin. J.Digest. Dis. 2004; 5: 51–5.

18 Anwar GA, McDonnell MJ, Worthy SA, Bourke SC, Afolabi G,Lordan J, Corris PA, Desoyza A, Middleton P, Ward C, RutherfordRM. Phenotyping adults with non-cystic fibrosis bronchiectasis:a prospective observational cohort study. Respir. Med. 2013; 107:1001–7.

19 King PT, Holdsworth SR, Freezer NJ, Villanueva E, Holmes PW.Characterisation of the onset and presenting clinical features ofadult bronchiectasis. Respir. Med. 2006; 100: 2183–9.

20 Li N, He B, Wang GF, Tang XY. A case report and literature reviewof cystic fibrosis. Chin. J. Tubercul. Respir. Dis. 2003; 26: 559–62.

21 McShane PJ, Naureckas ET, Strek ME. Bronchiectasis in a diverseUS population. Effects of ethnicity on etiology and sputumculture. Chest 2012; 142: 159–67.

22 Evans SA, Turner SM, Bosch BJ, Hardy CC, Woodhead MA. Lungfunction in bronchiectasis: the influence of Pseudomonasaeruginosa. Eur. Respir. J. 1996; 9: 1601–4.

23 Tsang KW, Chan KN, Ho PL, et al. Sputum elastase in steady-state bronchiectasis. Chest 2000; 117: 420–6.

24 Expert Panel for Diagnosis and Treatment of Adult Bronchiecta-sis. Expert consensus on the diagnosis and treatment of adultbronchiectasis. Zhonghua Jie He He Hu Xi Za Zhi 2012; 35: 485–92.

25 Patel IS, Vlahos I, Wilkinson TMA, Lloyd-Owen SJ, DonaldsonGC, Wilks M, Reznek RH, Wedzicha JA. Bronchiectasis, exacerba-tion indices, and inflammation in chronic obstructive pulmo-nary disease. Am. J. Respir. Crit. Care Med. 2004; 170: 400–7.

Supplementary InformationAdditional Supplementary Information can be accessed via theonline version of this article at the publisher’s web-site:

Appendix S1 Methods and Results.

Figure S1 Diagnostic flow chart of the aetiology of bronchiecta-sis.

Figure S2 Age distribution characteristics of bronchiectasis.

Table S1 Simplified questionnaire for gastroesophageal refluxdisease.

Table S2 List of screening outcomes.

Table S3 Humoral immunity assay results.

Table S4 Clinical characteristics of patients with GERD in bron-chiectasis.

Table S5 Clinical characteristics of patients susceptible of havingaspergillosis.

Table S6 Clinical characteristics of miscellaneous knownaetiologies.

Table S7 Socioeconomic status of the bronchiectasis cohort.

W Guan et al.748

© 2015 Asian Pacific Society of RespirologyRespirology (2015) 20, 739–748